Market Study of Innovative Biologics: Independent Market Research Report

Market Study of Innovative Biologics
Independent Market Research Report
Confidential For
Frost & Sullivan

Sept. 2023
© 2023 Frost & Sullivan. All rights reserved. This document contains highly confidential information and is the sole property of Frost & Sullivan.
No part of it may be circulated, quoted, copied or otherwise reproduced without the written approval of Frost & Sullivan.
China Aging Population Trend, 2018-2030E
• With the implementation of the ‘One Child Policy’ and increasing life expectancy, China has entered an aging society.
From 2018 to 2022, the population was aging rapidly in China with people aged above 65 growing at a CAGR of 5.9%.
According to the National Bureau of Statistics of China (NBSC), individuals aged above 65 years old were 209.8 million
in 2022. The number of individuals aged above 65 years old is growing at a fairly fast pace and is expected to continue
its growth momentum into the future. This number of people is expected to reach 243.3 million by 2026, 273.2 million by
2030, representing a CAGR of 3.8% from 2022 to 2026, 2.9% from 2026 to 2030.
• China’s demographic shift offers immense opportunities for healthcare market, as elder people generally have greater
need for medications and scientific disease management.
China Aging Population Trend, 2018-2030E

Period CAGR
2018-2022 5.9%
2022-2026E 3.8%
2026E-2030E 2.9%
Million 265.9 273.2
251 258.6
235.4 243.3
218.7 227.2
200.6 209.8
190.6
166.6 176
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: NBSC, Frost & Sullivan Analysis

2
China Healthcare Expenditure, 2017-2030E
• The total healthcare expenditure of China has experienced steady growth. From 2017 to 2021, the total healthcare
expenditure of China has increased from RMB 5,259.8 billion to RMB 7559.4 billion, representing a CAGR of 9.5%.
Furthermore, the rapid increasing trend in China‘s healthcare expenditures will continue in the near future. The total
healthcare expenditure of China is forecasted to reach to RMB 11047.1 billion, RMB 16260.9 billion by 2025, 2030
respectively, which represents a CAGR of 9.9% from 2021 to 2025, a CAGR of 8.0% from 2025 to 2030.
China Healthcare Expenditure, 2017-2030E
Period CAGR
2017-2021 9.5%
2021-2025E 9.9%
2025E-2030E 8.0%
16,260.9
15,154.6
Billion RMB 14,084.2
13,028.8
12,008.2
11,047.1
10,107.1
9,213.4
8,368.2
7,230.6 7,559.4
6,584.1
5,912.2
5,259.8
2017 2018 2019 2020 2021 2022E 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: NHC, Frost & Sullivan Analysis

3
Processes in New Drug Research and Development
4. Manufacturing
Early Stage Manufacturing Commercialization Manufacturing 6. Terminal
1. Discovery
Consumption
2. Pre-clinical 3. Clinical and Registration 5. Commercialization
1. Discovery 2. Pre-clinical 3. Clinical and Registration
Phase I Phase II
• The process of Safety Assessment: Pharmacokinetic
identifying the direct • A comprehensive and Pharmacology
Target molecular target of a and systematic Research: • Clinical
Identification small molecule. investigation and • The study of the Pharmacology • Exploratory
analysis of all disposition of a Clinical Trials
Research
• The process by which aspects of risks to drug after its
the predicted health and safety delivery to an
molecular target of a associated with organism, mainly
major incidents refer to the • Post-Marketing • Confirmatory
Target small molecule is
that may ADME(absorption, Study Clinical Trials
Validation verified.
potentially occur distribution,
in the course of metabolism, and
• The process by which operation of the excretion)
the targeted small major hazard Phase IV Phase III
research.
molecule is evaluated facility.
Lead and undergo limited
Generation optimization to identify
promising 4. Manufacturing
compounds.
• The process by which Early Stage Manufacturing
a drug candidate is (From Pre-clinical to Clinical)
Lead Pharmacodynamics Research:
designed after an • The quantitative study of the relationship between drug
Optimization initial lead compound exposure (concentrations or dose) and pharmacologic or
is identified. Commercialization
toxicologic responses.
Manufacturing
Source: Frost & Sullivan Analysis

4
Processes in New Drug Research and Development
4. Manufacturing
Early Stage Manufacturing Commercialization Manufacturing 6. Terminal
1. Discovery
Consumption
2. Pre-clinical 3. Clinical and Registration 5. Commercialization
5. Commercialization 6. Terminal Consumption

Commercial plan establishment
• To orchestrate the cross-functional
Factors involved in a new drug activities required to execute the Hospital terminal
commercialization process: launch
New drug launch plan
implementation • The primary drug sales channel.
Information Its selling drugs contain in-patient
Technology
• Execute market access strategies; drugs, out-patient RX drugs,
& Analytics Corporate • Establish pricing and reimbursement injection and non-injection, and
Medical
Affairs Affairs programs; out-patient OTC drugs.
• Conduct prescription fulfillment.
Manufacturin Legal &
g & Supply Regulatory Confirmation of launch project’s
Chain Affairs
scope: Retail terminal
Sales Force
Advocacy & • Set up goals, objectives, and life cycle
KOLs characteristics of the new drug;
Readiness New drug Engagement • The second largest drug sales
• Control and monitor the launch scope channel. Its selling drugs contain
and schedule RX drugs and OTC drugs.
Sales Ops Marketing
Risk management:
• Changes and developments in the
Vendor Managed regulatory approval process; Network terminal
Relations Markets
Pharma- Pricing, • Increased competition from branded
coeconomics Contracting, and generic drugs;
& Value &Reimburse • A promising drug sales channel. Its
• The level of acceptance from
Messaging ment selling drugs contain RX drugs and
patients, KOLs, and payers to the
OTC drugs.
new drug.

5
China R&D Expenditure, 2017-2030E
• China has great potential in the pharmaceutical R&D environment due to government policy incentives and business
strategy transformation of pharmaceutical companies, with China spending RMB205.7 billion on drug research and
development in 2021, with the CAGR of 20.8% from 2017 to 2021. This is expected to grow to RMB342.3 billion by
2025 and RMB530.3 billion by 2030, with CAGRs of 13.6% and 9.2%, respectively.
China R&D Expenditure, 2017-2030E
Period CAGR
2017-2021 20.8%
2021-2025E 13.6%
2025E-2030E 9.2% 530.3
492.9
455.5
417.9
Billion RMB
379.9
342.3
305.6
269.7
236.6
205.7
170.3
145.8
115.4
96.6
2017 2018 2019 2020 2021 2022E 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

6
Global Pharmaceutical Market, 2018-2030E
• Global pharmaceutical market is composed of two segments, namely chemical drugs and biologics. The size of global
pharmaceutical market was USD1,495.0 billion in 2022, and is expected to reach to USD1,829.4 billion and USD2,090.8
billion in 2026 and 2030 respectively, representing a CAGR of 5.2% from 2022 to 2026, 3.4% from 2026 to 2030.
• The chemical drugs took USD1,131.2 billion market size in 2022, and is expected to reach to USD1,248.4 billion and
USD1,307.6 billion respectively in 2026, 2030.
Global Pharmaceutical Market, 2018-2030E

CAGR
Period
Chemical Drugs Biologics Total
2018-2022 3.0% 8.6% 4.2%
2022-2026E 2.5% 12.4% 5.2%
2026E-2030E 1.2% 7.8% 3.4%
2,032.3 2,090.8
1,969.3
1,901.6
Billion USD 1,829.4
1,752.4
1,670.9
1,585.0 738.6 783.2
1,495.0 637.5 690.1
1,401.2 521.6 580.9
1,266.7 1,324.5 1,298.8 461.6
405.8
363.8
286.4 338.4
261.1 297.9
1,209.3 1,230.9 1,248.4 1,264.1 1,279.2 1,293.7 1,307.6

1,131.2 1,179.2
1,005.6 1,038.0 1,000.9 1,062.8
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Chemical Drugs Biologics
Source: Annual Reports of Listed Medical Companies, NMPA, CDE, NRDL, MOHRSS, FDA, Frost & Sullivan Analysis
7
China Pharmaceutical Market, 2018-2030E
• China pharmaceutical market, accompanying with the growth of economy and healthcare demand, increased from RMB
1,533.4 billion in 2018 to RMB1,554.1 billion in 2022 with CAGR of 0.3%. China pharmaceutical market will further
increase to RMB2,095.8 billion in 2026 and RMB2,624.5 billion in 2030, with CAGR of 7.8%, 5.8% respectively.
China Pharmaceutical Market, 2018-2030E

CAGR
Period
Chemical TCM Biologics Total
2018-2022 -2.5% -3.3% 12.6% 0.3%
2022-2026E 3.4% 5.1% 16.3% 7.8%
2026E-2030E 2.6% 2.9% 10.5% 5.8%
2,624.5
Billion RMB 2,491.3
2,358.5
2,226.6
2,095.8
1,962.7 1,149.1
1,828.0 1,056.8
1,692.4 963.2
1,633.0 1,591.2 867.1
1,533.4 1,554.1 769.8
1,448.0 675.2
312.0 587.1
262.2 410.0 503.4
345.7 421.0
547.1 563.2 577.9
483.7 502.0 497.3 514.7 530.9
430.2 449.3 474.7
393.8 422.3
787.5 819.0 751.0 766.1 790.2 811.4 828.7 848.3 871.3 897.6
708.5 710.7 739.8
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Chemical Drugs Traditional Chinese Medicine Biologics
Source: Annual Reports of Listed Medical Companies, NMPA, CDE, NRDL, MOHRSS, Frost & Sullivan Analysis
8
Segmentation of Biologics Market
• Globally, the pharmaceutical market can be divided into two categories: biological drugs and chemical drugs.
Biopharmaceuticals can be further divided into multiple categories. Based on the existing biological agents currently on
the market, the biological market can usually be segmented as follows. The following segmentation dimensions vary by
region.
Segmentation of Biologics Market
Biologics
Other Recombinant
Antibodies Vaccines Cell Therapy
Proteins
Antibodies therapy is a form The vast majority of

Cell therapy is one of the
of immunotherapy that uses recombinant protein drugs A vaccine is a biologics that
most advanced areas of
antibodies to bind specifically are human proteins or their provides active acquired
biologics. Cell therapy is a
to their target to treat patients mutants. The main immunity to a particular
therapy in which viable cells
for therapeutic purposes. The mechanism of action is to infectious disease. A vaccine
are injected, grafted or
most common form of make up for the defects of typically contains an agent
implanted into a patient in
antibodies drugs are certain functional proteins in that resembles disease-
order to effectuate a
monoclonal antibodies, which the body or increase the causing microorganism and
medicinal effect. For example,
are single specificity function of protein in the body. is often made from weakened
CAR T cell therapy is a type
antibodies that are produced Typical examples of or killed forms of the microbe,
of cancer therapy that uses a
artificially through genetic recombinant protein drugs its toxins, or one of its
patient's own modified white
engineering and related include peptide hormone surface proteins.
blood cells to kill cancer cells.
techniques. drugs and cytokine drugs.
Source: Literature Review, Frost & Sullivan Analysis

9
Analysis of China Pharmaceutical Industry
Systematic Reform on Pharmaceutical Industry
R&D ➢ Issued by the State Council on 11 March 2021, the 14th Five-year Health Plan（“十四五”
卫生健康规划）proposed the future development for China healthcare system, which
Preclinical & involved every aspect of the pharmaceutical industry from the drug R&D to the end-users
Clinical Trials & NDA including healthcare institutions and patients, such as encouragement of drug innovation,
IND
development of medical insurance and supervision of pharmaceutical distribution.
Reform of Review and Approval of Pharmaceutical ➢ Furthermore, the government will create a more rational allocation of scientific and
Application technological resources on the biomedical areas by upgrading national engineering
research centers and national technology innovation centers among other innovation
bases, and meanwhile promote the optimal allocation of research resources and sharing
Manufacturing of resources among research institutes, higher-education institutions, and enterprises, and
support the development of new forms of innovators such as research universities and
R&D institutions.
Manufacturing CMO
Marketing Authorization Holder (MAH)
Commercial
Distribution & Retailing Medical
Healthcare Insurance Acceleration
Distributor Development of Drug
Institution/Pharmacy
Innovation
Two-invoice System
Deepening the
Payers Healthcare
System Reform
Medical Insurance (NRDL)
Dynamic Adjustment of NRDL via Price Negotiation
Source: Government Website, Frost & Sullivan Analysis

10
Reform of the Drug and Medical Device Review and Approval
Reform of the Drug and Medical Device Review and Approval
《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》
Before Now
R&D • Requiring lengthy • Implied CTA approval (60 days)
Reforming approval for clinical • Accepting clinical trial data
Preclinical & Clinical Trials clinical trial trial applications generated abroad
management (12-18 months)
IND & NDA
• Lengthy review and • Priority review and enable

Accelerating approval process conditional approval
Manufacturing Review and • APIs and formulations • Linked approval of formulation and
Approval are approved API, excipients and packaging
separately • Leveraging eCTD for NDA review
Manufacturing CMO
• A drug must be in a Phase II • Accepting foreign clinical data

Realizing or Phase III clinical study or • Removing restrictions on clinical
Global has received marketing trials and registrations for imported
Distribution & Retailing Application authorization abroad before drugs
it begin international multi-
Healthcare Institution/ center trial (“IMCT”) in China
Distributor
Pharmacy
• Patent declaration • Patent linkage system
Protection of system • Drug patent term compensation
Innovators system
• Innovator's data protection
Payers • MAH program
In Oct 2017, the General Office of the CPC Central Committee and the General Office of the State Council
Medical Insurance (NRDL) issued the Opinions on Deepening the Reform of the Evaluation and Approval Systems and Encouraging
Innovation on Drugs and Medical Devices (《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》).
With the reform being realized, it leads to availability increase of clinical trial sites，shortening of the IND
Note: eCTD = electronic common technical document and NDA approval time, patent term extension and affordability of innovative drugs.

11
Marketing Authorization Holder (MAH)
R&D Evolution of MAH System in China
Preclinical & Clinical Trials

Pharmaceutical MAH Production
IND & NDA Authorization
Companies Application
Application
Marketing New Drug
Authorization Application
Manufacturing
Marketing Production
Production License
Manufacturing CMO Authorization Authorization
Commercialization Commercialization Manufacture
Distribution & Retailing
Healthcare Institution/
Distributor
Pharmacy ➢ MAH system enables the R&D organizations or personnel to apply for and
obtain drug marketing authorizations and drug approval license, and the
MAHs can entrust the CMOs to manufacture drugs instead of obtaining
production license themselves, so that they can focus on R&D rather than
Payers allocate the manpower and investment on manufacturing.
➢ MAH system helps to promote R&D innovation, accelerate industrial
restructuring and optimize resource allocation.
Medical Insurance (NRDL)

12
Two-Invoice System
Two-Invoice System
《关于在公立医疗机构药品采购中推行“两票制”的实施意见（试行）的通知》
R&D Before
Low ex-factory High tender
Preclinical & Clinical Trials & pricing (低开) Invoice pricing(高开)
IND NDA Transforming
Company
Logistic
Manufacturing Wholesaler
Manufacturer distributors in Hospitals
(代理商)
different levels
Manufacturing CMO Some wholesalers act as

distributors
Invoice Flow
Cargo Flow
After
Cash Flow
Distribution & Retailing
1st Invoice 2nd Invoice
Healthcare Institution/ Logistic
Distributor Manufacturer Hospitals
Pharmacy distributors
Contract with Commission CSO

Payers Companies
➢ The two-invoice system, aiming to improve transparency in drug prices and eliminate
Medical Insurance (NRDL) excessive profit margins associated with multi-tier distribution models, has important
implications for pharma companies, distribution companies as well as CSOs.

13
Favorable Government Policy of Pharmaceutical Industry
Review of Clinical Trial and New Drug Application
Release Issuing
Policies Comments
Date Authority
• Accelerating the review and approval of innovative drug trials.
Opinions of the State Council on Reform • Implementing specific review, evaluation and approval system to
of the System of Evaluation, Review and accelerating the review and approval process for innovative drugs
Aug, 2015 State Council Approval of Drugs and Medical Devices that are in use of prevention and treatment of AIDS, malignant
《国务院关于改革药品医疗器械审评审批 tumors, major infectious diseases, rare diseases, as well as drugs
制度的意见》 listed in national science and technology projects and national key
R&D programs.
• Deepening review and approval system reforms. Establishing a more

Guiding Opinions of the General Office of
scientific and efficient review and approval system for drug and
the State Council on Promoting the Sound
medical devices.
Mar, 2016 State Council Development of the Medical Industry
• Strengthening the construction of review teams, and recruiting
《国务院办公厅关于促进医药产业健康发
experts and scholars with international review and approval
展的指导意见》
experience.
• Strengthening drug safety supervision.
• Deepening the reform of the review and approval system for
Healthy China 2030
Oct, 2016 State Council pharmaceuticals (medical devices), establishing review and approval
《“健康中国2030”规划纲要》
system based on clinical curative effects.
• Improving the approval standards for drug (medical devices).
General
Drug registration with obvious clinical value meets one of the following
Office of the
Opinions of Encouraging Drug Innovation requirements:
CPC Central
to Implement Priority Review and • Application for registration of innovative drugs not listed and sold in
Committee
Dec, 2017 Approval China or abroad.
and the
《总局关于鼓励药品创新实行优先审评审 • Application for registration of innovative drugs transferred to China.
General
批的意见》 • Drug registration applications with advanced preparation technology,
Office of the
innovative treatment methods and obvious therapeutic advantages.
State Council

14
Release Issuing
Policies Comments
Date Authority
In order to improve the efficiency of review and approval of innovative
Notice for Optimizing the Examination, drugs as well as simplify the procedure:
Assessment and Approval of Drug • The review and approval for rare diseases that seriously endanger
May, 2018 CFDA Registration life with no effective treatment could be sped up through
《关于优化药品注册审评审批有关事宜的 communication system between CDE and applicants.
公告》 • The clinical data obtained overseas with no ethnic difference could
directly apply for drug launch registration.
Technical Guidelines for Accepting Data • In order to encourage the synchronous drug R&D both domestic and
Jul, 2018 CFDA from Overseas Clinical Trials of Drugs abroad, the acceptable overseas clinical trials data are clarified.
《接受药品境外临床试验数据的技术指导 • The overseas R&D of generic drug with complete and assessable
原则》 bioequivalence data can also be used for registration applications.
Announcement on Adjusting the
• Drug clinical trial filing system: The drug clinical trial can be carried
Examination and Approval Procedure of
out according to the submitted scheme if the applicant fails to receive
Jul, 2018 CFDA Drug Clinical Trials
the negative or doubtful opinions from CDE within 60 days from the
《关于调整药物临床试验审评审批程序的
accepted and payment date of the application.
公告》
Establish a special channel for review and approval of overseas
innovative drugs that are urgently needed, which has launched in the
United States, the EU or Japan in the past 10 years but not in China,
meeting one of the following circumstances:
Announcement on the urgent clinical • Drugs for the treatment of rare diseases
need for approval of new drugs abroad • Drugs for serious life-threatening diseases without effective
Oct, 2018 CFDA
《关于临床急需境外新药审评审批相关事 treatment
宜的公告（2018年第79号）》 • Drugs have obvious clinical advantages for serious life-threatening
diseases.
The innovative drugs from abroad can be declared for manufacturing
directly without domestic clinical data after demonstration of no ethnic
difference.

15
Release Issuing
Policies Comments
Date Authority
Notice for the Publication of the Health
• Establish a comprehensive clinical evaluation system for
NHC, China_ Implementation Plan for Cancer
anticancer drugs.
Sep, 2019 NHSA, Prevention (2019-2022 edition)
• Speed up the approval of new anticancer drugs at home and
NMPA 《关于印发健康中国行动——癌症防治实
abroad.
施方案（2019—2022年）的通知》
Notice on Soliciting Opinions on the • For innovative drugs or improved new drugs that are used to
Working Procedures of Breakthrough prevent or treat severely life-threatening diseases, and that have
Therapeutics and the Priority Review and no effective prevention measures or have sufficient evidence to
Nov, 2019 NMPA
Approval Process show obvious clinical advantages compared with existing therapies,
《关于突破性治疗药物工作程序和优先审 they can apply for Breakthrough Treatment Drugs.
评审批工作程序征求意见的通知》 • Breakthrough Treatment Drugs can be reviewed and approved first.
Announcement on the Release of • Meet the public clinical needs and support clinical experimental on
Administrative Regulations on Extended medical instruments as soon as possible.
NMPA,
Mar, 2020 Clinical Trials of Medical Devices (Trial) • Standardize the development of extended clinical trials and the
NHC
《关于发布医疗器械拓展性临床试验管理 collection of safety data for medical devices.
规定（试行）的公告》 • Safeguard the rights and interests of subjects.
Announcement on the Release of Quality

• Deepen the reform of drug evaluation and approval system and
Management Practices for Drug Clinical
NMPA, encourage innovation.
Apr, 2020 Trials
NHC • Further promote standardized research and improve the quality of
《关于发布药物临床试验质量管理规范的
drug clinical trials in China.
公告》
Guidelines for Statistical Design of • The statistical methods for the commonly used efficacy endpoints
Antitumor Drug Clinical Trials (Trial) are proposed in the guidelines, and the statistical design
Dec, 2020 NMPA
《抗肿瘤药物临床试验统计学设计指导原 requirements are putted forward from the perspectives of
则（试行）》 exploratory and confirmatory trials.

16
Review of Innovation Encouragement
Release Issuing
Policies Comments
Date Authority
• Accelerating the development of innovative drugs and biological
Guiding Opinions of Promoting the
products with major clinical needs;
Healthy Development of the
State • Speeding up the promotion of green and intelligent pharmaceutical
Mar, 2016 Pharmaceutical Industry
Council production technologies;
《国务院办公厅关于促进医药产业健康发
• Strengthening scientific and efficient supervision;
展的指导意见》
• Promoting the development of industrial internationalization.
• Drug research and development institutions or scientific research

Plan of the System of the Holders of Drug
personnel in the pilot administrative areas may serve as drug
Mar, 2016 CFDA Marketing Licenses
applicants for registration, and submit applications for drugs
《药品上市许可持有人制度试点方案》
clinical trials and marketing.
• Strengthening technical innovation by forming a Government-
Industry-University-Research Cooperation efficient system;
State Healthy China 2030
Oct, 2016 • Improving the quality control system of drug and medical devices. By
Council 《“健康中国2030”规划纲要》
2030, quality standards for drugs and medical devices would be fully
integrated with international standards.
• Accelerating the innovation and industrialization of new drugs.
13th Five-Year Plan for National Strategic
• Promoting the development of high-tech biosimilar drugs such as
State Emerging industry Development
Dec, 2016 monoclonal antibodies, long-acting recombinant proteins, and
Council 《“十三五”国家战略性新兴产业发展规
third-generation insulin, and increasing the accessibility of drugs
划》
to patients.
Policies of Encouraging Drug Medical
Equipment Innovation to Implement Drug
• Accelerating the informationization of review and approval system.
Medical Equipment Life Cycle
• Formulating the technical requirements for the electronic submission
May, 2017 CFDA Management
of drug and medical device registration.
《关于鼓励药品医疗器械创新实施药品医
• Improving the general electronic documentation system.
疗器械全生命周期管理的相关政策（征求
意见稿）》

17
Release Issuing
Policies Comments
Date Authority
• Seek to streamline the clinical trial process and shorten the time line.
• Provid for special fast-track approval for two kinds of drugs and
Reform of Review and Approval System medical devices:
for Drugs and Medical Devices to (i) new drugs and devices in urgent clinical need;
Oct, 2017 CFDA Encourage Innovation (the Opinion) (ii) drugs and devices for rare diseases.
《关于深化审评审批制度改革鼓励药品医 • Encouraging innovation and protect innovators through
疗器械创新的意见》 (i) the adoption of a patent linkage system,
(ii) restoration of patent term,
(iii) protection of innovator's data.
• Establish a comprehensive evaluation system with technical review
Opinions of Implementing Priority Review
as the core, in combination with risk-based on-site inspection and
and Approval to Encourage Drug
sample testing.
Dec, 2017 CFDA Innovation
• Accept foreign data to support MAA if meet China requirements;
《总局关于鼓励药品创新实行优先审评审
• Accept application of new dosage form based on clinical needs;
批的意见》
• Implement conditional approvals
Reform of Review and Approval System
• Promote the integration of drug registration technical standards with
for Drugs and Medical Devices to
international standards.
Jan, 2018 CFDA Encourage Innovation (the Opinion)
• Accelerate the drug examination and approval process.
《关于深化审评审批制度改革鼓励药品医
• Strengthening the management for drug life cycle.
疗器械创新的意见》
• Encourage innovation and protect innovators through
(i) Improve the support of scientific and technological innovation in
Opinions of Strengthening and Promoting the field of food and drug.
Scientific and Technological Innovation in (ii) Establish and improve the supporting network for scientific
Jan, 2018 CFDA Food and Drugs research.
《关于加强和促进食品药品科技创新工作 (iii) Enhance companies’ technological innovation capability.
的指导意见》 (iv) Strengthen the construction of major technological innovation
platforms.
(v) Establish incentive and reward mechanism for talents.

18
Release Issuing
Policies Comments
Date Authority
Guidance for Pharmaceutical Research in • Encourage R&D of new and innovative drugs.
Phase III Clinical Trials of Innovative • Accelerate establishment of the standard system of technical
Mar, 2018 CFDA Drugs (Chemicals) guidelines for R&D and examination and approval process of
《创新药(化学药) III期临床试验药学研究 innovative pharmaceuticals.
信息指南》 • Improve the quality and efficiency new R&D review.
• To encourage the development of the rare disease pharmaceutical
Notice on VAT policy for rare disease industry and reduce the cost of medication for patients. VAT
Feb, 2019 MoF drugs general taxpayers who produce, wholesale and retail rare disease
《关于罕见病药品增值税政策的通知》 drugs can pay VAT at a 3% levy rate according to the simple
method, starting from March 1, 2019.
Announcement on Further Improving the • Encourage innovative drugs by optimizing the approval process.
Correlated Matters of Drug Related • Further clarifies the review, approval and supervision of the
Jul, 2019 NMPA Evaluation, Approval and Supervision association between active pharmaceutical ingredients, excipients,
《关于进一步完善药品关联审评审批和监 and immediate packaging materials and containers as well as
管工作有关事宜的公告》 pharmaceutical products.
• It is the second major systematic and structural amendment to the
Pharmaceutical Administration Law since its first promulgation in
1984.
• Focus on supporting clinical value-oriented drug innovations which
have significant effects on human disease. Encourage the
Pharmaceutical Administration Law of the
development of new medicines with new treatment mechanism on
Aug, 2019 NMPA People’s Republic of China
severely life-threatening diseases, rare diseases and children’s
《中华人民共和国药品管理法》
diseases.
• Establish related laws of clinical trial acquiescence system, clinical
trial institution filing management system, priority review and
approval system, conditional approval system, etc.
• Established a listing authorization system to encourage innovation.

19
Release Issuing
Policies Comments
Date Authority
• To cooperate with the implementation of Drug Registration
Announcement on the Release of Three Administration Measures, hese work procedures are developed:
Documents such as the Work Procedure (i) Review and Evaluation Procedures for Breakthrough Therapy
for the Evaluation of Breakthrough Drugs (Trial)
Jul, 2020 NMPA
Therapy Drugs (trial) (ii) Review and Approval Procedures for conditionally approved
《关于发布《突破性治疗药物审评工作程 marketing application of drugs (Trial)
序（试行）》等三个文件的公告》 (iii) Procedure for Priority Evaluation and Approval of Drug Marketing
Authorization (Trial)
• In order to encourage the development of pharmaceutical industry,

Announcement on the Release of the
and reduce the cost of drugs for patients, the second list includes
Second Batch on Anticancer Drugs and
39 pharmaceutical products, 6 active pharmaceutical ingredients
Orphan Drugs Applicable to the VAT
Sep, 2020 MoF of anticancer drugs and 14 pharmaceutical products of orphan
Policy
drugs. VAT general taxpayers who produce, wholesale and retail
《关于发布第二批适用增值税政策的抗癌
those drugs can pay VAT at a 3% levy rate according to the simple
药品和罕见病药品清单的公告》
method, starting from Octor 1, 2020.
Announcement on the "Internet +
• Support the pharmaceutical industry by making the payment
healthcare" "five one" service action
Dec. 2020 NHSA process quicker and easier, simplifying the healthcare services and
《关于深入推进“互联网+医疗健
applying digitalization methods.
康”“五个一”服务行动的通知》
• Support high-quality industrial development of the regulatory
environment and system reform.
The “14th Five-Year Plan” National Drug
• Approving many innovative drugs in urgent clinical need.
Safety and High-quality Development
Sep. 2021 NHSA, • Accelerate the listing of innovative drugs with clinical value and
Plan Promotion
NMPA innovative medical devices as soon as possible in the domestic
《“十四五”国家药品安全及促进高质量
market.
发展规划印发》
• Formulate and revise 2650 standards and 480 new guidelines on
drugs, medical devices, and cosmetics.

20
Release Issuing
Policies Comments
Date Authority
Guidance from the National Health

Insurance Administration and the State
Administration of Traditional Chinese
• Medical insurance to support the development of Chinese medicine
Medicine on Medical Insurance Support
heritage and innovation
for the Development of Traditional
Dec. 2021 NHSA • Policy to include eligible TCM institutions into the medical insurance
Chinese Medicine Inheritance and
designated points and to include "Internet+" TCM services into the
Innovation
scope of medical insurance payment
《国家医疗保障局和国家中医药管理局关
于医保支持中医药传承创新发展的指导意
见》
• According to the policy, the 2022 medical insurance catalog

adjustment will mainly include COVID-19 drugs, children's drugs
Support rare disease drugs for children, and drugs for rare diseases.
medical insurance negotiations are • Negotiated drugs that expire at the end of this year, or drugs with
imminent, and competition rules will be significant changes in indications or functionalities will have the
Jun. 2022 MoF
improved opportunity to be re-included in the negotiation list.
《支持儿童用药罕见病用药医保谈判在即 • It is expected that this year's medical insurance catalog will have a
竞争规则再完善》 certain focus on pediatric drugs and rare disease drugs, and the
medical insurance catalog will further expand the scope of disease
coverage.

21
Historical Coverage of Basic Medical Insurance Scheme
• The Chinese government has dedicated strong effort to increasing the accessibility and affordability of healthcare
services through the healthcare reform. Huge investment has been made to construct and upgrade healthcare
infrastructure, and expand medical insurance coverage. A medical insurance system encompassing URBMIS and
UEBMIS has been established to cover nearly all the population of 96.4% in 2020.
Unit: Million People 2015 2016 2017 2018 2019 2020
URBMIS 376.9 448.6 873.6 897.4 1025.1 1016.8
UEBMIS 288.9 295.3 303.2 316.8 329.3 344.6
NRCMIS* 670.0 275.0 133.0 130.0 \ \
Total Population
Covered by 3 1,335.8 1,018.9 1,309.8 1,344.6 1,354.4 1,361.3
Schemes
Population in China 1,374.6 1,382.7 1,390.0 1,395.4 1,400.1 1,411.8
Coverage Rate 92.3% 73.7% 94.2% 96.4% 96.7% 96.4%
*2015 data excludes data in Tianjin, Zhejiang, Shandong, Guangdong, Chongqing, Qinghai and Ningxia etc.
2016 data only includes eleven provinces in Mainland China.
2017 data only includes five provinces in Mainland China (Liaoning, Jilin, Anhui, Guizhou and Shaanxi).
2018 data only includes seven provinces in Mainland China (Liaoning, Jilin, Anhui, Hainan, Guizhou and Shaanxi, Tibet)
In 2019, NRCMIS has been fully consolidated with URBMIS
Note: URBMIS = Urban and Rural Residents Basic Medical Insurance Scheme; UEBMIS = Urban Employee Basic Medical Insurance Scheme; NRCMIS = New
Rural Cooperative Medical Insurance Scheme
Source: MORHSS, Frost & Sullivan Analysis
22
Analysis of Healthcare Reimbursement System in China
Recent Progress and Impact of the 2019 NRDL
Progression of NRDL Recent Progression of 6th NRDL Keep Implication
1st
2000 NRDL • On Spt 18th, NHSA released the “2020
Work plan for the adjustment of the • This round of adjustment is the first
National Reimbursement Drug List attempt to negotiate the price
Spt. 2020 (NRDL)”. The adjustment of medicine reduction of the medicines already
2nd items can be divided into regular in the NRDL.
2004
NRDL access and negotiation access • The evaluation experts selected 14
processes. If the price of a new drug is kinds of exclusive medicines with
comparable to or lower than that of the high price or cost for price reduction
3rd existing drugs in the 2019 NRDL, it negotiation. The annual sales of
2009 may be included in the 2020 NRDL by
NRDL each of these medicines exceeded
conventional means. Patented 1 billion RMB.
medicines with higher prices or greater
impact on the Health Insurance Fund • After the negotiation, 14 kinds of
4th will be included through negotiation. drugs were successfully negotiated
2017
NRDL and kept in the NRDL, with an
average price reduction of 43.46%.
• On Dec 28th, 2020, NHSA and • This round of adjustment arouses
Dec. 2020
5th MOHRSS issued the 2020 NRDL. 119 great importance of the medicines
2019 drugs added into the list and 29
NRDL related to COVID-19 treatment. The
medicines moved out from the drugs listed in the latest version of
existing list, the final list of 2020 the national COVID-19 treatment
NRDL covers 2800 kinds of medicines. plan have all been included in the
6th The new NRDL will be effective from
2020 NRDL 2020 NRDL.
Mar 1st, 2021.
Source: Official Website, Frost & Sullivan Analysis

23
Number of Novel Drugs Approved by NMPA and Included in
National Reimbursement Drug List
• To speed up novel drug development and meet clinical needs, NMPA accelerates the process of clinical trial and product
approvals. Approval numbers have been rising fast since 2016.
• The National Reimbursement Drug List (NRDL) is the major mechanism for public reimbursement in China, covering 98 percent
of the entire population. It has been adjusted once a year in principle under a dynamic mechanism since 2017. Most of the
additions are new drugs of high clinical value that can be used to treat multiple diseases including cancer, diabetes and
tuberculosis.
• According to the analysis of NRDL data, the average time between new drugs from approval to being included in the NRDL from
2016-2021 (2017 not included) is 24.7, 20.3, 20.6, 12.9 and 6.7 months, respectively, with the length of time gradually shortening.
• Class A (甲类) drugs are fully reimbursed by basic medical insurance funds. Class B (乙类) drugs are not fully reimbursed, with a
component of out-of-pocket percentage about 70% to 80%, to be borne by the patient.
Annual Novel Drug Approvals by NMPA, 2016- 2021

36
Not in National Reimbursement Drug List(NRDL)

Included in NRDL more than one year of approval
Included in NRDL within one year of approval 25
1 15
11
9
3 9
1 4 11
9 8
1 1 5
3
2016 2017 2018 2019 2020 2021
Note: Novel drugs Approvals ONLY includes Class 1 NMDA drugs: Novel drugs that have not been marketed in China or overseas.
Source: FDA, Frost & Sullivan Analysis

24
NRDL Inclusion Impact on Oncology Drugs
• Representative Oncology Drugs in China

2000 NRDL The first version of NRDL.
In general, the revenue of a drug would be impacted after it’s listed in the NRDL.
The boosted sales of the drug could be the main reason for this influence. This
2004 NRDL situation is especially obvious for oncology drugs, due to their original high prices
and patients' reliance. This change is usually intensive during the first year of NRDL
2009 NRDL
inclusion, as shown in the following Cetuximab graph. The increase in revenue
Health Insurance would slow done after in the following years after a drug is listed in NRDL， as
Reform shown in the Rituximab graph.
The number of medicines
increased during the
period is considerable. Cetuximab Revenue in China
2015 NRDL
• 1st Negotiation The renewal period is Billion RMB
long and irregular.
96.3% 1.0
12.5%
2017 NRDL 0.4 0.5
2019 NRDL
Dynamic
2018 NRDL Adjustment
Increasing the total
2020 NRDL 2017 2018 2019
number of included drugs,
with emphasis on drugs NRDL inclusion: Oct 2018
with high clinical value.
The indications include Rituximab Revenue in China
2021 NRDL tumors, rare diseases,
hepatitis, diabetes and Billion RMB
• Totally included other chronic diseases.
366 kinds of The guarantee capability 32.9%
drugs 20.0% 3.4
in key areas was further
• Average improved, and the 2.1 2.5
decrease guarantee capability of
percentage
basic medical insurance
around 50%
reached a new height.
2017 2018 2019
NRDL inclusion: Jul 2017
Source: Annual Reports, Frost & Sullivan Analysis
25
Growth Drivers of Biologics Market
Feature of Better • Product research and development is the key to industry growth due to the knowledge-intensive nature of
the industry. Discovering and developing new medicines is a long, difficult and expensive process.
Clinical Outcomes and
• Global research and development investment for biologics is expected to increase in the future, hopefully
More Controllable bringing more products into the market. The continuous launch of new products and emerging of biologics
Safety companies will further drive the growth of global biologics industry.
• The application of biotechnology in pharmaceutical science has brought a series of breakthroughs in the
More Innovative Targets development of new drugs and therapeutics. Not only can biotechnology produce biological substances
and Therapies to compensating human defects, but also can it leverage human’s own immune system to fulfill therapeutic
Address Unmet Clinical needs. For example, the emerging CAR T cell therapy is developed to uses a patient's own modified
Needs immune cells to kill cancer cells, bringing potential cure to patients. The biologics market was driven
forward due to these emerging technologies.
• The majority of “advanced” biologics (recombinant proteins, mAbs, etc.), and new generation cell therapy
technologies, have shown high efficacy in treating certain diseases that were lack of efficient therapies in
the past, such as cancers and autoimmune diseases, with faster onset and fewer side effects. Such
superior efficacy of biologics results in growing acceptance of the therapies among patients and doctors,
Favorable Policies which stimulates demand and drive the market growth.
Support • The US Food and Drug Administration (FDA) has revised its regulations to eliminate outdated biologics
requirements, thus allowing drug manufacturers to employ new manufacturing technologies and testing
capabilities. The amendments in regulations are expected to increase regulatory flexibility by allowing the
pharmaceutical industry and the FDA to incorporate current scientific technologies in the manufacture of
licensed biological products.
• With a strong need to develop innovative new biologics but a corresponding high cost of R&D, local
biotechnology companies choose to shift from in-house dominated R&D model to a more diversified R&D
pattern combining in-house R&D, patent licensing and external R&D services. Such a diverse mode
Growth of the Overall enables local biotechnology firms to efficiently leverage technology resources from their global and local
Biologics Market partners, thereby generating a synergic effect and fueling the speed of biologics development. Moreover,
the rising geriatric population is much more susceptible to chronic diseases. According to the World Health
Organization statistics 2018, globally, chronic diseases kill more than 41 million people each year. This rise
in chronic diseases contributes to the biologics demand as well.

26
Future Trends of Biologics Market
• As developed economies continue to constrain or cut healthcare funding, governments in many

emerging markets are making healthcare a priority. They are investing in infrastructure, funding
Increasing Importance
services, and expanding health insurance to a broader population. As a result, emerging markets
of Emerging Markets
will be an important contributor to advanced pharma product sales growth over the next few
years, reorganizing geographic priorities for the industry.
• Biologics are among the most sophisticated and elegant achievements of modern science. The
huge, complex structures of these drugs offer high efficacy and few side effects. The efficacy and
safety of biopharmaceutical products, combined with their ability to address previously
untreatable conditions, allows pharmaceuticals to command high prices for biologics. With strong
Growth Driven by demands, biologics have set new standards for blockbuster drugs. Blockbusters are traditionally
Biologic Blockbusters defined as drugs that have $1 billion or more in annual sales; the top 5 biologics each enjoy
annual revenue of more than $7 billion, with some, such as the Humira, generating sales of more
than $20 billion a year. Therefore, biologics has been the fastest-growing segment of the
pharmaceutical industry, and such growth is projected to continue to keep driving the overall
market in the foreseeable future.
• For large global companies, their market share in innovative biologics market is threatened by
the new entrants. Therefore, they would like to invest more capital on both R&D and M&A for
new drug candidates to keep their leading position in the market. Meanwhile, because of the
Favorable Capital Market
increasing public attention, increasing external capital investment will also support small
Support
companies with innovative biologics development. As of 2020, the biologics market was valued
at USD 324.78 Billion and is expected to reach a value of USD 749.62 Billion by 2028, and
register a CAGR of 10.80% during the forecast period.

27
Development Path of Cancer Treatment
• Cancer treatment has gone through a long process of development in history, and it will continue to evolve over time
with the innovative and hard work of scientists around the world.
• Today, major treatments include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy.
Targeted Therapy and

Immunotherapy
Chemotherapy
1997, FDA approves the
Milestones in Cancer Treatment 1949, FDA approved first
first molecularly targeted
chemotherapy drug -
cancer drug, rituximab
nitrogen mustard - for the
treatment of Hodgkin
Radiotherapy lymphoma • Targeted therapies act on
1903, first successful use specific targets that are
Surgery of radiation to cure skin associated with cancer
cancer • Chemotherapy is a cancer growth, thus they do less
1881, first successful
treatment that uses chemical harm to normal cells. Most
surgery performed for substances, especially one or targeted therapies are either
stomach cancer • Radiotherapy is a cancer more anti-cancer drugs to stop or small-molecule drugs or
treatment that uses high doses of slow the growth of cancer cells. monoclonal antibodies.
radiation to kill cancer cells and • Chemotherapy can be used to • Immunotherapy induces
• Surgery is a procedure in which shrink tumors. treat many types of cancer alone the patient's own immune
a surgeon removes cancer from • Radiotherapy can be used to treat or in combination with other system to fight cancer.
patient’s body. many types of cancer including treatments. Immunotherapy includes
• Surgery works best for solid solid tumors and leukemia. And in • Chemotherapy also causes side cytokines, monoclonal
tumors that are contained in one many cases, patients receive effects such as mouth sores, antibodies, checkpoint
area. It is not used for leukemia radiotherapy with other cancer nausea, and hair loss. inhibitors (checkpoint
or for cancers that have spread. treatments, such as surgery and • Typical chemotherapeutic drugs monoclonal antibodies),
Surgery may be performed before chemotherapy. include alkylating agents, cellular immunotherapies
or after other forms of treatment. • Radiation not only kills or slows antimetabolites, anti-tumor and cancer vaccines.
• In addition to removal of the the growth of cancer cells, it can antibiotics and etc..
primary tumor, surgery is often also affect nearby healthy cells,
necessary for staging. which will cause side effects.

28
Oncology Treatment Evolvement
Primary Treatment Treatment Evolution
1. Surgery
5. Immuno-Oncology Therapy
• Cancer surgery removes the tumor and
• Induce the patient’s own immune system
nearby tissue during an operation. Best
to fight cancer
for early stage tumors that are
• Include cytokines, monoclonal antibodies,
contained in one area but is limited for
checkpoint inhibitors, cellular
cancers that have metastasized.
immunotherapies and cancer vaccines.
2. Radiotherapy
• High doses of radiation to kill cancer Significant Evolution
cells and shrink tumors including solid
• The use of chemotherapy to treat cancer began in the
tumors and leukemia.
early 20th century. in the 1960s and early 1970s,
• Affects nearby healthy cells, causing
combination chemotherapy showed efficacy in curing
side effects such as fatigue, hair loss
acute leukemia in children and advanced Hodgkin's
and skin changes.
disease, overcoming the pessimism that prevailed at the
3. Chemotherapy time about the ability of drugs to cure advanced cancer
• Uses one or more anti-cancer drugs to and promoting research in adjuvant chemotherapy.
stop or slow the growth of cancer cells. Today, important molecular mutations are often used to
• Targets all fast growing cells, causing screen for potential new drugs as well as targeted
side effects such fatigue, hair loss, easy therapies, and remain the cornerstone of anticancer
bruising and bleeding, and infection. drug therapy for many cancer patients.
• While monoclonal antibodies have become the
4. Targeted Therapy
backbone of cancer therapy, bispecific antibodies in
• Act on specific targets that are
immunotherapy are emerging as an important and
associated with cancer growth
promising component of the next generation of
• Less harmful to normal cells than
therapeutic antibodies due to their ability to
traditional therapies
simultaneously target two epitopes in the tumor cell or
• Include both small molecule drugs and
tumor microenvironment.
monoclonal antibodies

29
Global Incidence by Cancer Type, 2018-2030E
• In 2022, total cancer incidence has reached over 20 million around the globe, growing from 18.1 million in 2018. It is
estimated that in the future, cancer incidence will further increase, reaching over 24 million in 2030.
Incidence by Cancer Type of Global, 2018-2030E
Thousands
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Multiple Myeloma 160.0 164.3 176.4 180.6 185.7 190.8 196.1 201.4 206.8 212.4 218.0 223.7 229.4
Ovarian Cancer 295.4 301.7 314.0 319.8 326.4 333.0 339.6 346.3 353.0 359.7 366.4 373.2 379.9
Pancreas 458.9 471.5 495.8 508.9 523.7 538.9 554.4 570.3 586.5 603.2 620.1 637.5 655.1
Cervix 569.8 580.4 604.1 616.0 626.5 636.9 647.3 657.7 668.0 678.2 688.4 698.5 708.5
Lymphoma 589.6 602.6 627.4 640.3 654.7 669.3 684.2 699.2 714.4 729.8 745.4 761.2 777.1
Head and Neck 887.7 908.7 931.9 951.8 973.4 995.1 1017.0 1038.9 1061.0 1083.3 1105.5 1127.9 1150.2
Liver 841.1 862.2 905.7 929.6 952.9 976.4 1000.3 1024.5 1049.0 1073.8 1098.8 1124.2 1149.7
Stomach 1033.7 1061.4 1089.1 1120.5 1151.3 1182.6 1214.4 1246.9 1279.9 1313.4 1347.6 1382.1 1417.1
Skin 1329.8 1364.2 1522.7 1557.4 1604.3 1652.6 1702.3 1753.5 1806.1 1860.2 1916.0 1973.3 2032.2
Prostate 1276.1 1315.5 1414.3 1451.5 1497.2 1543.8 1591.3 1639.5 1688.6 1738.5 1789.2 1840.5 1892.3
Colorectum 1801.0 1849.1 1180.7 1928.0 1981.0 2035.1 2090.1 2146.2 2203.3 2261.4 2320.5 2380.6 2441.4
Lung 2093.9 2152.8 2206.8 2266.0 2330.4 2396.0 2462.7 2530.4 2599.3 2669.3 2740.3 2812.2 2884.9
Breast 2088.8 2133.7 2261.4 2301.2 2347.9 2394.8 2441.9 2489.1 2536.4 2583.7 2631.1 2678.4 2725.6
Source: GLOBOCAN, IARC, Frost & Sullivan Analysis

30
China Incidence by Cancer Type, 2018-2030E
• The incidence of cancer in China presents an increasing trend on the whole. Among all types of cancers, lung cancer,
stomach cancer, colorectal cancer, liver cancer, breast cancer and esophagus cancer are the top 5 in 2022 in China,
together they can hold a proportion more than 50% of each year’s new patients. In 2022, total cancer incidence has
reached 4.8 million in China, and it is estimated that the incidence will reach 5.8 million by 2030.
Incidence by Cancer Type of China, 2018-2030E

Thousands
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Multiple Myeloma 20.1 20.7 21.1 21.7 22.4 23.0 23.7 24.4 25.0 25.7 26.3 27.0 27.6
Ovarian Cancer 53.0 53.9 55.3 56.2 57.0 57.8 58.5 59.3 60.0 60.7 61.3 61.9 62.4
Uroepithelial Carcinoma 82.3 84.9 85.7 88.6 91.5 94.6 97.7 100.8 104.0 107.3 110.5 113.9 117.2
Lymphoma 93.1 95.4 99.7 102.1 104.6 107.0 109.5 112.0 114.6 117.1 119.6 122.1 124.5
Pancreas 104.9 108.4 112.0 115.9 120.0 124.1 128.4 132.7 137.1 141.5 146.0 150.6 155.2
Brain, CNS 112.8 115.1 117.3 119.5 121.7 123.9 126.0 128.2 130.3 132.3 134.4 136.3 138.2
Cervix 115.7 117.1 118.5 119.4 120.4 121.3 122.1 122.9 123.5 124.1 124.6 125.1 125.4
Thyroid 211.6 216.3 221.0 225.9 230.8 235.9 241.1 246.3 251.6 257.1 262.6 268.2 273.9
Esophagus 271.6 280.4 289.6 298.9 308.6 318.3 328.1 338.0 347.8 357.7 367.6 377.4 387.1
Breast 320.7 326.2 331.6 336.3 341.0 345.5 349.8 353.9 357.8 361.4 364.8 367.8 370.6
Liver 400.2 410.4 420.8 431.1 441.7 452.3 462.8 473.4 483.8 494.3 504.6 514.8 524.7
Colorectum 426.7 440.0 453.4 467.6 482.2 497.0 511.9 527.0 542.3 557.6 573.0 588.4 603.7
Stomach 442.3 455.8 469.6 483.9 498.6 513.5 528.5 543.6 558.8 574.0 589.4 604.6 619.6
Lung 867.5 895.3 924.1 953.8 984.5 1015.5 1046.8 1078.4 1110.2 1142.2 1174.4 1206.4 1238.1
Source: NCCR, Frost & Sullivan Analysis

31
Cancers with Top Incidence, 2022
• In 2022, the cancers with top incidence around the globe were breast cancer, lung cancer and colorectal cancer, each
having an incidence of 2,347.9 thousand, 2,330.4 thousand and 1,981 thousand.
• The cancers with top incidence in China in 2022 were lung cancer, gastric cancer and CRC, having an incidence of
984.5 thousand, 498.6 thousand and 482.2 thousand respectively.
• Lung cancer and CRC are the top incidence cancer both around the globe and in China. Breast cancer is the fifth
common type of cancer in China in 2022, with a incidence of 341.0 thousand.
Thousand
2,347.9 2,330.4
1,981.0
1,604.3 1,497.2
1,151.3
952.9
654.7 638.2 626.5
Breast Lung Colorectal Skin Prostate Stomach Liver Lymphoma Esophagus Cervix uteri
Thousand
984.5
498.6 482.2 441.7

341.0 308.6
230.8
127.9 121.7 120.4
Lung Stomach Colorectum Liver Breast Esophagus Thyroid Prostate CNS Cervix uteri
Source: GLOBOCAN, ACS, NCCR, Frost & Sullivan Analysis

32
Comparison of 5-year Survival Rate of Cancers in China and the U.S.
• China’s 5-year survival rate lags far behind the U.S. in prostate cancer, melanoma of skin, non Hodgkin lymphoma and
leukemia.
5-year Survival Rate of Cancers in China and the U.S.
China the U.S.

98.3% 99.3%
90.8% 93.2%
83.4%
78.5% 74.7%
68.8% 66.3% 67.0% 72.6%
62.7%
46.4%
84.3% 82.0% 31.1% 35.0%
72.9% 72.8% 69.8% 66.4% 20.5%
59.8% 56.9% 18.7% 18.1%
50.4% 45.1%
39.1% 37.0% 35.1% 8.5%
30.3% 26.7% 25.4%
19.7% 12.1% 7.2%
Source: GLOBOCAN, ACS, NCCR, Frost & Sullivan Analysis

33
Global Top 10 Best-selling Oncology Drugs by Sales Revenue,
2022
• Globally, the top 10 oncology drugs includes 5 biologics and 5 chemical drugs.
Rank Product Revenue (Million RMB) Category
1 Pembrolizumab 20,937.0 Biologics
2 Lenalidomide 9,978.0 Chemical
3 Nivolumab 9,492.0 Biologics
4 Daratumumab 7,977.0 Biologics
5 Denosumab 6,101.4 Biologics
6 Ibrutinib 5,820.0 Chemical
7 Osimertinib 5,444.0 Chemical
8 Palbociclib 5,120.0 Chemical
9 Enzalutamide 4,827.5 Chemical
10 Pertuzumab 4,280.0 Biologics
Source: Annual Report, Frost & Sullivan Analysis

34
China Top 10 Best-selling Oncology Drugs by Sales Revenue,
2022
• In China, the top 10 oncology drugs includes 5 biologics and 5 chemotherapy drugs.
• All the top 10 selling drugs in China are included in the NRDL.
Rank Product Revenue (Million RMB) Category
1 Bevacizumab 8,879.0 Biologics
2 Osimertinib 7,731.0 Chemotherapy Drug
3 Trastuzumab 7,173.0 Biologics
4 Nab-paclitaxe 5,341.0 Chemotherapy Drug
5 Anlotinib 4,504.0 Chemotherapy Drug
6 Pertuzumab 4,272.0 Biologics
7 Rituximab 4,065.0 Biologics
8 Doxorubicin 4,013.0 Chemotherapy Drug
9 Goserelin Acetate 3,752.1 Chemotherapy Drug
10 Leuprorelin 3,379.4 Biologics
Source: Annual Report, Frost & Sullivan Analysis

35
Global Oncology Drug Market, 2018-2030E
• From 2018 to 2022, global market of cancer drugs expanded from USD128.1 billion to USD205.1 billion, representing a
CAGR of 12.5% during this period. The steadily growing market results from the expanding patient pool and increasing
affordability of healthcare service.
• Global oncology market is expected to garner USD331.5 billion by 2026, with a CAGR of 12.8% during the forecasted
period from 2022 to 2026. Immunotherapies/ biologics are emerging as potential therapies to get the permanent cure for
various cancer types. Amongst various biologics, drugs based on monoclonal antibodies (mAbs) have gained significant
attention in recent years and would further propel the growth of oncology/cancer drugs market due to their high efficacy.
• Global oncology market is expected to generate USD458.6 billion revenue by 2030, with an annual growth rate of 8.4%
from 2026 to 2030.
Global Oncology Drug Market, 2018-2030E

Period CAGR
2018-2022 12.5%
2022-2026E 12.8%
2026E-2030E 8.4%
458.6
426.3
394.4
Billion USD 363.0
331.5
299.4
267.2
235.7
205.1
181.7
143.5 150.3
128.1
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: Annual Reports of Listed Medical Companies, NMPA, CDE, NRDL, MOHRSS, FDA, IARC, GLOBOCAN, Frost & Sullivan Analysis
36
China Oncology Drug Market, 2018-2030E
• In Chinese drug market, sales of oncology products has risen steadily in the recent years. China oncology market,
generating RMB233.6 billion in 2022, experienced a CAGR of 10.4% over the past 4 years.
• The ever-changing of successful innovative oncology treatments have promised a high return of pharmaceutical
manufacturers. China oncology market is expected to uptrend in the following years. From 2022 to 2026, China oncology
market is going to reach RMB401.9 billion at wholesale price level with CAGR of 14.5%. Forecasted data shows that
China oncology market would be RMB586.6 billion in 2030, representing a CAGR of 9.9% from 2026 to 2030.
• While competition in China’s oncology drug market is fierce, companies with in-house capabilities throughout the entire
value chain of oncology drug development, including drug discovery, process development, clinical development, quality
control and assurance and commercialization, are better positioned to capture the growth potential of this market.
China Oncology Drug Market, 2018-2030E

Period CAGR
2018-2022 10.4%
2022-2026E 14.5%
2026E-2030E 9.9%
586.6
538.1
Billion RMB
490.8
445.5
401.9
357.9
313.1
271.3
231.1 233.6
182.7 197.5
157.5
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: Annual Reports of Listed Medical Companies, NMPA, CDE, NRDL, MOHRSS, NCCR, Frost & Sullivan Analysis
37
Breakdown of Global Oncology Market by Therapy, 2022 and 2030E
• Currently, global oncology market is dominant by targeted therapy, which takes up to 61.3% of total market share.
Chemotherapy is taking a proportion of 14.2%, the left 24.5% corresponds to IO therapy in 2022.
• In 2022, the global market for targeted therapies and immunotherapies reached a combined USD205.1 billion. The
targeted therapy drug market is expected to grow to USD200.4 billion by 2030; Currently, targeted therapies and
immunotherapies comprise 85.8% of the global market and are expected to comprise 91.6% by 2030.
Breakdown of the Oncology Market by Therapy in Global, 2022 and 2030E
2022 2030E
Billion USD
8.4%
14.2%
24.5%
47.9%
43.7%
61.3% 43.7%
Total Market Size: Total Market Size:

$205.1 billion $458.6 billion
Chemotherapy IO Therapy Targeted Therapy
38
Breakdown of China Oncology Market by Therapy, 2022 and 2030E
• Currently, China oncology market is dominant by chemotherapy drugs which takes up to 54.3% of total. Targeted drugs
including small-molecularly targeted drugs, biologics, are taking a proportion of 37.0%, leaving 8.7% for IO therapy in
2022.
• With reimbursement policies, new drug development and patients’ increasing affordability, the targeted therapy and IO
therapy would occupy most of the market by 2030. It is expected that the share of IO therapy approaches 43.8% while
targeted drugs share would reach 43.4%.
Breakdown of China Oncology Market by Therapy, 2022 and 2030E

Billion RMB
At wholesale price level 2022 2030E
2.5 9.3
8.1%
8.7% 8.8%
12.8%
37.6
8.8
37.0% 35.8%
29.0% 19.1 43.8%
62.8%
54.3% 58.2
55.4%
43.4%
43.4%
Total Market Size: Total Market Size:

RMB233.6 billion RMB586.6 billion
Chemotherapy IO Therapy Targeted Therapy Company’s Addressable Market

39
Growth Drivers of Global Oncology Drug Market
Increasing Cancer • Global cancer incidence reached 19.3 million in 2020. Driven by an aging population, environment pollution, as well
as prevalence of unhealthy lifestyles such as smoking and high caloric diet, among others, global cancer incidence is
Patient Pool
estimated to further increase to 21.6 million in 2025, leading to a growing demand for oncology drugs.
• Technology advancements have revolutionized the pharmaceutical R&D and manufacturing processes, which have
Development of led to the development of novel therapies such as precision oncology and immuno-oncology therapies as well as
Advanced combination therapies. The availability of more effective and safer treatments have led to prolonged survival of
Treatment Options cancer patients, which in turn results in larger population of cancer patients that require treatment. This in turn further
drives the expansion in the oncology market.
Longer Duration of • Newer treatments extend survival and active treatment time frames. Furthermore, patients unable to take current
Treatment with cancer therapies or who have developed resistance to initial therapies may be able to take advantage of new options
Novel Therapies and lines of therapy.
• Continued development of diagnostic technology and biomarkers helps identify addressable patients and guide
clinical design of new drugs, which in turn provides better access to novel therapies. In addition, increased
Improved Access
disposable income, improved government medical reimbursement coverage and favorable pricing policies have
to Novel Therapies enhanced the accessibility of healthcare services and pharmaceutical medications for patients, further driving up
demand for oncology drugs.
• Mid-sized pharmas are more agile and flexible in pursuing novel drug candidates and brings innovation, creativity
Innovation and and productivity in comparison to large pharmaceutical. More capital investment in the biotech contribute to the
capital of Small growth of oncology drug market. Because smaller companies can be leaner in their processes and quicker in their
and Mid-sized actions, and their internal equity conversations can be a little bit easier. Stats also shows that in 2020, 39.6% novel
Pharmas drugs approved by FDA were contributed by small and mid-sized pharmas. Compared to 22.7% in 2016, there is a
big increase in the percentage of small and medium-sized pharmaceuticals.

40
Growth Drivers of China Oncology Drug Market
• China cancer incidence reached 4.6 million in 2020, accounting for around one forth of the global. Driven by aging
population, environment pollution as well as prevalence of unhealthy lifestyle like smoking, inactivity and high caloric
diet etc., China cancer incidence is estimated to further increase to 5.2 million in 2025, representing the growing
Large and
demand of increased diagnostic technology, which improves access to novel treatment and helps guide new drug
Increasing Patient
design. In addition, due to lack of access to general and specialized healthcare which resulted in a lower diagnosis
Pool rate, the currently reported number of cancer patients is generally believed to be lower than the actual number of
patients suffering from cancer. With improved diagnostic technologies, cancer incidences in China is expected to
grow at an accelerated rate.
• The availability of oncology therapies lagged far behind in China compared with developed regions. Currently, there
Significant Unmet are ony 43 oncology molecularly targeted drugs marketed in China while there are as many as 107 options in the
Clinical Needs U.S. Moreover, approved drugs have less approved indications compared with global peers as well, which further
limit the availability for clinical needs.
• With economic development, the living standards of Chinese residents have continuously improved, with per capita
disposable income has risen from RMB 21,966.2 (USD 3379.4) in 2015 to RMB32,189 (USD 4,952) in 2020 .
• Moreover, National Reimbursement Drug List has adopted dynamic adjustment. 53 oncology drugs (botanical
Improving
oncology drugs excluded) were included in the NRDL as List B drugs via price negotiation from 2017-2020. Such
Affordability
dynamic expansion of NRDL is expected to include more innovative oncology drugs in a regular interval. Both factor
have dramatically improve affordability of China cancer patients.
• In 2020, sales of Tagrisso, Herceptin and Avastin were respectively USD0.9 billion USD, 0.8 billion and 0.6 billion.
• China government promulgated a series of policies to shorten the review and approval time span for innovative
drugs IND and NDA applications, which will accelerate getting to the market process for drugs with potential to
address the urgently clinical needs. Patent protection is greatly enhanced as well. All these reforms will attract MNC
Regulatory pharmas to launch more global innovative biologics in China market.
Policies
• Furthermore, government has issued favorable policies in terms of tax reduction, talents incentive program and
special public R&D fund to support R&D activities of domestic companies in particular. Consequently, that available
novel oncology therapies will become increasingly diverse will boost consumption in the future.
• Combination therapies have shown enhanced efficacy compared to the mono-therapy approach. For example,
Emergence of clinical trials of combo of TKI and TKI inhibitors indicate great potential to address acquired resistance and
Combination improvement in ORR for cancer patients. Both MNCs and domestic pharmas are competing fiercely in clinical trials
Therapies schedule for their early launches, which is believed to further enrich the availability of oncology therapies and drive
the growth of the oncology drug market.
41
Future Trends of China Oncology Drug Market
• Keeping up with the global trend, China oncology market is also promoting precision treatment. In order to provide
precision treatment to different subtypes of patients, targeted cancer therapy emerges and develops rapidly, which
involves drugs or other substances to block the growth and spread of cancer by interfering with those specific
Precision Cancer
molecular targets. With the continuous exploration on innovative targeted drugs, precision treatment of cancer will
Treatment be applied to a wider tumor-related targets, making it a future trend. For example, in China, besides a previous hot
fad of exploring targets such as TNF-α, EGFR and CD20, emerging cellular therapies targeting CD19, BCMA and
etc. are being investigated more recently, urging the precision treatment of related cancer.
• New therapies such as immunotherapy and cell therapy occurred in recent years in treatment of cancer, and the
efficacy of combination therapy is improved from monotherapies, leading to better treatment outcomes and reflecting
Wider Use of a future development direction. For example, the anti PD-1 therapy combined with bevacizumab for the treatment of
Combination NSCLC had a significantly longer medium PFS (8.3m VS 6.8m), and combination therapy of PD-1/PD-L1 inhibitors
Therapies and TKIs in the first line setting of HCC. Continuous attempts are being made to involve new drugs and new
combinations such as CAR T with chemotherapy and other monoclonal antibodies, which will further encourage and
expediate potential effective combinations to be applied in clinical practices more extensively.
• Newer treatments extend survival and active treatment time frames. Furthermore, patients unable to take current
cancer therapies or who have developed resistance to initial therapies may be able to take advantage of new
options and lines of therapy, resulting longer lifespan.
Managing Cancer
• With the availability of oncology drugs and awareness of health management, cancer is expected to have longer 5-
as a Chronic
year survival rate, becoming a kind of chronic disease like diabetes and hypertension and making cancer requires
Disease
more than treatment but also follow-up and rehabilitation after treatment, which develops an increasing demand for
more advanced screening methods, such as gene sequencing and imaging detection, and rehabilitation solutions,
such as special nutritional support, cachexia treatment and comorbidity treatment.
• The National Medical Products Administration (NMPA) has incorporated an accelerated review in the access
process which has been widely used for the review and approval of new drugs in recent years. Because of the large
Favorable Access
unmet need in oncology treatment, drug regulators have shown increasing flexibility in supporting oncology drug
Policy and Trends development.
of Decreasing
• At present, a variety of anti-tumor drugs have entered the new medical insurance catalog through accelerated
Economic Burdens
approval, and the reimbursement ratio of drugs entering medical insurance can reach about 80% from now on,
for Patients which greatly reduces the economic burden of patients' diseases, for example, the out-of-pocket cost of endocrine
drugs for breast cancer patients is only less than 20% of the past..
42
Overview of Cancer Immuno-Oncology Therapy
• Over the last few years, immuno-oncology therapy has revolutionized cancer care. Immuno-oncology therapy is designed to stimulate the
patient’s own immune system to generate or augment an antitumor immune response in order to control or eradicate cancer cells. Due to its
ability to provide durable remissions while being generally well-tolerated in certain patients with advanced cancers, the discovery and
development of immuno-oncology therapy in recent years mark a milestone in cancer treatment.
• Innate immunity and adaptive immunity are two types of immunity. Intrinsic immunity, which is present from birth, enables a rapid response to
various invading pathogenic microorganisms and also plays an important role in the process of initiation and effect of specific immunity. Adaptive
immunity involves specialized immune cells and antibodies that attack and destroy foreign invaders and are able to prevent disease in the future
by remembering what those substances look like and mounting a new immune response.
Trp
Krn
TNF Receptor IDO

T cell Superfamily
CD28
Family
LAG-3 GITR Macrophage
TIM-3 CD27
VISTA ICOS SIRPα
TIGIT NA
PD-1 CTLA-4
MHC-II GITR-L
Galectin-9 CD70
NA ICOS-L
CD112/ PD-L1/ B7-H3 CD47
CD80/ TNF
CD155 PD-L2 CD86 Family NK Cell
B7 Superfamily HLA KIR
NKG2A CD94
Note: Burugu S, Dancsok AR, Nielsen TO. Emerging targets in cancer immunotherapy. Semin Cancer Biol. 2018;52(Pt 2):39‐52.

43
Classification of Immuno-Oncology Therapy
• Immuno-Oncology therapy is an emerging pillar of cancer treatment, alongside with surgery, chemotherapy and
radiation, inducing parts of human’s immune system to fight diseases. The process can be down in either stimulating
immune system to attack cancer cells or giving immune system components. Such immuno-oncology therapy comprises
cytokines, therapeutic cancer vaccine, checkpoint mAbs, and cellular immunotherapy such as chimeric antigen receptor
modified T cells (CAR T).
• Although there are many types of immuno-oncology therapies, most of them are actually using T cells for the anti-tumor
effects. Because of the difference in the development and regulation of immuno-oncology therapies between China and
U.S., a part of the advanced immuno-oncology therapies, especially cellular immunotherapies are currently not
marketed in China but marketed in U.S.
Immuno-Oncology Therapy Type Sub-type Marketed Drugs

® ®
CAR T (Kymriah , Yescarta )
Genetically Modified
TCR-T
Cellular Immunotherapy TM ®
AAL (Immuncell-LC , EAL )
Non-genetically Modified
CIK, NK, LAK, DC, TIL
IL-2 Ontak®, Proleukin®

Cytokines
IFN Multiferon® , Pegasys®
Therapeutic Cancer Vaccine Cell Vaccine BiovaxID®, Provenge®
® ® ® ®
PD-1 (Keytruda , Opdivo , Libtayo , Tyvyt )
PD-1/PD-L1 ® ® ®
Checkpoint Monoclonal Antibodies PD-L1 (Tecentriq , Bavencio , Imfinzi )
®
CTLA-4 Yervoy
® ® ®
Oncolytic virus Imlygic , Rigvir , Oncorine
Others Immunomodulatory Polypeptide Thymopentin, Thymosin α-1
Traditional Chinese Medicine Kang’ai, Ai’di,

44
Overview of Development Path of Immuno-Oncology Therapy
• Reviewing the development of cancer treatment, the immunotherapy has been emerging since 1890s and experienced
three phases on the way.
• The development of cancer immunotherapy has speeded up since 2010, when FDA approved the first vaccine for
prostate cancer. The immunotherapy is one of the hottest sectors in healthcare industry with a strong growth
momentum.
Upsurge Period Controversial Period Revival Period

（1978 ~ 1985）（1985 ~ 1997）（1997 ~）
1986 2010 2016

IFN-α was approved FDA approved Provenge, FDA approved the first
for HCL one of therapeutic tumor PD-1 inhibitor, Tecentriq,
immunotherapy. vaccine, for prostate cancer. for bladder cancer.
1960s 1978 1999 2014
Immunostimulants Tumor-specific Canada government approved the Two PD-1 antibodies,
were found to remove McAb was first therapeutic tumor vaccine, Keytruda and Opdivo, were
some types of tumor. discovered. Melacine, for advanced melanoma. approved for melanoma.
60s 70s 80s 90s 2000 2011 2014 2017
1890s 1991 2011

American orthopedic Successfully cloned the Ipilimumab, which is an anti CTLA-4 antibody,
surgeon Coley discover first tumor-associated was approved for advanced melanoma.
the first tumor vaccine. antigen, MEGA-1. Pegylated interferons got approval.
1985 1998 2017

Adoptive cellular therapy IL-2 was approved FDA unanimously (10-0)
was discovered for for RCC and recommended approval of CTL019,
hybridoma and cancer. melanoma. a CAR T therapy from Norvatis.
45
Development Path of Immuno-Oncology Therapies
Description ORR Examples
• Definition: refers to the monotherapy that Immune checkpoint inhibitors:

ICI
uses immune checkpoint inhibitor (ICI) to • Ipilimumab (CTLA-4 inhibitor)
(Immune
enhance T cell mediated antitumor immune ~ 20%
1st Wave checkpoint • Pembrolizumab (PD-1 inhibitor)
responses, thus inhibiting the growth of
inhibitor therapy) tumor cells. • Nivolumab (PD-1 inhibitor)
• CI + ICI: Nivolumab+Ipilimumab on
ICI melanoma, RCC etc.
+ • Definition: refers to the simple ICI • ICI + Chemotherapy:
Pembrolizumab+Chemo on NSCLC;
ICI combination therapies that demonstrate
Atezolizumab+Chemo on TNBC
2ed Wave / significantly improved clinical outcomes, ~ 40-50%
• ICI + anti-angiogenesis:
Chemotherapy including the combinations of ICI with ICI, Atezolizumab+bevacizumab on HCC;
/ chemotherapy, or anti-angiogenesis agents. Pembrolizumab+Axitinib on RCC;
anti-angiogenesis Pembrolizymab+lenvatinib on
endometrial
• Definition: refers to the sophisticated ICI

combination therapies that systemically • Combinational design that
exploit the immune system to achieve systemically targets the immune
3rd Wave ‘Cocktail’ Therapy > 80%
maximal antitumor effects. steps in Daniel Chen’s Cancer-
• ‘Cocktail’ Therapy could be the future Immunity Cycle
trend and mission of I/O therapy.

46
Clinical Applications of Immuno-Oncology Therapies
Immuno-Oncology Therapies in China

• Compared with traditional treatment methods, cellular immuno-oncology therapy is expected to become the mainstream treatment for
tumors in the future because it can be clinically tailored to specific patients/diseases, enhance their body immune function, and is safer
and more durable. At present, most of domestic clinical anti-tumor therapy still makes use of T cells, but clinical trials related to cellular
immunotherapy are also being accelerated.
• In order to overcome the problem of drug resistance in immuno-oncology therapy and avoid patients' non-response to treatment, clinical
measures should be taken to overcome drug resistance at different stages of immune response according to the characteristics of
different immunophenotypes, as well as considering different links or targets of action and different combinations of drugs.
Clinical Applications
1 PD-1/PD-L1 3 Combination immuno-oncology strategy

• PD-1/PD-L1 inhibitors are mainly used to eliminate tumors by • Combination therapy strategies can improve or activate
inhibiting the immune escape of tumor cells and enhancing the antitumor immune responses and overcome resistance
immune response of T cells. Although PD-1/PD-L1 inhibitors mediated by different mechanisms. Immunotherapy is
inhibitors have achieved good efficacy in a variety of most often used in combination with conventional
malignancies, including melanoma, non-small cell lung cancer radiotherapy. Chemotherapeutic agents can directly or
and renal cell carcinoma. indirectly stimulate the immune response and increase
tumor immunogenicity, thereby improving progression-free
survival and overall survival and extending the clinical
2 CAR-T benefit of immune-combination chemotherapy.
• CAR-T therapy refers to the genetic engineering to obtain T • Bispecific antibody therapy can simultaneously bind two
cells carrying specific receptors for tumor antigens and different epitopes or antigens to achieve a synergistic
transfuse them back to patients, so as to enhance the tumor- multi-pathway resistance function. For example, the
killing effect of T cells by recognizing tumor-related antigens, bifunctional fusion protein M7824 (MSB0011359C)
accurately locating tumor targets and expressing them for a antagonizes both PD-L1 and "captures" transforming
long time. This therapy is effective in the treatment of growth factor β to more effectively inhibit tumor growth and
hematological tumors such as leukemia, lymphoma, multiple metastasis, and reduces the complexity of clinical
myeloma or cancers such as liver and ovarian cancers. development and drug side effects.
Source: WHO, Frost & Sullivan Analysis

47
Benefits and Drawbacks of Immuno-Oncology Products
Type Overview Benefits Drawbacks

• CAR T treatment showed • Cytokine release syndrome.
encouraging results in clinical • Long-term side effects are
• Adoptive cell transfer, which is a treatment that attempts to trials.
Cellular still unclear for CAR T
boost the natural ability of your T cells to fight cancer. In this
Immunotherapy treatment, T cells are taken from your tumor. • Cancer could not be found treatment.
after treatment for many • Limited efficacy in solid
patients. tumor
• Cytokines are proteins that modulate the expansion, • Cytokines can inhibit the
• Lack specificity ,and toxicity
activation, and survival of lymphocytes. They are thought to growth of tumor cells, and
Cytokines can result in autoimmunity or
facilitate T cell, B cell, and NK cell proliferation and effector significantly prolong the life of tissue damage.
function, thereby strengthening the antitumor response.
patients.
• Therapeutic cancer vaccines are designed to stimulate the • Side effects are mild, while a
patient’s own immune system against tumor antigens. By few patient might have severe
Therapeutic • Therapeutics effects are
triggering the immune system, therapeutic vaccines can symptoms, like problem
Cancer Vaccine initiate a durable anti-tumor response that can attack tumor breathing and high blood limited.
cells and lead to improved survival. pressure.
• Checkpoint inhibitors, which are drugs that help the immune
system respond more strongly to a tumor. These drugs • Allergic reaction and side
Checkpoint work by releasing “brakes” that keep T cells (a type of white • Checkpoint mAbs can block effects.
Monoclonal blood cell and part of the immune system) from killing the pathway and simulate the
cancer cells. These drugs do not target the tumor directly. immune system. • Antibodies can not stimulate
Antibodies T cells attack tumors.
Instead, they interfere with the ability of cancer cells to
avoid immune system attack.
• Oncolytic viruses can replicate in cancer cells but not in
• Genetically modified oncolytic
normal cells, leading to lysis of the tumor mass and can
viruses can specifically • The efficacy may be
stimulate the immune system by enhancing antigen
Oncolytic Virus recognize tumors, which diminished by the presence
release/recognition and subsequent immune activation to
increases potency and of circulating antibodies.
counteract the immune evasiveness of malignant cells as
reduces side effects
well.
Source: BIOPHARM INTERNATIONAL, 2022, 35(1): 32-37., Signal Transduction and Targeted Therapy, 2022, 7(1): 1-28, Monoclonal antibodies. BoD–Books on
Demand, 2021., Front Immunol. 2021 May 5;12:626616., Seminars in cancer biology. Academic Press, 2020, 64: 1-12, Int J Mol Sci. 2020 Jul 31, Cell Mol Immunol.
2020 May;17(5):451-461., BioDrugs, 2014, 28(4): 331-343., Br J Pharmacol.2009 May;157(2):220-33., Frost & Sullivan Analysis
48
Main Product Categories of Immuno-Oncology Therapies
• According to the different therapeutic principles, immunotherapy can be mainly divided into: non-specific immune
stimulation, tumor vaccine, relay cell therapy, immune checkpoint inhibitors, etc. Up to now, immunotherapy has
gradually developed from non-specific immunity to specific immunity, and from adjuvant to traditional treatment to
simple immunotherapy or immunotherapy combination therapy. Adoptive cell therapy and immune checkpoint
inhibitors are currently the most mainstream immunotherapies. Moreover, lots of immune checkpoint inhibitors have
been listed, and their safety and efficacy have been clinically verified.
Catrgories Mechanism
• Cellular immunotherapy is based on immunological principles and methods, collecting human
immune cells, culturing and expanding them in vitro to enhance the targeted killing function, and
Cellular Immunotherapy then infusing them back into the human body to kill pathogens, cancer cells and mutated cells in
blood and tissues by mobilizing the body's immune system to inhibit tumor growth and enhance the
body's immune capability.
• During immunotherapy, cytokines directly stimulate immune effector cells and stromal cells at the
Cytokines
tumor site, enhancing cytotoxicity.
• Therapeutic tumor vaccines are prepared in vitro on a large scale by carrying tumor antigen-
presenting cells carrying tumor-associated antigens or modified tumor cells as therapeutic vaccines
for tumor patients. The therapeutic vaccine is used to stimulate the specific immunity of the patient's
Therapeutic Cancer Vaccine
body against tumor cells. tumor cells, thereby inhibiting tumor growth and treating tumors. The
purpose is to stimulate the specific immune response against tumor cells to inhibit tumor growth
and treat tumors.
• ICIs act as negative regulators of multiple immune checkpoints, particularly in cytotoxic T cells,
leading to inhibition of T cell stimulation. The negative costimulatory molecules such as CTLA-4,
PD-1 are expressed in different immune cell types, exhibiting immunosuppressive functions. As a
Immune Checkpoint Inhibitors
result, T cells are exhausted and the anti-cancer functions of the immune system are weakened.
ICIs remove these inhibitory signals, restore T cells from their exhausted status, and recover their
cytotoxicity on tumor cells.

49
Global Market Size of Immuno-Oncology Therapies, 2018-2030E
• The global market size of Immuno-oncology therapies is experiencing a rapid growth. The market size has grown from
USD21.1 billion in 2018 to USD50.2 billion in 2022, representing a CAGR of 24.3%. After 2022, the market is anticipated
to reach USD 123.9 billion by 2026 and USD 219.7 billion by 2030 with a CAGR of 25.3% and 15.4% respectively.
Global Market Size of Immuno-Oncology Therapies, 2018-2030E
Period CAGR
2018-2022 24.3%
2022-2026E 25.3%
2026E-2030E 15.4%
Billion USD
219.7
200.4
177.0
149.8
123.9
102.2
81.6
63.5
42.6 50.2
29.0 35.1
21.1
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: Frost & Sullivan analysis

50
China Market Size of Immuno-Oncology Therapies, 2018-2030E
• The market size of immuno-oncology therapies in China is experiencing a rapid growth as well. In 2018, the market
size reached RMB 1.9 billion and increased into RMB 20.2 billion in 2022, with a CAGR of 80.6% from 2018 to 2022.
After that, it will keep growing and it is anticipated to reach RMB 96.5 billion by 2026 and RMB 256.8 billion by 2030,
with a CAGR of 47.8% and 27.7% respectively.
China Market Size of Immuno-Oncology Therapies, 2018-2030E

Period CAGR
2018-2022 80.6%
2022-2026E 47.8%
2026E-2030E 27.7%
Billion RMB
256.8
214.5
173.8
137.6
96.5
67.3
42.9
14.8 16.3 20.2 26.7
1.9 7.4
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

51
Analysis of Antibody Drug Development and Milestone Events
The Development History of Antibody Drug
1975 1994 1998 2009 2018

monoclonal antibody was first approved chimeric first approved mAb drug first approved bispecific first approved
produced for the first time mAb for the treatment of solid antibody (Removab) sdab
in mouse tumor (Trastuzumab) (Caplacizumab)
1 2 3 4 5 6 7 8 9
1986 1997 2001 2011

first approved murin mAb first approved mAb drug first approved antibody-drug first approved checkpoint
(Muromonab) for the treatment of cancer conjugate (Gemtuzumab inhibitor antibody (Ipilimumab)
by FDA (Rituximab) Ozogamicin)
The Key Development Trends

• Increasing Safety Profile Antibody drug development has experienced the murine antibody, chimeric antibody, humanized antibody, and now
developed to fully human antibody, greatly improved the antibody drug safety by effectively reducing the immunogenicity and anti-drug antibody
(ADA), which will cause corresponding side effect, fully human antibody has become the mainstream of the antibody drug development trend.
• Improving efficacy The efficacy of antibody drugs has been significantly improved through Fab affinity modification, Fc glycosylation and other
antibody engineering technologies. At the same time, in recent years, antibody-conjugated drugs (ADC) that combine cytotoxic drugs, bispecific
antibodies that can simultaneously target of two antigens, Single-domain antibodies with stronger affinity have also been developed to improve
the efficacy of antibody drugs.
• Expanding therapeutic area With the continuous progress of antibody engineering technology and the discovery of more therapeutic targets,
the therapeutic area of antibody drugs has been greatly expanded. It has expanded from the initial reducing acute rejection in patients with organ
transplants to cancer, autoimmune diseases and ophthalmology, etc.

52
Classification and Comparative Analysis of Antibody Drugs
Overview of Antibody Drugs
Categories Structure and Functions Advantages Limitations
Mono-Antibodies that are made by

Proven therapeutic effect for several mAbs diffuse poorly and large tumor masses
identical immune cells that are all
kinds of diseases, especially for cancers may be more difficult to treat by mAb therapy.
Mono-antibody clones of a unique parent cell. mAb
and autoimmune diseases. High Triggering of ADCC by therapeutic antibodies
(mAb) can have monovalent affinity, in that
homogeneity. Possibility to produce large faces several limitations, especially for low
they bind to the same antigenic
quantities of identical antibody. affinity variant of the receptor.
determinant.
Potential used in various cancers, the Low expression of the target structures.
A bispecific monoclonal antibody
application to retarget effector cells of Non-human nature, limiting the doses and the
Bispecific (BsMAb, BsAb) is an artificial protein
the immune system and stimulate them number of injections that can be given to
antibody (BsAb) that can simultaneously bind to two
through the interaction to achieve an patients. Difficulties in chemical, manufacturing
different types of antigen.
efficient lysis of tumor cells. and control (CMC) development.
ADC consists of antibody, linker and
cytotoxin. The antibody can ADC drugs have larger tolerated doses,
specifically target a specific antigen and smaller effective doses. ADC drugs may be off-target in the blood,
which is expressed in the tumor cells; ADCs are now also available in resulting in the killing of normal cells. Antibody
Antibody-drug the linker acts as a bridge for the combination with other classes of drugs preparation cannot guarantee equal drug
Conjugate (ADC) ADC drug and is connected to the to enhance the effect of a single attachment for each antibody in each batch.
antibody by cleavable or non- treatment. And ADC also targets non- Antigens are expressed only in tumor cells and
cleavable linkers; the toxin small oncology therapeutic areas, including not in normal cells.
molecule should have high toxic imaging, CAR-T, etc.
activity and low immunity.
Multi-specific antibody constructs Hetero-dimerization of chains may make the

potentiate antibody-mediated effects, via molecule inefficient. Potential antigenic
Multispecific antibody (msAb) is an
simultaneously blocking multiple tumor- cytokine release syndrome. Tight white cell
Multi-Specific artificial protein targeting two or more
associated antigens (TAA), and/or binding may change bio-distribution. Large
Antibodies unique epitopes, which can bind
triggering more intensified immune molecules have less intertumoral penetration
more than one type of antigen.
reactions. Multiple functions translate and they are hard to be cleared with risk of
into improved response rates. aggregation.

53
Classification and Comparative Analysis of Antibody Drugs
Comparison of Antibody Drugs and Chemical Drugs
• Compared to traditional chemical drugs, monoclonal antibodies are less available, more expensive and not fully covered
by medical insurance. However, in terms of clinical value, antibodies have high specificity and high affinity for the
corresponding antigens, making them unparalleled in the diagnosis and treatment of diseases, especially for the
treatment of tumors.
• As the aging population in China and the morbidity and mortality rates of tumors continue to rise, patient demand for
monoclonal antibodies will further increase, with huge market potential for antibody drugs for preventive vaccines,
hormone deficiencies, molecular diagnostics and tumor therapy. At present, the international anti-tumor drug market is
dominated by antibody drug. With the continuous development and depth of new technologies and antibody group drugs
in the future, many new targets, new antibodies and antibody drug conjugation programs will be continuously developed
and put into use, and antibody drugs with anti-tumor drugs as the core still have great development potential in the
future.
Attributes Antibody Drugs Chemical Drugs
Category Less diverse A more comprehensive range
High prices and few types of health insurance Lower prices and comprehensive health insurance
Price
coverage coverage
Very high potency; very high specific affinity for

Efficiency Poor affinity for antigens; high dosing
antigens; high sensitivity; low dosage
Low side-effects; metabolized by the liver; kill only

Safety High side effects; even on normal cells
specific cells

54
Clinical Advantages of Antibody Drugs
• Monoclonal antibody only binds one epitope of target antigens, • As monoclonal antibody only targets and binds specific antigens, it could
which could reduce the risk caused by cross reaction and drug side selectively kill target cells and exhibit a specific distribution in vivo for the
effects. Most patients only show a slight adverse effect during the treatment of cancer. This highly specific therapy provides more potent
monoclonal antibody therapy. Meanwhile the chance of getting and concentrated efficacy.
systematic toxicity by monoclonal antibody is lower compared with
chemotherapeutic drugs, due to its more concentrated therapeutic • Many mAb drugs have been proved to be very effective in
effect. With highly humanized monoclonal antibody the immunogenic the treatment of cancer. For instance, bevacizumab has
response has been greatly reduced. been used in China for the treatment of non-small cell lung
cancer in recent years and has become a first-line treatment
• In the trial of rituximab in the treatment of diffuse option in the latest edition of the guidelines. Clinical trials
large B-cell lymphoma, the myelosuppression, have shown that bevacizumab combined with chemotherapy
gastrointestinal reactions, neurotoxicity, and can significantly improve the objective remission rate of non-
hematological toxicity of the experimental group small cell lung cancer.
were significantly less than chemotherapy. Safety Efficacy
• Monoclonal antibody drugs possess a better Clinical • The emergence of monoclonal antibodies has alleviated
tolerance compared with conventional Compliance
chemotherapy and radiotherapy. During the
Demands the lack of effective therapies in many cancers. The
discovery of new monoclonal antibodies and new
treatment of monoclonal antibody, most of the indications has increased the possibility of developing
common adverse effects are at low to middle level. more therapeutic areas for monoclonal antibodies.
Patients have a good tolerance and don’t have to
stop the treatment. For example, in the case of
infusion of rituximab only less than1% patients had • Colorectal cancer is one of the most common malignant tumors of the
severe adverse effects and most patients could digestive tract in China. It is the fourth most common type of cancer in
continue using this drug with a lower infusion rate China in 2018. Because of its low early diagnosis rate, traditional
after the symptoms disappeared. chemotherapy is often used in patients with advanced disease. The
cetuximab approved by FDA in 2004 is important for the treatment of
• Monoclonal antibody has a long half time in vivo, so the frequency of metastatic colorectal cancer with Kras/Nras/Braf wild type. In the
administration could be reduced, which can reduce the CRSTAL study, median progression-free survival was significantly
psychological burden of patients and make them more acceptable to extended to 8.9 months in the patients treated with cetuximab, and the
treatment. risk of disease progression was reduced by 15%.

55
Antibody Drugs Development Process Analysis
• The development of antibody drugs can usually be divided into three parts: from 0 to the discovery of pre-clinical
candidate compounds; the validation process from PCC-IND (new drug clinical application) and the human clinical trial
phase from IND-NDA (new drug application to market).
Pre-IND
Drug Discovery
Target assessment,
Select disease PCC Defining the TPP
identification
Pre-IND
Pharmacological research
Candidate antibody Candidate antibody Pharmacodynamic and mechanistic

screening optimisation pharmacokinetics
Pre-IND IND Post-IND
Pre-clinical studies Clinical research Approval & Listing
Phase I-III Post-marketing Phase

CMC Safety evaluation
clinical trails
NDA
IV clinical trials

56
Analysis of the Value Chain of Antibody Industry
• The upstream industry in antibody manufacturing is mainly raw material suppliers. The raw materials required for the production of
antibodies include cell lines, culture medium, chromatographic media and so on. The quality of raw materials will directly affect the
drug quality and fluctuations in their price will also affect the manufacturing costs of drugs.
• Pharmaceutical distribution companies and hospitals are downstream industries for mAb drugs. Hospitals provide patients with
medical services and prescriptions of drugs and are main sales terminals while pharmaceutical distribution companies are
responsible for the logistics such as cold chain and warehousing.
The first step for monoclonal antibody development is to validate potential targets, which involve
biophysics evaluation and cell- or tissue-based assessment. The following discovery procedures are
Raw material Drug discovery
involved with cell line construction, cell culture and purification, characterization of physicochemical
suppliers and biological properties. Perfect and high efficient discovery process is dependent on high accurate
and efficient analytic equipment. Meantime seeking a reasonable formulation in the pre-clinical
experimental stage is beneficial for the development of subsequent clinical research.
Persuasive clinical results are a key factor in drug approval. Review and approval by national
Drug manufacturers
regulators is a necessity for drugs to be marketed. The higher safety and effectiveness of drugs
Clinical Research showed in clinical trials are also highly valuable for doctors and patients in selecting treatments.
Therefore, screening for potential indications and patient populations is also one of the important
considerations for clinical research.
Pharmaceutical
Distribution The manufacturing process of monoclonal antibody drugs is complicated, and its manufacturing cost
Companies accounts for a large proportion of total investment. Building large-scale production lines and
improving cell culture processes are the main ways to increase productivity in the monoclonal
Manufacturing antibody manufacturing industry. A well-developed technology platform can speed up the transition
Process from pharmaceutical production to clinical use. However, while improving the productivity, we should
try to avoid the adverse effects on the quality of the product due to unreasonable design in the
Medical Institutes
production process to ensure the final quality of the drug.
The downstream industry of monoclonal antibody drugs is mainly in the hospital drug market, which
is the main distribution channel and trading place for monoclonal antibody drugs; patients can obtain
Commercialization drugs through doctor's prescription. However, the long payback period of the hospital will directly
Patients affect the cash flow of pharmaceutical companies. Due to the generally high price of monoclonal
antibody drugs, it is necessary to focus on the patient's affordability and the coverage of medical
insurance in the process of commercialization.

57
Analysis of the Development Process and Mechanism of Bispecific
Antibody Drugs
• Bispecific antibodies can recognize and specifically bind to two antigens or epitopes of antigens. Theoretically, it can
block the biological functions mediated by two antigens/epitopes at the same time or draw the two antigen cells closer,
thereby enhancing their interaction.
• In recent years, with the in-depth understanding of the pathogenesis of various diseases and the development and
progress of monoclonal antibodies, the development and progress of bispecific antibodies have been promoted. With
the development of antibody construction, expression and purification technology, dozens of structures of bispecific
antibodies have appeared. At present, tumor is one of the hot areas of double antibody research.
2014: FDA
1983: Initial bispecific 1990: Introduce the application of approved the first
antibody synthesized by bispecific antibodies in clinical bispecific antibody,
hybridoma cells treatment Blincyto
1984: Found that bispecific antibodies 2009: EMA approved

1961:First appearance of
can specifically recognize T cells and Removab, the world's
the production of chimeric
stimulate cytotoxicity of T cell- first bispecific antibody
bispecific antibodies
mediated
Killing Blocking the proliferation Receptor co-stimulation or

Dual target inhibition
mediated immune cell signaling pathway inhibition
It uses bridging effector T Blocking the signal Acting on two different Target two different receptors
cells and tumor cells, and transduction pathways of targets on cancer cells in on immune cells, promote the
individually bridging NK cells. growth factor receptors of order to inhibit compensatory activation of immune cells or
Mechanism The antibody activates and tumor cells nad their or synergistic effects block the suppression of
relocates immune cells to downstream. immune cells
promote the immune cells to
kill the cancer cells.
• CD19+CD3 • HER2+HER3 • VEGF+Ang-2 BsAb • PD-1 + CTLA-4

Example
• EpCAM+CD3 • IGF-1R+HER3 • EGFR+C-met • PD-1 + LAG3

58
Structural Classification of Bispecific Antibodies
• Currently, bispecific antibodies are generally divided into two categories according to their structure: IgG-type structure
and non-IgG-type structure. Among them, the IgG structure can be divided into two types: symmetric and asymmetric,
where the asymmetric structure has obvious advantages.
Non-IgG Symmetric IgG Asymmetric IgG
• Solved the technical limits of Knob-into-hole

• Simple Structure
• Similar to the structure and technology in common light chain
• The clinical dosage is low, less
stability of natural IgG • Realizes the bivalent binding of tumor
Advantage than one-tenth of the original
• Mature technology, high antigens, which can reduce the toxicity
amount of antibodies
expression caused by CD3 antibodies when binding to
• Weak immunogenicity
tumor antigens
• Short half-life (only 2 hours)

• Long technical route, difficult design and
Disadvantage • Unstable structure, low expression • limited spatial bispecific binding
process
and difficult process effect
• Emicizumab applies KIH technology

platform, marketed by Roche in 2017,
hemophilia A
• Blinatumomab applies Tandem PD-1 and CTLA-4 bispecific
Marketed • Catumaxomab applies Triomab asyme 1+1
scFV and BiTE technology antibody Cadonilimab which listed
Examples (Rat-mouse hybrid lgG) platform, developed
platform.Amgen is marketed in in 2022
by TRION Pharma GmbH and Neovii
2014, acute lymphocytic leukemia
Biotech GmbH in 2009 (withdrawn from the
market in 2017), malignant pleural effusion
Source: Frontiers in Immunology, 2021: 1555., Analysis and Characterization of Antibody-based Therapeutics. Elsevier, 2020: 167-179., Journal of Immunology
Research, 2019, 2019., Antibodies, 2018, 7(3): 28., Journal of hematology & oncology, 2015, 8(1): 1-14., Frost & Sullivan Analysis
59
Comparison of Monoclonal Antibodies and Bispecific Antibodies
Attributes Monoclonal Antibodies Bispecific Antibodies
➢ It is widely used in many therapeutic fields such

as cancer, metabolic diseases, ophthalmology, ➢ Currently approved indications of bispecific
Indications autoimmunity, etc. It has good clinical therapeutic antibodies are still limited.
value
➢ Can be applied in monotherapy and combination

➢ Can be applied in monotherapy and combination
therapy
therapy
• Advantage：Due to the dual goal of
• Advantage：Large amount of evidence-based
Advantages and limits medical support
compensation, the likelihood of drug
tolerance is low
• Limits：Potential drug tolerance because of
• Limits：Clinical use and technology are at
single-target.
an early stage
• The manufacturing system of bispecific

antibodies is still under development. At present,
more than 60 new platforms are exploring new
ways to manufacture bispecific antibodies.
• The preparation process of monoclonal Compared with monoclonal antibodies, the
antibodies mainly includes establishment of preparation of bispecific antibodies requires more
expression system, establishment and filling of modifications on both the expression system and
Process cell bank, cell culture and purification. Compared the antibody. Currently, there are only two
with bispecific antibodies, the production system commercialized bispecific antibody products,
of monoclonal antibodies is quite mature. therefore, there is no general industrial practice
in the commercial production route. The
exploration of commercial manufacturing mainly
focuses on chemical combination, tetramer
technology and genetic engineering.
Source: FDA，Frost & Sullivan Analysis

60
Global Analysis of Marketed Bi-specific Antibodies
Marketed products globally

Product Drug Name Company Target Indications Approval Time
Malignant Ascites, EpCAM-
REMOVAB™ Catumaxomab Neovii Biotech GmbH CD3/EpCAM 04/2009(EMA)
positive Carcinomas
Precursor B-cell Acute
Lymphoblastic Leukemia (ALL), 12/2014 (FDA)
BLINCYTO™ Blinatumomab Amgen CD3/CD19
Refractory or Relapsed (R/R) 11/2015 (EMA)
ALL
11/2017 (FDA)
HEMLIBRA™ Emicizumab Roche Fixa/FX Hemophilia A
02/2018 (EMA)
Non-Small Cell Lung Cancer 05/2021 (FDA)
RYBREVANT™ Amivantamab Johnson & Johnson EGFR/c-Met
(NSCLC) 12/2021 (EMA)
Neovascular (Wet) Age-related
VABYSMO™ Faricimab Genentech Ang-2/VEGF Macular Degeneration (AMD), 01/2022 (FDA)
Diabetic Macular Edema (DME)
Relapsed or Refractory Diffuse
EPKINLY TM Epcoritamab Genmab CD20，CD3 Large B-Cell Lymphoma 05/2023(FDA)
(DLBCL)
Nanozora Ozoralizumab Sanofi/Ablynx TNF-α Rheumatoid arthritis 09/2022(JAPAN)
07/2022(FDA)
Lunsumio Mosunetuzumab Roche CD20，CD3 Follicular lymphoma(FL)
06/2022(EMA)
Johnson & Johnson,
08/2022(EMA)
TECVAYLI Teclistamab Johnson & Johnson BCMA, CD3 Malignant blood diseases
01/2023(FDA)
(China) Ltd.
Diffuse Large B-Cell
Columvi Glofitamab Roche CD20，CD3 06/2023(FDA)
Lymphoma (DLBCL)
Source: FDA, EMA, Frost & Sullivan Analysis

61
Overview of the Global Bispecific Antibody Technology Platforms
Technology
Company Platform Advantages Examples
characteristics
Formation of heterodimer through

Genentech/ modified Fc CH3 segment;
Maintain the stable
affinity of the Fc Emicizumab
Roche Knobs-in-Holes （KIH） asymmetric structure of IgG-like （IX factor × X
antibody segment to the two
targets Factor）
Avoid light and heavy chain
mismatches through CrossMab; Keep the Fc
Genentech/ allow the production of a variety of RG7221
KIH CrossMab segment stable,
Roche bispecific antibodies and Fab- （VEGF × ANG2）
simple production
based antibody derivatives; IgG-
quality control
like antibody asymmetric structure
Enhances efficacy by
simultaneously binding with two Hemlibra
Genentech/ types of antigen or provides new Easinessfor
ART-Ig (Factor VIII ×
Roche pharmacology by bridging two manufacturing
Factor VIIIa)
antigens
The modified Fc CH3 segment is Simple production

formed into a heavy chain
process and XmAb14045
heterodimer through charge action,
Xencor X-Mab (Fab-scFv) and light and heavy chain quality control, （CD123 × CD3）
mismatches are avoided through Xmab improves
Fab-scFv; IgG-like antibody thermal stability
asymmetric structure
On the light and heavy chains of the
variable region of an IgG antibody, Constant segment
Abbott DVD-Ig the light and heavy chain variable ABT122
that increases
regions that target another antigen （TNF × IL-17）
are respectively connected in
affinity to antigen
tandem; IgG-like symmetric
antibody

62
Overview of the Global Bispecific Antibody Technology Platforms
Technology
characteristics
Using CD16A targeting Fv Higher potency

AFM13
AffiMed TandAb domains,identifying Hodgkin and efficacy of
lymphoma cells the TandAb (CD30 x CD16a)
Simple structure,
Apply a short peptide chain to
easy to eliminate in Blinatumomab
Amgen BiTE connect the four parts of VLA-
VHB+VLB-VHA in series
the body, with few （CD19 × CD3）
side effects
Simple structure, easy

VLA-VHB+VLB-VHA,
Macrogenics DART to eliminate in the Flotetuzumab
connect two chains relying
body, with few side （CD123 × CD3）
on covalent chain
effects
Binding of tumor cells and T
Little mismatch in light Catumaxomab
Trion Pharma Triomabs cells through the SCFv
and heavy chains （EpCAM × CD3）
functional region, respectively
Technical differences between IgG- type structure and Non-IgG-Type Structure
• Technically, IgG-type structure and non-IgG-type structure are very different from each other. IgG- type structure has Fc-
mediated functional effects including ADCC, CDC and ADCP so that it can improve anti- tumor ability. It also has longer serum
half life time. At the same time, IgG- type structure’s manufacturing is more mature and convenient due to Fc’s contribution to
stability of purified antibodies.
• In comparison with IgG- type structure, Non-IgG- type structure has lower immunogenicity and higher security. Since its
molecule is pretty small, it can penetrate into tumor tissue efficiently, offering better therapeutic effects. However, it has
relatively shorter serum half life time (2 hours) which challenges the manufacturing process.

63
Overview of China Bispecific Antibody Technology Platforms
Technology
characteristics
The asymmetric structure,PK/PD and
Avoid mismatch
process are similar to those of mab;
between heavy chain
merged KiH and charge interaction M701
YZY Bio YBODY and light chain; fine
strategy to achieve correct match of
PK features; allow (EpCAM × CD3)
heavy chains; the Fc segment was
mass production
modified by Knob hole and salt
High biological
Generate bispecific antibody and activity; avoid A-319
ITabMed iTAb poly-specific antibodies via T cell potential off-target (CD19 × CD3)
Engager side effect brought by
Fc chain
Adjust the charge network distribution

Structure-oriented Fc
between different Fc chains by
Alphamab optimization; prevent KN026
CRIB complete antibody frame structure,
Oncology enhance the formation of
interactions between (HER2 × HER2)
homodimer
heterodimer; reduce homodimer
formation
Does not require any amino acid

Avoid mismatches
EpimAb mutations or include any linkers or EMB-06
FIT-Ig between different
Biotherapeutics non-antibody sequence to form
heavy and light chains
(BCMA × CD3)
bispecific antibodies
Composed of 3 technologies:
NEOboday, SAFEboby and
Uncover new
POWERbody; Generate antibodies
mechanism; limit on- ADG138
with dynamic binding sites; generate
Adagene DPL masked antibodies designed to be
target off-tumer (HER2× CD3)
toxicity in normal
selectively activated in TME;
tissue
generate bispecific antibody via T-cell
engager

64
Clinical Advantage of Bispecific Antibody
Compared with Mono Therapy Compared with Combo Therapy
• Mediate Immune Cell Killing towards Tumors: BsAbs • Reduce the Cost of Treatment: In terms of dosage, since
have two antigen-binding arms, one of which binds to the therapeutic effect of BsAbs can reach 100-1000 folds of
the target antigen and the other binds to the labeled the common antibody, the lowest dose can be 1/2000 of
antigen on the effector T cell, which activates the the original, which significantly reduces the cost of drug
effector T cell to kill tumor cells. treatment. The use of BsAbs compared to combination
• Stronger Specificity and Reduced Off-target Toxicity: therapy with two monospecific drugs makes it possible to
In contrast to mAbs, BsAbs interact with two different optimize expenses by reducing the cost of development
surface antigens respectively, which can effectively and clinical trials.
enhance the binding specificity and reduce side effects • Better Clinical-Doability: Bispecific antibodies require
such as off-target. only single administration compared to combo therapies
• Lower Drug Resistance: Since one disease modulator that require multiple injections of two or more antibodies,
may play an essential role in several independent simplifying the frequency and practice of administration, it
pathways and co-expression of different receptors has shows great advantages in clinical trial development,
been found in many tumors, targeting of two different clinical application as well as patient compliance.
growth-promoting receptors on a single tumor cell may • Improved Safety: In some clinical trials, the incidence of
increase the antiproliferative effect and help to avoid the SAE of combo therapy of Nivolumab and Ipilimumab is
development of resistance. higher than mon therapy, such as CheckMate 067.
However, currently the early clinical trials have shown that
PD-1/PD-L1 x CTLA-4 BsAbs has improved safety.

65
Clinical Advantage of Bispecific Antibody
Advantages in Treating Retina Disorders Advantages in Treating Hemophilia
• Most treatments for retinal disorders target the • Hemophilia A is a bleeding disorder resulting from coagulation
VEGF(vascular endothelial growth factor), but not all factor VIII (FVIII) deficiency. the common treatment for this
patients respond to these treatments. BsAbs drugs disease is exogenously provided FVIII, which can reduce
target two pathways simultaneously, so patients who are bleeding complications in patients with severe hemophilia A.
not sensitive to anti-VEGF therapies might benefit from However, approximately 30% of such patients develop
blocking the other angiogenesis pathway. inhibitory antibodies against FVIII (inhibitors), precluding FVIII
• Dual inhibition of Ang-2 and VEGF-A improves both treatment in this set of patients. Moreover, the poor
structural and functional outcomes for patients with pharmacokinetics of FVIII, attributed to low subcutaneous
neovascular AMD and DME. When inhibiting Ang-2 in bioavailability and a short half-life of 0.5 d, necessitates
preclinical models, it seems to translate into a more frequent intravenous injections
robust VEGF-A inhibition effect. Manipulating both • Bispecific antibodies for curing hemphilia like Emicizumab can
pathways simultaneously appears to be additive. recognize both the enzyme factor IXa and the substrate factor
• BsAbs has better treatment durability and helps to X. By simultaneously binding enzyme and substrate, BsAb
reduce patients’ injection frequency. Studies showed drug could mimic some part of the function exerted by the
that more than 50% of patients were able to go 16 original cofactor, FVIII, even in the presence of inhibitors.
weeks or longer between treatments and more than • besides, bsabs have high subcutaneous bioavailability and a 2-
70% of patients were able to extend the treatment week half-life and would not be expected to elicit the
interval by 12 weeks or longer. development of FVIII-specific inhibitory antibodies. Higher
durability reduces the burden of care for the treatment of
hemophilia A.
66
Global Therapeutic Antibody Market Size and Forecast, 2018-2030E
• In 2022, global therapeutic antibody market grew to USD216.8 billion, with a CAGR of 11.8% from 2018 to 2022. The
monospecific antibody is the largest category in global therapeutic monoclonal antibody market by revenue, and
accounts for over 95% proportion. Though the bispecific antibody (BsAb), antibody-drug conjugates (ADC) and other
antibody types, such as nanobody, are still in the initial stage of market, it is anticipated that the market of them will
grow fast with the breakthrough of technology and clinical studies.
• In the next 10 years, global therapeutic antibody market will continue to grow to USD 281.8 billion in 2026 due to rising
medical demand and innovative antibody pipelines, showing a CAGR of 9.8% from 2022 to 2026. Global therapeutic
antibody market size will further to reach USD306.1 billion in 2030.
Historical and Forecasted Global Therapeutic Antibody Market Size, 2018-2030E

Other Multi-
CAGR mAbs BsAbs ADC Total
Specific Antibodies
439.4 …
2018-2022 10.6% 85.8% 40.4% 3.7% 11.8%
415.4 …
2022-2026E 6.8% 51.6% 31.7% 25.1% 9.8% 387.9 0.6 64.7
2026E-2030E 2.1% 23.6% 28.4% 76.2% 7.0% 362.3 52.8
0.3
41.2
334.6 31.5
57.9 67.4
310.3 23.8 48.0
Billion USD 284.2 … 18.7 38.2
28.9
257.9 11.4 20.6
230.2 7.9 13.9
8.9
205.4 5.5
5.5
4.1
2.8 177.1
2.0 163.8
147.3 3.8
292.4 298.1 303.8 306.1
2.7 271.0 281.8
237.6 256.1
1.7 216.8
196.1
0.5 159.3 170.3
144.8
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
mAbs BsAbs ADC Other Multi-Specific Antibodies
67
China Therapeutic Antibody Market Size and Forecast, 2018-2030E
• In 2022, China therapeutic monoclonal antibody market grew to RMB 75.9 billion, with a CAGR of 47.6% from 2018 to
2022. The monoclonal antibody will remain the largest category in China therapeutic monoclonal antibody market.
However, there is also sufficient pipelines of BsAb and ADCs, as well as others innovative antibody types, such as
HcAb and multi-specific antibody, under development. It is anticipated that the market of those innovative antibody
drugs will grow fast with the breakthrough of technology and clinical studies.
• In the next 10 years, with more antibody drugs included in NRDL and increasing biosimilar availability as well as
innovative antibodies launch in China, the domestic therapeutic antibody market will continue to grow to RMB 228.3
billion in 2026, showing a CAGR of 31.7% from 2022 to 2026, and the market size will further to reach RMB 479.3
billion in 2030.
Historical and Forecasted Market Size of Therapeutic Antibody Market in China, 2018-2030E 479.3 1.3
Other Multi-Specific
CAGR mAbs BsAbs ADC Total 66.2
Antibodies 418.2 …
2018-2022 46.8% NA NA NA 47.6% 53.1
353.6 0.5 68.2
2022-2026E 27.2% 113.6% 109.2% 27.4% 31.7%
2026E-2030E 15.3% 39.8% 42.8% 113.5% 20.4% 39.3 55.8
288.6 0.2
42.5
26.4
Billion RMB 228.3 15.9 29.3
17.2 8.5 17.8
4.4 343.6
137.4 308.3
9.6 271.3
103.8 232.7
0.8 2.1 4.3
75.9 194.4
58.5 0.1 161.1
128.7
28.8 41.1 99.4 1.9
16.0 16.0 28.8 58.0 74.2 0.9
41.0
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
mAbs BsAb ADC Other Multi-Specific Antibodies
68
Growth Drivers and Restraints of China Antibody Drugs Market
Increasing Patient Need

With the rising prevalence of chronic diseases brought by trend of aging, Increasing R&D Costs
accelerating urbanization, and environmental changes, there’s growing healthcare Developing a new drug is more difficult than before,
need for Chinese people to prevent and cure disease, and to improve the quality needs more resources and time as well. This situation
of living. makes many small and medium pharmaceutical
companies cannot afford the R&D investments, and
Strong Support from Government slow down the development of whole pharmaceuticals
The government has released a series of policies, such as “Guidelines for R&D industry.
Pharmaceutical Industry Development Plan” and “Opinions on Deepening the
Reform of the Evaluation and Approval Systems and Encouraging Innovation on
Drugs and Medical Devices ” to encourage the innovation of new drugs and
improve the drug quality.
Strengthened Intellectual Property Protection Low success rate

the Chinese government has made significant progress in improving the level of Even if the companies have the abilities to development
intellectual property rights in the country, a necessary requirement to encourage new drugs, the results would probably discourage the
R&D. This included changing the country's faith in drug R&D as the drug success rate from clinical
patent examination guidelines in 2013 as well as implementing national programs trails to NDA is very low.
to crack down on the sale of counterfeit medicines.
Enlarging Talent Pool

The R&D talent pool has kept growing, with scientist trained either overseas or
locally. Especially, in recent year, more and more ‘sea turtles’ have returned to
China with years of US or European lab experience under their belts, and utilize
their experience to helped local companies upgrade their R&D platforms.
Novelty and quality of innovation still
lagging
Although more and more local pharmaceutical
companies adjust their R&D interest into innovation
R&D collaboration with MNCs drugs, there are many companies still focusing on “me-
A number of leading foreign companies have operated domestic drug research too” and “me better” targets in drug R&D
facilities and actively conducted trials in China. In addition, co-development deals
have been on a dramatic rise, which also facilitate the R&D capabilities of local
players.
Drivers Restraints
69
Growth Drivers of Antibody Drugs Market
• China's antibody drug industry has a huge room for development. In the face of the huge market demand, the
production of antibody drugs will be a huge opportunity and challenge, and it is of great economic and social
Growing Needs of importance to develop new antibody drugs, optimize the production process of antibody drugs to increase the
Domestic Antibody yield and reduce the production cost of antibody drugs.
Drugs Market • Although bispecific antibody drugs have not yet achieved significant market share in the Chinese market, their
development potential is huge. The market size of biclonal antibody drugs in China is expected to grow
rapidly to 12.1 billion RMB by 2025, with a CAGR of 160.95% from 2021 to 2025.
• The biopharmaceutical industry has been listed as a strategic emerging industry in China during the 12th
Progressive Increase Five-Year Plan period. In recent years, China has established the "National Engineering Center for Antibody
Drugs" (Shang Hai), "State Key Laboratory for Antibody Drug Development" (Shi Jia Zhuang) and other
in Antibody Drug national key laboratories. The industry has also formed its own internal industry " Antibody Industry Alliance"
Financing and other organizations. The market demand drive, industrial policy support, all for China's antibody industry
development provides a good opportunity.
• The representative domestic enterprises include Baji Shenzhou (Beijing) Biotechnology Company Limited,
Leading Domestic Xinda Biopharmaceutical Company Limited, Shang Hai Hai Mai Biotechnology Company Limited, Suzhou
Kangning Jere Biotechnology Company Limited, Pumis Biotechnology (Zhuhai) Company Limited, Wuhan
Company’s Entering
Youzhi You Biopharmaceutical Company Limited, etc. Due to the strong investment of these pharmaceutical
the Ranks of BsAbs giants, the clinical trials of bispecific antibody drugs have surged, although many of them are in pre-clinical
R&D stage, but with the continuous promotion of clinical trials of these products, the future development potential
of dual anti-drug track is huge.
• Compared to other types of drugs, antibody drugs have a high market conversion rate, and indications are
High Market gradually expanding to other disease areas. In terms of the conversion rate of antibody drugs at various
Conversion Rate stages, clinical phase I has the highest success rate. The current global utilization of antibody capacity is
increasing and clinical capacity is also increasing.
• The high price of antibody drugs guarantees a very high rate of return. In recent years, the national
bioengineering and monoclonal antibody drugs have shown rapid development from R&D pipeline to market
High Return Rate sales performance. Guided by the concept of high investment, high output and high return, major domestic
pharmaceutical companies have increased their investment efforts.

70
Future Trends of Antibody Drugs Market
• In comparison with mAbs marketed abroad, the mAbs have relatively a shorter history in China with less
approved drugs. Therefore the mAbs available in China cover fewer indications. Under this circumstance
Development of New there are extensive unmet clinical demands. With the acceleration of R&D and approval process mAbs will
Targets/ Therapies cover more therapeutic areas that are currently not met, including cardiovascular, ophthalmology, nervous
system, etc. Novel therapies including bispecific antibody (BsAb), heavy chain antibody (HCAb), single-chain
variable fragment (ScFV), single-domain antibody (sdAb), etc..
• Previously the permeability of mAbs in patients was quite low due to its expensive price and not being
included in NRDL. Since 2017 the amount of mAbs that have been approved and included in NRDL has
Increase of increased dramatically, greatly increasing the accessibility of drugs to patients. At the same time, the launch
Penetration of biosimilars has driven the continued growth of the entire biopharmaceutical market, increasing the
accessibility of mAbs to patients. As emergence of biosimilars has also reduced the cost of patients, the
affordability and accessibility of the mAbs will increase its permeability simultaneously.
• To reduce immunogenicity, the developing platforms of mAbs has undergone the process from murine to
chimeric, humanized and fully human. With the rapid development of DNA recombination technology, major
Diversity of Antibody breakthroughs have been made in antibody screening, Fc engineering and other aspects. The diversity of
Drugs antibodies has been greatly enriched, such as BsAb, HCAb and scFv. These diversified structure would be
beneficial to suit respective functional needs. The development of antibodies is gradually developing towards
humanization, functionalization, miniaturization, and specialization.
• Currently most of the share in Chines mAbs market is held by MNCs, domestic monoclonal antibody industry
is still in its starting stage. As domestic companies are focusing on the research of similar targets and the
Value Creation expected targeted indication is close, these will intensity the commercial competition.
Through Innovation • Innovative pipelines which have proven clinical value should distinguish companies in such a competition
environment. Further, innovative mAbs have great opportunities to stand out in the mAbs market mainly
based on the clinical value.
• There is real enthusiasm for the ongoing studies of BsAbs in solid tumors, which are supposed to yield
BsAbs Focus More on promising results in the near future, although translating BsAbs into clinically applicable drugs may be time
Solid Tumors consuming and requires tremendous effort. With the biotechnology advance and new target identification,
therapeutic bi-specific antibodies are a hot field for drug development.

71
Growth Drivers and Future Trends of BsAb Drugs Market
• BiAb could block two signal pathways simultaneously which enhances the synergistic effects of the two. As for
superior cytotoxic effects, there is a lower rate of resistance to BsAb due to the targeting of two different
antigens. This mechanism can reduce tumor cell escape, diminish the side-effects that might be caused by
More Durable
Growth Drivers
mAb, and then improve therapeutic efficacy.

Efficacy • Cancer and other diseases are multifactorial, with many signaling pathways implicated in pathogenesis, so
single-target immunotherapy is not sufficient to eliminate tumor cells. However, BsAbs can potentially increase
binding specificity by interacting with two different cell-surface antigens instead of one, which brings higher
safety and efficacy
Higher Potential • The dual specificity of BsAbs opens up a wide range of applications, including redirecting T cells to tumor cells,
blocking two different signaling pathways simultaneously, dual targeting of different disease mediators, and
for Multiple delivering payloads to targeted sites. The multi-potential feature enables BsAb to serve as the new solution for
Usage incurable diseases.
• The development of BsAbs has long been hampered by manufacturing problems such as product instability,
Development of low expression yields, and immunogenicity. The optimism of BsAbs generating process enables newer
BsAb formats of BsAbs that are more stable, easier to produce, and less immunogenic have been made available.
Manufacturing • Large-scale production and purity are long-term pursuits. Thus, the ideal platform should encompass the
Technologies entire development process from discovery and preclinical studies to clinical material production. Simplifying
the structure and production procedure are the keys when designing a BsAb format.
Future Trends
• Contrary to the success BsAbs in hematological malignancies, the effect of these antibodies in solid tumors is
More still rather limited. The essential hurdles are critical on-target off-tumor binding, sparse T-cell infiltration, and
Investigations quality of tumor-infiltrating lymphocyte (TIL) effector cells due to the presence of an immunosuppressive
in Curing Solid tumor microenvironment (TME). Due to continuous research efforts, more tumor-specific TAAs would become
Tumors available, and combined with constantly evolving technologies allowing conditional masking of BsAbs, and
on-target off-tumor effects should be manageable in the near future.
• Beyond the treatment of tumors, bispecific antibody therapies also serve as an important therapeutic modality
for the treatment of other disease types such as inflammatory diseases. They also have multiple other modes
Expended
of action such as helping macromolecules cross the blood-brain barrier and acting as cofactors to activate
Indications signaling cascade pathways. With more new targets uncovered, this innovative therapeutic modality is
expected to benefit many more patients in the future.
72
Overview of CD3 Targets
• CD3(cluster of differentiator 3) is a protein complex and T-cell co-receptor that is involved in activating both the
cytotoxic T cell(CD8+ naive T cells) and T helper cells(CD4 + naive T cells).
• These chains are associated with the T-cell receptor (TCR) and the CD3-zeta (ζ-chain) which is a homodimer to
generate an important activation signal in T lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together
constitute the TCR complex. The cytoplasmic tail of the TCR is extremely short and it is around three amino acid long
so the other components such as CD3 are needed for an activation.
α β
Extracellular
Intracellular
ε γ ε δ
ζζ
73
Analysis of CD3 and TCR Complex
• Given that the intracellular region of the αβ subunit of TCR is very short and cannot complete the function of signal
transduction independently, the signal transduction of T cells requires a complex formed by CD3 and TCR to complete.
• CD3-BsAbs can employ all available T cells and are not limited to tumor-specific T cells, contrary to the key requirement for
effective immune checkpoint therapy. CD3-targeting bsTCEs require preferably complete suppression of Fc-mediated
effector functions in order to minimized off-target toxicity and to maximize therapeutic efficacy. The affinity for CD3
dramatically affects the biodistribution of bsTCEs and bsTCEs with optimized CD3 affinity could effectively inhibit tumor
distribution in vivo.
• Currently, CD3-BsAbs show great potential for hematological cancers, with the FDA-approved blinatumomab (CD3xCD19)
being successfully used in the clinic to treat some B-cell malignancies. As of August 2021, over 123 different CD3-BsAb
formats are known, which also indicates CD3 is the most selected target in current dual anti-drug development..
TCR
CD3 α β CD3
Whole TCR Complex Structure
ε γ ε δ
ζ ζ
Extracellular
Cytoplasm
Source: The Journal of Cells, Molecules, Systems and Technologies

74
Global Competitive Landscape of CD3 Targeted Antibody Drugs
Global Marketed Drugs
First Posted
Product Drug Name Company Target Drug Type Indication Price (USD)
Date
ELREXFIO Elranatamab Pfizer BCMA, CD3 BsAb MM August 14,2023 NA
Janssen Biotech, Inc. GPRC5D,

TALVEY Talquetamab BsAb MM August 10,2023 NA
Genmab CD3
10mg/ml
TECVAYLI Teclistamab Janssen Biotech, Inc. BCMA, CD3 BsAb MM October 25,2022
3ml; 1,873
100mcg/0.5ml
KIMMTRAK Tebentafusp Immunocore Ltd. GP100, CD3 ADC Uveal Melanoma January 25,2022
0.5ml; 20,257
Source: CDE, Frost & Sullivan Analysis

75
China Competitive Landscape of CD3 Targeted BsAbs
China Pipeline
Highest
First Posted
Product Company Target Indication Clinical
Date
Phase
Advanced gastric cancer with

Catumaxomab Vetter Pharma-Fertigung GmbH＆Co. peritoneal metastasis, Non-muscle
CD3,EpCAM III 2020-07-17
Injection KG, Guangzhou LintonPharm Co., Ltd. invasive bladder cancer with BCG-
failure or BCG--intolerance
F. HOFFMANN-LA ROCHE LTD.,

Relapsed/refractory diffuse large B-
Mosunetuzumab Genentech Inc, Roche(China)Holding CD20, CD3 III 2020-11-09
cell lymphoma
Limited
Teclistamab Johnson & Johnson, Johnson & Johnson
BCMA, CD3 Malignant blood diseases III 2021-11-01
Injection (China) Ltd.
F.Hoffmann-La Roche Ltd, Genentech

Glofitamab CD20, CD3 Follicular lymphoma III 2021-11-02
Inc., Roche Ltd
Pfizer Inc, Pfizer Manufacturing Belgium

PF-06863135 BCMA, CD3 Multiple myeloma III 2021-11-26
NV, Pfizer Investment Co., Ltd.
Pfizer Inc, Pfizer Investment Co., Ltd, Relapsed or refractory multiple

Elranatamab BCMA, CD3 III 2022-05-31
Pharmacia & Upjohn Company LLC. myeloma
Epcoritamab Genmab US, Inc., AbbVie

Concentrated Pharmaceutical Trading (Shanghai) Co., Relapsed or refractory diffuse large
CD20, CD3 III 2022-07-05
Solution for Ltd., Vetter Pharma-Fertigung GmbH & B-cell lymphoma
Injection Co.KG.

76
China Pipeline
Highest First Posted
Product Company Target Indication
Clinical Phase Date
Beijing Tiannuo Jiancheng Relapsed or refractory B-cell non-
CM355 CD20, CD3 II 2021-10-27
Pharmaceutical Technology Co., Ltd. Hodgkinlymphoma
Relapsed or refractory multiple
EMB-06 Injection Shanghai EpimAb Biotherapeutics Co., Ltd. BCMA, CD3 II 2021-11-17
myeloma
Janssen Research & Development, LLC,
CD3, Relapsed or refractory multiple
Talquetamab Johnson & Johnson (CHINA) Investment II 2021-11-17
GPRC5D myeloma
Ltd.
Keymed Biomedical Technology (Chengdu)
CM350 CD3, GPC3 Advanced solid tumor II 2022-02-16
Co., Ltd.
Keymed Biomedical Technology (Chengdu)
CM336 BCMA, CD3 Multiple myeloma II 2022-02-21
Co., Ltd.
Relapsed or refractory B-cell non-
Hodgkinlymphoma
Injectable GB261 Genor Biopharma Co., Ltd. CD20, CD3 II 2022-07-22
Chronic lymphocytic leukemia/Small
lymphocytic lymphoma (CLL/SLL)
REGN1979 Regeneron Pharmaceuticals,Inc., Catalent Relapsed or refractory B-cell non-
CD20, CD3 II 2020-10-10
Injection Indiana, LLC. Hodgkinlymphoma
EGFR positive advanced/metastatic
SMET12 injection Zhejiang CentryMed Pharmaceutical EGFR, CD3 II 2023-05-12
solid tumors
Shanghai Kanda Biotechnology Technology
KD6001 Injection Co.,ltd.|Shanghai Celgen Bio- CTLA4, CD3 Advanced melanoma II 2023-03-20
Pharmaceutical Co.,Ltd.
LBL-033 Injection Nanjing Leads Biolabs Co., Ltd. MUC16,CD3 Malignancy II 2023-03-08
Recurrent/refractory CD20 positive
MBS303 Beijing Mabworks Biotechnology Co.,Ltd CD20, CD3 B-cell Non-Hodgkin's lymphoma with II 2023-02-14
failed standard treatment

77
China Pipeline
Highest Clinical First Posted

Phase Date
M701 Wuhan YZY Biopharma Co., Ltd. CD3, EpCAM Malignant ascites II 2022-12-05
REGN1979 Regeneron Pharmaceuticals,Inc., Catalent Relapsed or refractory B-cell non-

CD20, CD3 II 2020-10-10
Injection Indiana, LLC. Hodgkinlymphoma
Recombinant Anti-
CD19m-CD3 Nutrilite Can Long Medical Relapsed or refractory B - cell
CD19, CD3 I 2019-04-08
Antibody Injection Technology (Shanghai) Co., Ltd. lymphoma
(A-319)
K193 Antibody Relapsed or refractory B-cell non-

Beijing Lvzhu Biological Technology Co., Ltd. CD19, CD3 I 2019-11-18
Injection Hodgkinlymphoma
Recombinant Anti- Relapsed or refractory precursor

Nutrilite Can Long Medical
CD19m-CD3 CD19, CD3 B-cell acute lymphoblastic I 2021-02-26
Technology (Shanghai) Co., Ltd.
Antibody Injection leukemia
Y150 Wuhan YZY Biopharma Co., Ltd. CD38, CD3 Multiple myeloma I 2021-05-28
HER2-positive advanced solid

M802 Wuhan YZY Biopharma Co., Ltd. HER2, CD3 I 2018-07-26
tumors

78
China Pipeline
Clinical Phase Date
Recombinant
humanized bispecific
Shandong New Time Pharmaceutical Relapsed or refractory multiple
antibody against BCMA, CD3 I 2021-06-28
Co., Ltd. myeloma
BCMA/CD3 for
injection
Relapsed or refractory
Guangzhou AI Simai Biomedical
EX103 Injection CD20, CD3 CD20-positive non- I 2021-08-20
Technology Co., Ltd.
Hodgkinlymphoma
Malignant tumour expressed by
Injectable QLS31905 QILU Pharmaceutical Co., Ltd. CD3, CLDN-18.2 I 2021-08-27
Claudin18.2
Guangzhou AI Simai Biomedical HER2-positive advanced solid
EX101 Injection HER2, CD3 I 2021-09-15
Technology Co., Ltd. tumors
Nanjing Shunxin Pharmaceuticals
Injectable TQB2825 Co.,LTD.of Chiatai Tianqing CD20, CD3 Tumors I 2021-11-26
Pharmaceutical Group
IBI389 Innovent Biologics(Suzhou) Co., Ltd. CD3, CLDN-18.2 Advanced malignant tumors I 2021-12-01
Wuxi Zhikang Hongyi Biotechnology Co.,
Injectable BC3448 EGFR, CD3 Advanced solid tumors I 2021-12-23
Ltd.
Chongqing Genrix Biopharmaceutical
Co.,Ltd.,
GR1803 Injection BCMA, CD3 Multiple myeloma I 2022-02-28
Zhixiang (Shanghai) Medical Technology
Co., Ltd.
Relapsed or refractory,
Injectable QLS31904 QILU Pharmaceutical Co., Ltd. CD3, DLL3 unresectable locally advanced or I 2022-07-14
metastatic advanced solid tumors
Recurrent/refractory B-cell Non-
YK012 Injection EXCYTE CD19,CD3 I 2023-02-01
Hodgkin's lymphoma

79
Challenges of CD3-Targeted Bispecific Antibodies Development
• Currently, CD3-BsAbs show great potential for hematological cancers, with the FDA- approved
blinatumomab (CD3xCD19) being successfully used in the clinic to treat some B-cell malignancies. Many
other CD3-BsAbs are being tested in (pre)clinical studies for both hematological and solid tumors.
Limited Effects on Solid
However, contrary to the success of CD3-BsAbs in hematological malignancies, the effect of these
Tumors
antibodies in solid tumors is still rather limited. The observation that CD3-BsAbs seem more efficacious in
hematological malignancies than in solid tumors can be attributed to several challenges that are specific to
solid tumors.
• Over 40% of adult patients treated with blinatumomab show a complete or partial response and median
overall survival is improved by several months compared to standard of care chemotherapy. Unfortunately,
Limited Effectiveness of most patients still relapse eventually after primary response to blinatumomab therapy. These relapses are
BsAbs currently being extensively investigated and the data have thus far indicated that relapses are frequently
found at immune-privileged extramedullary locations and some relapses have lost CD19 antigen
expression, but more research is required to further elucidate these resistance mechanisms
• In the case of hematological cancers, the temporary depletion of B cells or myeloid subsets is reversible,
Risk of On-Target Off- as long as hematopoietic stem cells are not targeted, allowing replenishment of the blood pool. However,
Tumor Toxicities on Solid solid tumor TAAs are often also expressed on tissues of healthy organs, which can lead to immune
Tumors pathology and organ failure with a potential fatality, as shown in a preclinical mouse study using a CD3-
BsAb targeting EGFR. Critical selection of a tumor-specific TAA is thus crucial.
Complex Structural • The biggest challenge to the research and development of CD3 small molecules is the structural
Characteristics of the CD3 characteristics of the CD3 protein. It is difficult for pharmaceutical chemists to design effective compounds
protein with specific binding according to their structure.
• Multiple immunosuppressive cell types, such as cancer-associated fibroblasts, regulatory T cells, and
tumor-associated macrophages, are present in the tumor microenvironment (TME) of solid tumors. This
Low Efficacy under the TME compromises the quality of effector T cells, which reduces the effectiveness of the immunological synapse
of Solid Tumor created by CD3-BsAb. Immune checkpoints also reduce the effector capabilities of tumor-infiltrating
lymphocytes (TILs). Additionally, CD3-BsAbs may cause activation-induced cell death in TILs, which
inhibits a potent anti-tumor response.

80
Future Trends of CD3-Targeted Bispecific Antibodies
Combination of CD3 • A number of clinical and preclinical studies demonstrated that CD3 BsAb treatment increased
BsAbs with Other PD-L1 on tumor and immune cells as well as PD-1 on T cells, at least in part, due to the
Therapies to Reach induction of IFNγ. This suggests that a combination of CD3 BsAb and checkpoint blockade could
Better Treatment improve responses. Indeed, the combination of CD3 BsAbs with checkpoint inhibitors have
Outcomes shown success preclinically and are being explored clinically.
• CD3-BsAb (CD3 Redirected Dual Antibody) is an early entry in the development of dual
antibodies as a typical case of aggregation/localization of immune cells. One of the advantages
Focus More on Solid of CD3-BsAb is that regardless of TCR specificity, the T cell subpopulation (Pan T cell
Tumors population) can be turned into "Effector T Cells", allowing T cells to effectively recognize and kill
tumor cells. Several CD3- BsAb have been successfully used in the clinic for the treatment of
hematologic tumors, and the indications are actively expanding towards solid tumors.
• Cytokine storm (CRS) is one of the most important toxic side effects in both most CD3-BsAb and
CAR-T therapies. Targeting CD3 antigens when tumor cells are in the same environment as a
large number of healthy B and T cells causes T cell activation to proceed abruptly and excessive
release of inflammatory cytokines such as IFN-γ, IL-6 and TNF-α, ultimately leading to symptoms
ranging from fever to multiple organ failure.
Tendency to Mitigate • Further work is required here to understand how dexamethasone may impact T-cell killing in
the Toxicities with New certain circumstances. Additional methods to mitigate toxicity include intra-patient escalation
Strategies (step dosing) and subcutaneous dosing. Step dosing takes advantage of the first dose effect. A
low concentration of BsAb is given first resulting in low levels of cytokine release and this is
followed by increasing amounts of the drug in subsequent doses. The use of step dosing in the
clinic is reasonably new and the step regimens are being determined empirically. A better
understanding of the mechanism of how step dosing ameliorates toxicity is needed to determine
what the best step regimen will be and whether it has any impact on T-cell activation or efficacy.

81
Overview of Malignant Pleural Effusion and Malignant Ascites
• A malignant pleural effusion (MPE) is the build up of fluid and cancer cells that collects between the chest wall and the lung. This can
cause the patient to feel short of breath and/or have chest discomfort. It is a fairly common complication in various different cancers.
• Malignant ascites (MA) is a sign of peritoneal carcinomatosis, the presence of malignant cells in the peritoneal cavity. Malignant ascites
may be associated with a variety of neoplasms including, ovarian, breast, gastric, lung, pancreatic and cancers.
Causes
Pathogenesis of MPE and MA MPE MA
• Malignant cells can enter the pleural space via the hematogenous, direct or lymphatic Ovarian
Lung Cancer Cancer
spread. Direct tumor involvement of pleura can lead to a pleural fluid accumulation by
increasingly producing the liquid and thus influencing the normal parietal pleural lymphatic Hepatocellular
functioning. Tumor may extensively infiltrate pleural capillaries, leading to increased Carcinoma
filtration, or may produce different cytokines that increase capillary permeability, while Breast
decreased plasma osmotic pressure or decreased pleural pressure can contribute to the Cancer Pancreatic
enhanced entry of liquid as well. Cancer
• On the other hand, tumor growth infiltrating the draining lymphatics or lymph nodes may Gastric
Lymphoma
block the lymphatic drainage thus decreasing the absorbtion rate of pleural fluid, with the Cancer
Cancer
subsequent accumulation of fluid in the pleural space, while different extrinsic factors
including limited respiratory mobility, mechanical compression of lymphatics with blockage Esophageal
of their stomata, may be responsible in the cases when lymphatics activity is significantly Cancer
Ovarian
disturbed, but not due to direct damage of the vessels. Cancer
• Malignant ascites originates from an imbalance between fluid secretion and absorption by Colorectal
peritoneum. This is secondary to increased fluid production by tumor cells lining peritoneal Cancer
cavity in cases of peritoneal carcinomatosis (PC), alteration in vascular permeability, Gastric Breast
release of inflammatory cytokines and decreased lymphatic drainage due to tumor Cancer Cancer
involvement and increased portal pressure due to tumor metastasis.
Shortness of Chest pain or Cough and Progressive Lower extremity

breath pressure respiratory stress dyspnoea Dyspnea Weight gain
edema
Symptoms of MPE Symptoms of MA
Source: American Thoracic Society, AME Medical Journal, An International Journal of Medicine, Experimental and Therapeutic Medicine, The Eurasian Journal of Medicine
82
Treatment Paradiam of Malignant Pleural Effusion and Malignant
Ascites
• Malignant pleural effusion and malignant ascites is a complication of cancer. It‘s official treatment cannot be divided into first line, second line and third line
treatment like cancer.
• There are no approved drugs for the treatment of malignant pleural effusion and malignant ascites by the Chinese and US FDA, and no drug guidelines that can
guide oncologists for the treatment of malignant pleural effusion and malignant ascites have been issued by the NCCN, ASCO, CMA, CSCO. Clinical palliative
treatment such as puncture and drainage is the main treatment, but there are also some research based clinical data and expert consensus recommending the
use of intraperitoneal injection of chemotherapeutic drugs or anti-vascular production drugs, intraperitoneal thermal perfusion and other therapies.
• After completing the registered clinical trial, M701 will obtain approval from the drug regulatory department for the treatment of malignant pleural effusion and
malignant ascites, which means it will be able to compete with all current therapies. When a drug’s listing requires approval through registered clinical trials,
usually it is necessary to compare certain evidence-based medical evidence before the drug can be included in the guidelines.
Treatment Paradigm of MPE

Thoracentesis Pleurodesis Indwelling Pleural Catheter (IPC)
• This device is a small catheter that is placed
• This is a procedure where medical • This is a procedure where a chemical is instilled
under the skin and into the pleural fluid, which
oncologists and radiation oncologists may into the chest cavity after the pleural fluid has been
allows repeated drainage at home to relieve
treat the underlying cancer with drained to help get the lung to stick up to the chest
symptoms. These catheters are placed using
chemotherapy, immunotherapy and/or wall and reduce the risk of new build-up of fluid.
local anesthesia as an outpatient procedure.
radiation to prevent the fluid from This procedure can be done either by placing a
The catheter may help allow the lung to
accumulating. The pulmonologist or thoracic small catheter between the ribs into the fluid and
eventually expand fully up to the chest wall.
surgeon will work to remove the fluid and/or instilling a chemical through the tube or by
Once the fluid build-up resolves, the catheter
prevent it from re-accumulating with the goal thoracoscopy and spraying the chemical onto the
can be removed in many patients after 2-3
of keeping the patient from respiratory stress. inside of the chest wall in the pleural space.
months.
Treatment Paradigm of MA
Hyperthermic Intraperitoneal
Conventional Management Newer modalities
Chemotherapy
• Rationale behind this procedure includes
•
Therapeutic paracentesis can be used for rapid • Antibodies against cellular adhesions molecules
cytoreduction with prolonged contact on tumor
symptom control. Large volume paracentesis like Epilthelial cell adhesion molecule (EpCAM)
nodules, selective cytotoxicity due to protein
(upto 5 litre) can be done without undue like Catumaxomab after therapeutic
denaturation, impaired DNA repair due to
complications. paracentesis are associated with prolonged
hyperthermia and hyperthermia induced
• Peritoneovenous shunts are recommended if paracentesis-free survival, improved quality of
Note: eCTD = electronic common technical document vasodilatation with improvement in tumor
life expectancy is more than 3 months. life and prolonged overall survival
oxygenation.
Source: CMA, Biospace, The Oncology Nurse

83
China Incidence of Malignant Pleural Effusion, 2018-2030E
• The most common etiologies for malignant pleural effusion (MPE) are lung caner, breast cancer, lymphoma, ovarian
cancer and gastric cancer, in order of decreasing frequency. Around 45% of people with lung cancer develop a pleural
effusion at some point during the course of their cancer; about 2% to 11% of patients with breast cancer developing
MPEs; 41.6% of people with lymphoblastic lymphoma and 7% of those who suffer from ovarian cancer are diagnosed
with MPE during the courses. And 2% of patients with gastric cancer will have MPE.
• The incidence of MPE in China has grown from 553.06 thousand in 2018 to 624.08 thousand in 2022, representing a
CAGR of 3.8%. It is expected that the prevalence will increase to 699.43 thousand in 2026, and 775.43 thousand in
2030, at a CAGR of 2.2% and 2.6%, from 2022 to 2026 and from 2026 to 2030, respectively.
Incidence of Malignant Pleural Effusion, 2018-2030E

Period CAGR
2018-2022 3.8%
2022-2026E 2.2%
2026E-2030E 2.6%
Thousand
756.7 775.4
718.5 737.7
680.4 699.4
642.7 661.5
605.6 624.1
570.0 587.7
553.1
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: NCCR, Medicine, 2020, 99(39)., Journal of ethnopharmacology, 2020, 249: 112412, Journal of Practical Oncology 2021, 36(01): 89-94, Frost & Sullivan
Analysis 84
China Market Size of Malignant Pleural Effusion Therapies, 2018-
2030E
• In 2018, the market size of Malignant Pleural Effusion Therapies reached 10.9 billion RMB, and reached 11.7 billion
RMB in 2022 with a CAGR of 1.7%. It is predicted that the number will continue to grow, and reach 13.5 billion RMB by
the year of 2026, 15.1 billion RMB by the year of 2030, with CAGR of 3.7% and 2.7% respectively.
China Market Size of Malignant Pleural Effusion Therapies, 2018-2030E
Period CAGR
2018-2022 1.7%
2022-2026E 3.7%
2026E-2030E 2.7%
Billion RMB
14.5 14.9 15.1

13.5 14.0
12.1 13.0
11.1 11.4 11.6 11.7 11.9
10.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: Annual Reports of Listed Medical Companies, NCCR, MOHRSS, Medicine, 2020, 99(39)., Journal of ethnopharmacology, 2020, 249: 112412, Journal of
Practical Oncology 2021, 36(01): 89-94, Frost & Sullivan Analysis
85
China Incidence of Malignant Ascites, 2018-2030E
• The most common etiologies for malignant ascites (MA) are ovarian caner, hepatocellular carcinoma (HCC), pancreatic
cancer, gastric cancer, esophageal cancer, colorectal cancer and breast cancer, in order of decreasing frequency.
Ovarian cancer had the highest proportion of patients who developed ascites at 45%, followed by HCC (25%),
pancreatic cancer (21%), gastric cancer (25%), esophageal cancer (4.0%), colorectal cancer (3.7%), and breast cancer
(3.0%).
• The incidence of MA in China has grown from 547.61 thousand in 2018 to 606.87 thousand in 2022, representing a
CAGR of 2.6%. It is expected that the prevalence will increase to 667.21 thousand in 2026, and 726.60 thousand in
2030, at a CAGR of 2.4% and 2.2%, from 2022 to 2026 and from 2026 to 2030, respectively.
Incidence of Malignant Ascites, 2018-2030E

Period CAGR
2018-2022 2.6%
2022-2026E 2.4%
2026E-2030E 2.2%
Thousand
682.6 697.7 712.5 726.6

621.9 636.8 651.7 667.2
562.1 576.9 591.8 606.9
547.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: NCCR, Practical Pharmacy and Clinical Remedies. 2020,23(10):905-908., Chinese Journal of Gastroenterology and Hepatology. 2017, Hepatology
International. 2013 Mar;7(1):188-198., 26(04):476-478., Frost & Sullivan Analysis
86
China Market Size of Malignant AscitesTherapies, 2018-2030E
• In 2018, the market size of Malignant Ascites Therapies reached 9.9 billion RMB, and reached 10.8 billion RMB in 2022
with a CAGR of 2.3%. It is predicted that the number will continue to grow, and reach 12.6 billion RMB by the year of
2026, 14.4 billion RMB by the year of 2030, with CAGR of 3.9% and 3.3% respectively.
China Market Size of Malignant Ascites Therapies, 2018-2030E
Period CAGR
2018-2022 2.3%
2022-2026E 3.9%
2026E-2030E 3.3%
Billion RMB
13.7 14.0 14.4

12.6 13.2
11.3 12.0
10.1 10.4 10.7 10.8 11.0
9.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: Annual Reports of Listed Medical Companies, NCCR, MOHRSS, Practical Pharmacy and Clinical Remedies. 2020,23(10):905-908., Chinese Journal
of Gastroenterology and Hepatology. 2017, Hepatology International. 2013 Mar;7(1):188-198., 26(04):476-478., Frost & Sullivan Analysis
87
Overview of Drugs for Malignant Pleural Effusion and Malignant
Ascites
• To date, fewer common international guidelines recommend the use of anti-tumor medical treatment prior to standard palliative procedures for the management
of Malignant Pleural Effusion (MPE) and Malignant Ascites (MA). Nowadays marketed drugs (e.g., drugs used in chemotherapy, targeted therapy, and/or
immunotherapy) are mainly used in systemic and local therapy for MPE and MA, with the core ideas of curing primary tumors in early-stage patients or
symptom relief in advanced cancer patients. Since massive ascites and pleural effusion, in particular, are frequently associated with malignancies in several
organs that have an extremely poor prognosis, patients in this advanced situation hardly benefit from marketed drugs. However, several innovative "Wonder
drugs" specific to MPE and MA are being developed now, which can target primary and secondary tumors simultaneously with minimal by-effect and promise
higher efficacy and safety.
Marketed Medicines for Systemic Therapy and Local Therapy

Systemic Therapy Local Therapy
• When the causes of MPE or MA are clear, • Local therapy of MA and MPE is commonly used for patients with advanced cancer and developed
chemotherapy, targeted therapy, and/or resistance to multiple drugs. Medicines are directly used in the thoracic or abdominal cavity after
immunotherapy medicines are systemically chest piercing or abdominal paracentesis, which brings higher drug concentration and better targeting.
used to suppress the primary tumors while
• Except for the same medicines used in systemic therapy, other drugs like recombinant human
reducing ascites or pleural effusion.
adenovirus type 5 Injection, and immunopotentiators like thymopentin are used for pleurodesis in local
• Systemic therapy is the first option when MA therapy. Treatment rate of local therapy for MPE and MA is over 90%.
and MPE are diagnosed in the first line of
• One cycle of hyperthermic intraperitoneal chemotherapy(HIPEC) costs around 15,000 ~ 30,000 RMB
cancer treatment.
Targeted Therapy Chemotherapy Immunotherapy

• Recombinant human endostatin • Carboplatin • Recombinant Human Tumor Necrosis Factor
• Bevacizumab • Cisplatin
• Pemetrexed Disodium • Staphylococcal Enterotoxin C
• Camrelizumab • Bleomycin
• Oxaliplatin • Recombinant Human Interleukin-2
• Toripalimab • Epirubicin
(Present Commonly • Lentinan
(Present Commonly Used Ones) • Etoposide
Used Ones) (Present Commonly Used Ones)
• Docetaxel
Developing Innovative Medicines Specific to MPE and MA
• Innovative medicines specific to MPE and MA denote drugs with MPA and/or MA approved adaptations that function as targeted therapy and/or
immunotherapy. Medicines specific to MPE and MA can inhibit the progression of various tumors and relieve MPE and MA symptoms by blocking universal
and essential supports for tumor metastasis like angiogenesis or targeting biomarkers on spread-expressed various tumors and enhancing an immune
reaction on tumor cells. At present, there are two innovative drugs specific to MPE and MA is under development globally.
Source: Annals of the American Thoracic Society, Biospace, The Oncology Nurse
88
Competitive Landscape of Malignant Pleural Effusion and Malignant
Ascites Drugs
Global Pipeline
First Posted
Product Company Target Drug Type Indication Highest Clinical Phase
Date
Approved in 2009,
withdrew from
France, market in 2017,
TRION Pharma GmbH Cancer,
Germany, applied for
Catumaxomab and CD3, EpCAM BsAb Neoplasms, -
Italy, renewal of the
Neovii Biotech GmbH Carcinoma, MA
Spain marketing
authorization
in 2022
Jiangsu Simcere Bio- Other MPE, Malignant

ENDOSTARTM Endostatin China III 2021/5/27
Pharmaceutical Co.,Ltd. protein Peritoneal Effusion
Wuhan YZY Biopharma

M701 CD3, EpCAM BsAb MA Global II 2021/7/23
Co., Ltd.
Wuhan YZY Biopharma
M701 CD3, EpCAM BsAb MPE China Phase Ib/II 2022/9/14
Co., Ltd.
Note:
• “Global First Posted Date" indicates the date when the study corresponding to the global highest clinical phase(except China) was first
available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded.
• “China First Posted Date” indicates the date when the study corresponding to the highest clinical phase in China was first available on
chinadrugtrials.org.cn after Center for Drug Evaluation（CDE）review has concluded. Center for Drug Evaluation（CDE）is an affiliated
institution of National Medical Products Administration(NMPA).
Source: NMPA, CDE, FDA, Frost & Sullivan Analysis

89
Competitive Landscape of Malignant Pleural Effusion and Malignant
Ascites Drugs
Global Pipeline
First Posted
Product Company Target Drug Type Indication Highest Clinical Phase
Date
MA, Stomach
Gaia BioMedicine
Cell Neoplasms, Pancreatic
GAIA-102 Inc; Kyushu University - Japan II 2021/11/19
Therapy Neoplasms, Carcinoma,
Hospital
NSCLC
MPE, Malignant Pleural

Mesothelioma, United
RSO-102 RS Oncology LLC - Polypeptide I/II 2022/02/07
Mesothelioma, Solid Kingdom
Tumor
Wuhan Binhui
MPE, Malignant
VAK Biotechnology Co., - Cell Therapy China I 2022/09/29
Peritoneal Effusion
Ltd.
IFN-γ and CIK cells,
Affiliated Hospital of
Tcm cells or CAR-T - Cell Therapy MPE China I 2022/03/07
Jiangnan University
cells

90
Unmet Needs of Malignant Pleural Effusion and Malignant Ascites
Treatment
Unmet Needs
• In most MPE patients, disease is not curable, and the aim of treatment is mainly palliative. MPE is an aggressive
disease with a uniformly fatal prognosis and a life expectancy of only 3 to 12 months. The development of an
effective targeted therapy represents a pressing unmet need.
Most Current
• Most of current drugs for MA and MPE can only relieve symptoms but are seldomly effective in increasing the
Treatments are
survival rate. Among marketed drug, the innovative ones with MPA and/or MA as approved adaptations are rare.
Palliative Besides, the efficacy of marketed drugs are unstable with high recurrence after treatment.
• Newer modalities of MA treatment, including cytokines like interferon alpha, interleukin 2 and tumor necrosis factor,
still need to be validated in further large-scale clinical trials.
• The guidelines for malignant ascites are quite rare at present. In addition, relevant studies showed significant
Lacking of heterogeneity existing in the quality, recommendations, and level of evidence among different treatment guidelines,
Common and even within the same guidelines.
Guidelines for • The main reasons for the variances among these guidelines are the different emphases of the guidelines,
Treatment contradicting recommendations and unreasonably cited evidence.
• Different guidelines have completely different emphases on the management of malignant ascites.
Disadvantages of • Medical therapy, primarily paracentesis and diuretics, are first-line treatments in managing MA. Each of them has
Current Treatments significant short comes. Paracentesis is widely adopted but it is associated with significant patient discomfort and
several risks. Diuretic therapy is effective at the very beginning of the disease but efficacy declines with tumor
are Obvious and
progression. There are no randomized controlled trials assessing their real efficacy in reducing ascites and
Mechanism of symptoms.
Treatment is • Intraperitoneal chemotherapy, targeted therapy, immunotherapy and radioisotopes are promising medical options
Blurred but their clinical application is not yet completely elucidated, and further investigations and trials are necessary.
91
Future Trends and Unmet Needs of Malignant Pleural Effusion and
Malignant Ascites Treatment
Future Trends
• The current movement toward personalized medicine includes development of biomarkers as diagnostic and
Development of monitoring tools. This trend has extended to potential biomarkers of malignancy, among them circulating tumor DNA
biomarkers as (ctDNA). The entry of ctDNA into the bloodstream is presumed to occur by way of tumor necrosis or apoptosis, and
it is anticipated that its detection may lead to the future development of a so-called, ctDNA may therefore become a
diagnostic and
helpful blood-based adjunct in the evaluation of a patient with an undliquid biopsy. It is doubtful, however, that its
monitoring tools use would preclude invasive sampling in cases of suspected pleural malignancy. Notably, the definition of a “liquid
for MPE biopsy” could be extended to PF such that soluble tumor-derived biomarkers may be part of the future of MPE
diagnostics.
• Several prominent companies have invested in research and development to find innovative treatments for
Research and malignant pleural effusion. For instance, Novartis Pharmaceuticals studying effects of “zometa” as adjuvant
innovation will treatment of malignant pleural effusion due to non-small cell lung cancer, Advantagene, Inc. in collaboration with
prestigious University of Pennsylvania is developing intrapleural “AdV-tk” therapy in patients with malignant pleural
contribute to a
effusion, Jiangsu Simcere Pharmaceutical Co., Ltd evaluating usage of endostar and cisplatin for treatment of
more effective and malignant pleural effusion.
cost-effective • The innovative medicines specific to MPE and MA are under developing, by blocking universal and essential
treatment supports for tumor metastasis and releasing MPE and MA symptoms, these new drugs could become one of the
most successful ways to treat MPE and MA in the future.
Treatment will focus • Several research studies reviewed patients’ quality of life based on the type of MPE treatment. These studies found
more on patient that patients were more satisfied when they had a TPC; their symptoms were relieved and they were able to care for
outcomes and the catheter at home, increasing their quality of life. Research is also looking at the outcomes of relieving shortness
quality of life of breath, pain, and other symptoms and how those outcomes for patients are being met.
Unmet Needs of MPE and MA Treatment
92
Overview of EpCAM
• The EpCAM gene provides instructions for making a protein known as epithelial cellular adhesion molecule (EpCAM).
This protein is found in epithelial cells, which are the cells that line the surfaces and cavities of the body. The EpCAM
protein is found spanning the membrane that surrounds epithelial cells, where it helps cells stick to one another (cell
adhesion).
Extracellular
Tetraspanin-enriched microdomain EpEX Proteolysis
E-Cadherin
ADAM17
1
β-catenin
CD9 CO-029 α-catenin

Claudin-7 2
EpCAM CD44v6 ү-secretase
ADAM10
EpICD Actin
Regulation of cell-
Promotion of tumorigenicity; cell proliferation; survival
Intracellular cell adhesion

93
Mechanisms and Advantages of CD3×EpCAM in MPE and MA
Treatment
CD3×EpCAM BsAbs has dual effects on proliferation and cytokine secretion of immune cells in MA and MPE.
• The spread of infiltrating tumor

• CD3 x EpCAM BsAbs could induce
cells into the peritoneal cavity
a simultaneous activation of
• EpCAM binds with tumor cells while is the main cause of abnormal
different immune cell types at the
Mechanism
CD3 binds with T cells, which accumulation of body fluids in

tumor site and then results in an
induces a simultaneous activation of the abdominal cavity.
effective destruction of tumor cells.
different immune cell types at the Therefore, direct attack on
• Compared with EpCAM mAb or
tumor site and then results in an these infiltrating tumor cells
CD3 mAb, T cells are significantly
effective destruction of tumor cells. should be effective in relieving
redirected to tumor cells by
• The CD3×EpCAM BsAb eliminates MA symptoms.
CD3×EpCAM BsAb and
the tumor cells with high EpCAM • Similarly, direct killing of tumor
CD3×EpCAM BsAb efficiently
expression level, activates T cells cells on the pleura can reduce
activates T cells, resulting in
and induces T cells redirected to the compression of lymphatic
increased CD69 and CD25
tumor cells in vitro and in vivo. vessels and blood vessels,
expression on CD8+ and CD4+ T
which in turn alleviates MPE
cells
symptoms.
The advantage of CD3×EpCAM in MPE and MA treatment lies in its effectiveness.
• Tumor cells in malignant effusions express EpCAM in 70%–100% of those cases that commonly cause malignant ascites, e.g.
ovarian, gastric, breast and colorectal cancer. This indicates that EpCAM is an attractive target for antibody therapy.
Advantages
• Within the peritoneal cavity, EpCAM expression is tumor-specific because normal cells in the peritoneal compartment are of
mesothelial origin and do not express EpCAM on their surface
• When compared with popular treatment methods, the use of CD3×EpCAM requires less hospital stay time and less
complications. In patients treated with chemical pleurodesis, a mean hospital stay of 2.33 days, complication rates of 16.5% and
mean survival length of 23.8±16.3 months were observed. Though adverse effects from the use of CD3×EpCAM include
nausea, vomiting, abdominal pain, pyrexia, and skin reactions, most of these effects occurred on the day of or the day after
infusion and were fully reversible.
• The harnessing of the immune system suggests that this antibody may not only be effective for advanced disease but may also
be beneficial for patients with earlier stages of disease.
Source: Medicina, 2019, 55(8): 490., Cellular and Molecular Life Sciences, 2018, 75(3): 509-525., Cancer treatment reviews, 2010, 36(6): 458-467., International
journal of cancer, 2014, 135(11): 2623-2632., Blood, The Journal of the American Society of Hematology, 2001, 98(8): 2526-2534., Frost & Sullivan Analysis
94
Overview of Multiple Myeloma
• Multiple Myeloma (MM) is a cancer of the plasma cells in the bone marrow. Plasma cells are antibody-producing white
blood cells that are critical to the immune system. Myeloma begins when healthy plasma cells become cancerous and
grow out of control. MM often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or
pathologic fractures.
• Multiple myeloma can be subdivided into hyperdiploid MM (h-MM) and non-hyperdiploid MM (nh-MM) based on their
aneuploidy status, and the two subtypes have different prognosis and survival outcomes. Patients with hyperdiploid
multiple myeloma tend to have a better prognosis than those with non-hyperdiploid subtype.
Risk Factors
Subtypes of Multiple Myeloma
Increasing Age
hyperdiploid (h-MM) non-hyperdiploid (nh-MM)
Sex
• Encompasses hypodiploid, pseudopiploid,
• Characterized by trisomies
and near tetraploid MM
• More indolent form of disease Race
• More aggressive form of the disease with
• Tendency toward more favorable outcome
a worse prognosis
• Slightly more common among males
• Prevalent among younger patients
• More common in the elderly Family History
• Can be further divided into subtypes based
• Higher incidence of MM bone disease
on genetic translocation
Workplace exposures
Obesity
High blood levels of Nervous system
Bone pain Low blood counts
calcium symptoms
Other plasma cell
diseases
Symptoms of MM
Source: American Cancer Society, International Myeloma Foundation, Frost & Sullivan Analysis
95
China Incidence of Multiple Myeloma, 2018-2030E
• Multiple myeloma (MM) is an uncommon malignancy in persons younger than 40 years and the median age of patients
diagnosed with multiple myeloma is approximately 70 years old globally. The number of aging population is growing at a
fairly fast pace and is expected to continue its growth momentum into the future.
• The incidence of MM in China has grown from 20.1 thousand in 2018 to 22.4 thousand in 2022, representing a CAGR of
2.8%. It is expected that the prevalence will increase to 25.0 thousand in 2026, and 27.6 thousand in 2030, at a CAGR
of 2.8% and 2.5%, from 2022 to 2026 and from 2026 to 2030, respectively.
Incidence of Multiple Myeloma, 2018-2030E

Period CAGR
2018-2022 2.8%
2022-2026E 2.8%
2026E-2030E 2.5%
Thousand
26.3 27.0 27.6

24.4 25.0 25.7
22.4 23.0 23.7
20.7 21.1 21.7
20.1
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

96
China Market Size of Multiple Myeloma Therapies, 2018-2030E
• In 2018, the market size of Multiple Myeloma Therapies reached 4.2 billion RMB, and reached 7.8 billion RMB in 2022
China Market Size of Multiple Myeloma Therapies, 2018-2030E
Period CAGR
2018-2022 17.0%
2022-2026E 22.4%
2026E-2030E 11.7%
Billion RMB
27.4
25.1
22.9
20.2
17.6
14.8
12.3
9.9
7.1 7.4 7.8
4.2 5.7
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: Annual Reports of Listed Medical Companies, NCCR, MOHRSS, Frost & Sullivan Analysis
97
Treatment Paradigm of Multiple Myeloma in China
• Multiple myeloma (MM) is a malignant disease with abnormal proliferation of cloned plasma cell. In many countries, MM
is the second most common malignant tumor in the blood system. It occurs in the elderly and is still incurable.
Multiple Myeloma primary diagnosis

If suitable for stem cell transplantation If not suitable for stem cell transplantation
Autologous hematopoietic stem cell transplantation

Induction therapy+consolidation
(ASCT) after induction therapy ± consolidation
Initial chemotherapy+maintenance therapy
chemotherapy+maintenance therapy
Treatment
The treatment goal is to achieve maximum relief and extend the

progression free survival (PFS) period.
First and • Combination of 3-4 drugs containing proteasome inhibitors

Second (caffezomil, isazomil, bortezomib), immune modulators (pomadol,
Recurrence lenalidomide), daretozumab, and nuclear output protein inhibitors
(serenixol) Salvage ASCT (for those who have achieved PR or
above efficacy again and have frozen autologous stem cells)
The main treatment goal is to improve the patient's quality of life,

Third and and on this basis, to achieve the maximum possible relief.
after
Recurrence Consideration should be given to the use of 2-4 drug combination
chemotherapy containing proteasome inhibitors, immunomodulators,
anti-CD38 antibody, nuclear output protein inhibitors, cytotoxic drugs,
etc.
CAR-T Dexamethasone/thalidomide/cisplatin/dox autologous or allogeneic Dexamethasone/cyclophosphami

(clinical trials, researchers orubicin/cyclophosphamide/ hematopoietic stem cell de/etoposide/cisplatin ±
initiated studies) etoposide ± Bortezomib (dT PACE ± V) transplantation bortezomib (dCEP ± V)
Source: CMDA, Frost & Sullivan analysis
98
Treatment Paradigm of Multiple Myeloma in the U.S.
Multiple Myeloma
For Transplant patients For Non-transplant Patients Maintenance Therapy

Preferred Options Preferred Options Preferred Options
• Bortezomib, dexamethasone, lenalidomide • Bortezomib, lenalidomide, dexamethasone, • Lenalidomide
First • Bortezomib, cyclophosphamide, dexamethasone • Daratumumab, lenalidomide, dexamethasone Other Options
Line Other Options • Lenalidomide, low-dose dexamethasone • Ixazomib
• Carfilzomib, lenalidomide, dexamethasone • Bortezomib, cyclosphosphamide, dexamethasone • Bortezomib
• Ixazomib, lenalidomide, dexamethasone Other Options Useful Under Certain Circumstances
Useful Under Certain Circumstances • Carfilzomib, lenalidomide, dexamethasone • Bortezomib,lenalidomide
• Bortezomib, doxorubicin, dexamethasone, • Ixazomib, lenalidomide, dexamethasone
• Carfilzomib, cyclosphosphamide, dexamethasone • Daratumumab, bortezomib, melphalan, prednisone
• Ixazomib, cyclosphosphamide, dexamethasone Useful Under Certain Circumstances
• Bortezomib, thalidomide, dexamethasone • Bortezomib, dexamethasone
• Cyclosphosphamide, lenalidomide, dexamethasone • Cyclosphosphamide, lenalidomide, dexamethasone
• Dexamethasone,thalidomide,cisplatin,doxorubicin,cyclop • Carfilzomib, cyclosphosphamide, dexamethasone
hosphamide,etoposide,bortezomib
Disease
Progression
Preferred Options Other Options for Previously Treated MM Useful for Some Patients
• Bortezomib, lenalidomide, • Bendamustine
dexamethasone • Bendamustine, bortezomib, dexamethasone • Elotuzumab, bortezomib, dexamethasone • Carfilzomib,
• Carfilzomib(twice • Bendamustine, lenalidomide, dexamethasone • Elotuzumab, pomalidomide, dexamethasone cyclophosphamide,
weekly),dexamethasone • Bortezomib, liposomal doxorubicin, • Ixazomib, cyclophosphamide, dexamethasone thalidomide, dexamethasone
• Carfilzomib(weekly),dexamet dexamethasone • Ixazomib, dexamethasone • Dexamethasone,
hasone • Bortezomib, cyclophosphamide, • Ixazomib, pomalidomide, dexamethasone cyclophosphamide, etoposide,
• Carfilzomib, lenalidomide, dexamethasone • Lenalidomide, dexamethasone cisplatin(DCEP)
Second •
dexamethasone • Carfilzomib, cyclophosphamide, • Panobinostat, bortezomib, dexamethasone Dexamethasone, thalidomide,
Line • Daratumumab, bortezomib, dexamethasone • Panobinostat, carfilzomib cisplatin, doxorubicin,
dexamethasone • Cyclophosphamide, enalidomide, • Panobinostat, lenalidomide, dexamethasone cyclophosphamide, etoposide
• Daratumumab, lenalidomide, dexamethasone • Pomalidomide, cyclophosphamide, (DT-PACE) ±
dexamethasone • Bortezomib, dexamethasone dexamethasone bortezomib(VTD-PACE)
• Elotuzumab, lenalidomide, • Daratumumab • Pomalidomide, dexamethasone • High-dose cyclophosphamide
dexamethasone • Daratumumab, cyclophosphamide, • Pomalidomide, bortezomib, dexamethasone • Selinexor, dexamethasone
• Ixazomib, lenalidomide, dexamethasone • Pomalidomide, carfilzomib, dexamethasone
dexamethasone • Daratumumab, pomalidomide, dexamethasone
Comma “,” = “in combination with”; Brackets “()” = “may or may not be needed”; Slash “/” = “or”
Source: NCCN, Frost & Sullivan Analysis
99
Comparison of Treatment Paradigms of Multiple Myeloma
• The treatment paradigms in China and the U.S. are composed of similar drugs but with varying combinations. The medicines used in
combination therapies will be determined by patient’s age, disease risk factors, and performance status.
Suggested Treatment Regimens in China Preferred Treatment Regimens in the US

• Bortezomib, dexamethasone
• Lenalidomide, dexamethasone
• Lenalidomide, bortezomib, dexamethasone
Primary therapy for • Bortezomib, doxorubicin, dexamethasone
• Bortezomib, dexamethasone, lenalidomide
transplant • Bortezomib, cyclophosphamide, dexamethasone
• Bortezomib, cyclophosphamide, dexamethasone
candidates • Bortezomib, thalidomide, dexamethasone
• Thalidomide, doxorubicin, dexamethasone
• Thalidomide, cyclophosphamide, dexamethasone
• Lenalidomide, cyclophosphamide, dexamethasone
• Same therapy as transfer candidates • Bortezomib, lenalidomide, dexamethasone,

Primary therapy for
• Melphalan, prednisone, bortezomib • Daratumumab, lenalidomide, dexamethasone
non-transplant
• Melphalan, prednisone, thalidomide • Lenalidomide, low-dose dexamethasone
candidates • Melphalan, prednisone, lenalidomide • Bortezomib, cyclosphosphamide, dexamethasone
Maintenance • Lenalidomide/bortezomib/ixazomib/thalidomide alone, or combined

• Lenalidomide
therapy with glucocorticoids.
• Ixazomib, lenalidomide, dexamethasone

• Daratumumab, lenalidomide, dexamethasone • Bortezomib, lenalidomide, dexamethasone
• Daratumumab, bortezomib, dexamethasone • Carfilzomib(twice weekly),dexamethasone
• Daratumumab, ixazomib, dexamethasone • Carfilzomib(weekly),dexamethasone
• Dexamethasone, cyclophosphamide, • Carfilzomib, lenalidomide, dexamethasone
Relapsed MM
etoposide,cisplatin±bortezomib • Daratumumab, bortezomib, dexamethasone
• Dexamethasone, thalidomide, cisplatin, doxorubicin, • Daratumumab, lenalidomide, dexamethasone
cyclophosphamide, etoposide±bortezomib • Elotuzumab, lenalidomide, dexamethasone
• Allogenic stem cell transplant (Allo-SCT), Autologous stem cell • Ixazomib, lenalidomide, dexamethasone
transplantation (Auto-SCT)
• CAR T**
Emerging Therapies • CAR T**
• BiTE**
**Mentioned in guideline

100
Unmet Needs of Multiple Myeloma Treatment
• The 5-year survival rate of MM is only 35.0%. The prognosis of an MM patient is very heterogeneous and is
subject to various factors, such as genetics, performance status and stage of disease, which in turn determine
the treatment and management of the disease. Current treatment regimens can prolong patient survival;
however, MM remains incurable and patients will eventually relapse and succumb to their disease. As a result,
patients may require continuous treatment in order to manage MM as a chronic disease and regimens with
convenient administration that can provide the convenience of outpatient treatment. Existing treatment options
Feature of “incurable” with different mechanisms of action are usually exhausted early on in the treatment, as patients are treated with
will eventually cause doublet and triplet combination regimens in early treatment lines. Therefore, new classes of therapy with novel
disease recurrence mechanisms of action are required for patients that relapse or are refractory to the current classes of drugs.
There are a few new classes of MM therapy, for example, the BCMA ADC, which could reach an ORR of 31%
as a third or later line treatment, and 73% of the patients who responded to the treatment continued to respond
at month six, and SINE inhibitors such as selinexor. However, such new classes of MM therapies may not be
able to completely cure MM. With about 16.2 thousand and 117.1 thousand deaths expected to be caused by
MM in China and globally in 2020, respectively, there remains a significant unmet need for therapies for
patients whose disease has relapsed after, or is refractory to, available MM therapies.
• Treatment for MM is costly. For example, the price of daratumumab, an anti-CD38 target therapy, could be as
high as $617 per 5 milliliter dose and patients need frequent administration of daratumumab to manage MM as
a chronic disease. Overall, daratumumab alone costs approximately US$134.5 thousand annual for each MM
patient. In addition, as anti-CD38 target therapy usually needs to be combined with other therapeutics, the total
Lower drug treatment cost for MM may be significantly higher. For example, a combination therapy of daratumumab,
accessibility and lenalidomide and dexamethasone would cost an additional US$53.8 thousand each year. Beyond direct costs
significant Cost of associated with therapeutics, MM patients, or the healthcare system as the case may be, also need to pay for
treatment hospitalization, which could cost US$20.8 thousand for single stay. Generally, MM patients need to incur
hospitalization costs for each treatment cycle that could be as frequent as once every month. In addition,
treatment cost of MM also include other expensive supporting therapies, such as bisphosphonate for the MM-
related bone disease and dialysis for possible renal failure which might add to the total cost for each patient of
US$165.0 thousand and US$88.6 thousand, respectively, each year.

101
Future Trends of Multiple Myeloma Treatment
• Numerous recently approved and emerging pipeline therapies along with combinations of newer
Strategies focus more agents with established regimens, all set the stage for continued improvement in long-term
on continued outcomes. Newer strategies likely to have a therapeutic presence in MM include CAR-T therapy,
improvement in long- immune checkpoint inhibitors, as well as novel small molecule targeting agents. Outstanding
term outcomes challenges include determining the optimal timing and combinations based on an individual’s
clinical characteristics and biological profile.
Developing indicators • Multiple myeloma is an incurable disease. For some patients, they will still face disease relapse
that can predict after CAR-T treatment, requiring subsequent sequential transplantation and other treatments.
Therefore, one of the future research directions for multiple myeloma is to find certain indicators
different treatment
and methods that can predict different treatment responses and different prognoses of patients,
responses and so as to distinguish patients with an excellent prognosis (without any need for excessive
different prognoses intervention) from those with a very poor prognosis (with needs for early intervention), and thus
of patients guide the treatment choice of patients.
• Clinical management of MM patients remains challenging because acquisition of drug resistance

Clinical application is the basis for disease relapse in most patients. Relevant scientific studies on patient samples
are describing the mechanisms of resistance to targeted and immune agents in order to inform
focus on overcoming
clinical strategies to overcome resistance and improve patient prognosis. Identification of
resistance biomarkers of MM resistance/sensitivity in patients may further inform future sequential and
combination therapies.

102
CD38 Targeted Treatment for Multiple Myeloma
• CD38 antigen is highly and uniformly expressed on plasma cells and thus represents an ideal target for the treatment of
multiple myeloma (MM) with anti-CD38 monoclonal antibodies (mAbs).
• Daratumumab is the most advanced anti-CD38 mAb in the clinical development with approval in several indications,
nevertheless isatuximab that targets completely different epitope of CD38 molecule is also very promising drug.
• Based on their favourable toxicity profile and distinct mechanism of action, anti-CD38 mAbs represents very attractive
partner to back-bone anti-myeloma drugs. Indeed, daratumumab is already recommended as a part of three distinct
combination regimens in relapsed setting.
Limitations
Daratumumab
• Anti-CD38 targeted therapy usually needs to be combined with
other drugs, but the price is relatively high. The price of
+ Daratumumab alone is as high as $617/ 5ml dose. In the early
stage of treatment, patients need frequent injections of these
drugs.
• Reported data from a clinical trial assessing daratumumab as
monotherapy in R/R MM patients in the fourth or later line
Lenalidomide Bortezomib Ixazomib setting showed a median PFS of 3.7 month. Published data of
a clinical trial in 103 R/R MM patients to assess the
combination therapy of daratumumab, pomalidomide and
dexamethasone as third or later line therapy showed a mPFS
of 8.8 months.
Dexamethasone • With a certain degree of adverse reactions, the most
concerned adverse effect for anti-CD38 agent is infusion
reaction, as well as other common grade 3/4 adverse events
include neutropenia, lymphopenia, thrombocytopenia, anemia,
leukopenia, pneumonia and fatigue, which will reduce patient
compliance to a certain extent.

103
Mechanisms and Advantages of CD3×CD38 in Multiple Myeloma
Treatment
CD3×CD38 BsAbs recruit T cells to tumor cells by targeting CD38 antigen and CD3 antigen to activate T cells for immune
killing of tumor cells.
• As an extracellular enzyme, CD38 can • CD3-BsAbs act by simultaneously

• CD38 is generally
then catalyze the cleavage of NAD+ binding to a tumor-associated antigen
expressed in plasma
into cyclic adenosine diphosphate (TAA) expressed on tumor cells and to
Mechanism
cells but is highly

ribose (cADPR). CD3 on a T cell (CD3xTAA). This
expressed on the
• CD38 catalyzes the production of synapse results in T-cell activation and
surface of MM cells.
NAADP, cADPR and NAADP by thereby the secretion of inflammatory
Behaving like a
cation exchange catalyzing cytokines and cytolytic molecules that
metabolic sensor,
nicotinamide adenine dinucleotide are able to kill the tumor cells in the
CD38 can detect high
(NADP) as a "secondary messenger". process. To be specific, CD3 x CD38,
concentrations of
As a result, CD38 is an excellent BsAbs could engage and active T cells
NAD+ in the bone
therapeutic target as it allows immune at the tumor site simultaneously and
marrow
escape and is closely involved in then result in the effective destruction
microenvironment.
multiple myeloma cell growth. of tumor cells.
The advantage of CD3×CD38 in multiple myeloma treatment includes better efficacy, less likely to develop drug resistance
and smaller dosage.
Advantages
• In recent years, the clinical application of Thalidomide, Lenalidomide, Bortezomib and CD38 monoclonal antibody has
greatly improved the remission rate of multiple myeloma, but it cannot completely avoid the relapse caused by minimal
residual disease (MRD), these patients are facing the situation of no drug available. CD3×CD38 BsAbs is suitable for
patients with multiple myeloma whose disease has progressed after conventional chemotherapy or CD38 monoclonal
antibody treatmentCD3×CD38 BsAbs has the advantage. Compared with CD38 or CD3 monoclonal antibody products, T
cells are significantly redirected to tumor cells by CD3×CD38 BsAb efficiently activates T cells, resulting in increased
CD69 and CD25 expression on CD8+ and CD4+ T cells. Thus, es of better efficacy, less likely to develop drug resistance,
and smaller dose. The expected effective dose is 1/20 of that of monoclonal antibodies, which can significantly reduce the
cost of drugs and improve the quality of patients' survival.
Source: International Journal of Molecular Sciences, 2022, 23(10): 5686., Cells, 2019, 8(12): 1629., EMBO Molecular Medicine, 2021, 13(9): e14291., Frontiers in
Immunology, 2020, 11: 501., Frost & Sullivan Analysis 104
Updated
Competitive Landscape of CD38 Targeted Antibodies for Multiple
Myeloma
Global Marketed Products
FDA Approval
Product Drug Name Company Target Drug Type Indication Price (USD)
Time
Genmab A/S, 20mg/ml

DARZALEX Daratumumab CD38 mAb Multiple myeloma 2015/11/16
Janssen Biotech Inc. 5ml: 713
Sanofi-Aventis 20mg/ml
SARCLISA Isatuximab. CD38 mAb Multiple myeloma 2020/03/02
U.S. LLC. 5ml: 783
Multiple myeloma,
DARZALEX 1800mg/15ml
Daratumumab Janssen Biotech Inc. CD38 mAb Light chain (AL) 2020/05/01
FASPRO 15ml: 9,611
amyloidosis
China Marketed Products
FDA Approval
Product Drug Name Company Target Drug Type Indication Price (RMB)
Time
Multiple
兆珂 DARZALEX Daratumumab Janssen Biotech Inc. CD38 mAb 2019/07/04 100mg: 2,358
myeloma
Source: NMPA, CDE, Frost & Sullivan Analysis

105
Myeloma
China Pipeline

Product Company Target Drug Type Indication
Clinical Phase Date
Isatuximab Sanofi-Aventis CD38 mAb Multiple myeloma III 2018/9/27
I-Mab Biopharma Co.
TJ202 Ltd.， Patheon Italia CD38 mAb Multiple myeloma III 2019/12/19
S.P.A.
WuhanYZYBIOPHARM
Y150 CD38, CD3 BsAb Multiple myeloma I 2020/07/28
A Co., LTD.
Shanghai Henlius
HLX15 CD38 mAb Multiple myeloma I 2021/1/12
Biotech, Inc.
Keymed Biosciences
CM313 CD38 mAb Multiple myeloma I 2021/3/15
Co.Ltd
Hangzhou Sumgen
SG301 CD38 mAb Hematological malignancies I 2021/11/01
Biotech Co., Ltd.
STI-6129 ACEA Therapeutics, Inc CD38 ADC Multiple myeloma I 2022/10/14
Takeda Development
TAK-573 IFNAR, CD38 ADC Multiple myeloma I 2022/07/07
Center Americas, Inc
intellectivebio|Jiangsu
Recurrent or refractory multiple
KYS202002A Injection Kanion Pharmaceutical CD38 mAb I 2023-03-23
myeloma
Co.,Ltd

106
Myeloma
Global Pipeline

Phase Date
Almac Clinical Services
Limited|BSP
Pharmaceuticals Recurrent or
Modakafusp Alfa Injection
S.p.A|Takeda CD38,IFNAR Antibody fusion protein refractory multiple II 2023-04-17
(TAK-573)
Pharmaceuticals|Takeda(Chi myeloma
na)International Trading
Co.,Ltd.
Biotest Pharmaceuticals
BT062 CD38 ADC Multiple myeloma I/II 2009/10/26
Corporation
Takeda Pharmaceutical
TAK-079 CD38 mAb Multiple myeloma I/II 2018/2/20
Co Ltd
CASI Pharmaceuticals,
CID-103 CD38 ADC Multiple myeloma I/II 2021/2/17
Inc.
GEN3014
Genmab CD38 mAb Multiple myeloma I/II 2021/4/1
(HexaBody®-CD38)
ISB 1442 Ichnos Sciences SA CD38, CD47 BsAb Multiple myeloma I/II 2022/6/22
Ichnos Sciences SA，

ISB 1342 Glenmark CD38, CD3 BsAb Multiple myeloma I 2017/10/13
Pharmaceuticals S.A.
Multi-specific
SAR442085 Sanofi CD38 Multiple myeloma I 2019/6/27
antibody(msAb)
Fusion
MT-0169 Molecular Templates Inc CD38 Protein(engineered Multiple myeloma I 2019/7/12
toxin body, ETB)

107
Myeloma
Global Pipeline

Clinical Phase Date
CD38, CD3,
SAR442257 Sanofi msAb Multiple Myeloma I 2020/5/26
CD28
Multiple Myeloma;
TAK-169 Molecular Templates, Inc. CD38 Fusion Protein Non Hodgkin I 2019/7/12
Lymphoma
WuhanYZYBIOPHARMA
Y150 CD38, CD3 BsAb Multiple myeloma I 2021/8/18
Co., LTD.
Acute Myeloid
Leukemia; T Cell Acute
Medical College of Lymphoblastic
XmAb18968 CD3, CD38 BsAb I 2021/9/9
Wisconsin Leukemia; T Cell
Lymphoblastic
Lymphoma
Refractory
Hangzhou Sumgen Hematological
SG2501 CD38, CD47 BsAb I 2022/3/24
Biotech Co., Ltd. Malignancies and
Lymphoma
Sorrento Therapeutics,
STI-6129 CD38 ADC Multiple myeloma I 2022/10/4
Inc.
intellectivebio|Jiangsu
Recurrent or refractory
KYS202002A Injection Kanion Pharmaceutical CD38 mAb I 2023-03-23
multiple myeloma
Co.,Ltd
108
Competitive Landscape of CD38 Targeted BsAbs for Multiple
Myeloma
Global Pipeline
Drug Highest Clinical First Posted

Type Phase Date
FDA IND
Global \
Wuhan YZY Biopharma Approval
Y150 CD38, CD3 BsAb Multiple myeloma
Co., Ltd.
China I 2021/05/28
ISB 1442 Ichnos Sciences SA CD38, CD47 BsAb Multiple myeloma Global I/II 2022/06/14
Ichnos Sciences SA，
ISB 1342 Glenmark CD38, CD3 BsAb Multiple myeloma Global I 2017/10/04
Pharmaceuticals S.A.
Relapsed or Refractory
Hangzhou Sumgen
SG2501 CD38, CD47 BsAb Hematological Malignancies Global I 2022/03/01
Biotech Co., Ltd.
and Lymphoma
Multiple myeloma
VP301 Virtuoso Therapeutics CD38, ICAM1 BsAb Lymphoma Global I 2022/12/12
Solid Tumors
IGM-2644 IGM Biosciences CD38, CD3 BsAb Multiple myeloma Global I 2023/05/26
Note:
Source: NMPA, CDE, ClinicalTrial.gov, FDA, Frost & Sullivan Analysis

109
Overview of Breast Cancer
• Breast cancer is one of the most common cancers in women, and the new cases increase year by year. Breast cancer
mostly happens in women aged 50. Developing from breast tissue, breast cancer may present as a lump in the breast,
a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly
patch of skin. According to TNM staging system, the breast cancer stages divide into stage 0 to stage 4.
Risk Factors
Breast Cancer Stages
• Genetic predisposition(BRCA1 or
BRCA2 mutations)
Stage 0 • In the ducts and lobules, not spread to the surrounding
• Estrogen and progesterone exposure tissue of the breast.
Stage 1 • Cancer cells are breaking through to or invading normal

• Oral contraceptives or birth control surrounding breast tissue.
drugs
• Atypical hyperplasia of the breast • Cancer cells are growing, but it is still contained in the
Stage 2
breast or growth has only extended to the nearby lymph
• Lobular carcinoma in situ nodes.
• Lifestyle factors(weight, food, alcohol,

Stage 3 • Cancer cells have extended to beyond the immediate
physical activity) region of the tumor and may have invaded nearby lymph
nodes and muscles, but has not spread to distant organs.
• Breast density(dense breast tissue)
• Family history of breast cancer Stage 4 • Cancer cells have spread beyond the breast and nearby
lymph nodes to other organs of the body.
Source: Literature review, Frost & Sullivan analysis

110
High Prevalence Type of HER2+ Tumors
• HER2 refers to cells that have HER2 protein on their surface. In healthy cells, HER2 helps regulate cell development,
while cancers with increased levels of HER2 are said to be HER2-positive. Overproduction of HER2 in cancer cells can
lead to faster growth and a higher risk of metastasis (cancer spreading to other organs). Breast, bladder, pancreatic,
ovarian and gastric cancers can all be HER2-positive.
HER2+ Tumors
Breast Cancer Bladder Cancer Pancreatic Cancer Ovarian Cancer Gastric Cancer
HER2-positive breast
cancer is when breast Pancreatic ductal
A negative correlation
cancer cells have a adenocarcinoma (PDA)
exists between HER2 HER2-overexpression
protein receptor called has a 5-year survival rate
expression and the in gastric cancer was
HER2. This protein aids of less than 5% and is
survival rate of ovarian mostly reported to be
in the growth, division, In bladder cancer, HER2 the sixth leading cause of
cancer patients. Either associated with
and self-repair of breast was reported to have one cancer death. In a mouse
gene amplification or reduced overall survival
cells. But occasionally, of the highest rates of model, activated HER2
overexpression may lead (OS). In contrast to
something goes wrong in expression, with up to overexpression in the
to dysregulation of HER2 breast cancer, HER2-
the gene that regulates 34% of the tumours pancreas has resulted in
signaling in ovarian positivity in gastric
the HER2 protein and the being HER2-positive. cystic neoplastic lesions
cancer, which in turn cancer might still have
body generates too many similar to human
leads to accelerated cell other prognostic
of these receptors, which intraductal papillary
growth, DNA damage implications.
causes breast cells to mucinous tumor-like
and tumor progression.
grow and divide lesions.
uncontrollably.
Source: NIH, Frost & Sullivan Analysis

111
China Incidence of Breast Cancer, 2018-2030E
• Breast cancer places as one of the top 10 cancer types ranking by incidence, and approximately 25% of people with
breast cancer in China are diagnosed as HER2+ positive. In 2022, 341.0 thousand new cases of breast cancer occurred
in China, and this number grows to 357.8 thousand in 2026 with a CAGR of 1.2% during the period from 2022 to 2026.
It is expected to reach 370.6 thousand in 2030, with a CAGR of 0.9% from 2026 to 2030.
• The growth rate of incidence is slower year by year, which is associated with the raising awareness on cancer
management. In addition, the system on controlling the risk factors of breast cancer will be more thorough, which is
useful on controlling cancer incidence.
Incidence of Breast Cancer in China, 2018-2030E
Period CAGR
2018-2022 1.5%
2022-2026E 1.2%
2026E-2030E 0.9%
Thousand
349.8 353.9 357.8 361.4 364.8 367.8 370.6

326.2 331.6 336.3 341.0 345.5
320.7
80.2 81.5 82.9 84.1 85.3 86.4 87.5 88.5 89.4 90.3 91.2 92.0 92.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Incidence of Breast Cancer
HER2+ Breast Cancer
Source: NCCR, Frost & Sullivan analysis
112
Recommended Therapy Regimens of Breast Cancer from NCCN
Treatment of Recurrent or Stage IV Disease
• According to NCCN guideline of breast cancer, the basic therapy of breast cancer is systemic therapies. Once disease progress,
multiple targeted drugs or non-specific drugs are available. Depending on the hormones estrogen/progesterone and HER2
receptors, the recommended therapy are different.
• NCCN guidelines recommend sacituzumab govitecan-hziy, in systemic treatment of recurrent or stage IV TNBC.
Indication Treatment
Visceral crisis • Initial systemic therapy (Chemotherapy1)
• Ovarian ablation or suppression + Systemic therapy2

Prior endocrine Premenopausal • Continue Endocrine therapy
therapy within
one year • Systemic therapy2
ER+ and/or PR+; Postmenopausal • Continue Endocrine therapy
HER2- No visceral
crisis • Ovarian ablation or suppression + Systemic therapy
No prior Premenopausal • Selective ER modulators4
endocrine • Continue Endocrine therapy
therapy within
• Systemic therapy2
one year Postmenopausal
• Continue Endocrine therapy
ER- and PR-, • Chemotherapy1+ PD-1 (pembrolizumab) as neo/adjuvant therapy

HER2- (Triple • Chemotherapy + pembrolizumab/ sacituzumab govitecan for advanced TNBC
negative) • PARP inhibitors for BRCA mutation TNBC
Notes: 1.Chemotherapy (Preferred Regimens+Other Recommended Regimens)= Anthracyclines, taxanes, anthracyclines, anti-metabolites, microtubule inhibitors,
platinum, cyclophosphamide, docetaxel, albumin-bound paclitaxel, epirubicin, Ixabepilone; 2. Systemic therapy (Preferred Regimens-First-Line)=Aromatase
inhibitor+ CDK4/6 inhibitor, Selective ER down-regulator± non-steroidal aromatase inhibitor, Fulvestrant + CDK4/6 inhibitor, Non-steroidal aromatase inhibitor,
Selective estrogen receptors modulator, Steroidal aromatase inactivator.
Source: NCCN 2020 V4, Frost & Sullivan Analysis

113
Recommended Therapy Regimens of Breast Cancer from CSCO
Treatment of Recurrent or Stage IV Disease(2022)
• Treatment for TNBC is not clearly stated in the CSCO Guideline. However, salvage chemotherapy is recommended as the first-line
treatment for recurrent or metastatic breast cancer. Endocrine therapy is recommended for hormone receptor-positive breast
cancer. For TNBC, patients are lack of treatment options, especially novel therapies, representing large unmet clinical needs.
Indication Treatment
• Paclitaxel- • TP • Paclitaxel- • Paclitaxel

albumin/docetax • X albumin+ PD-1 Liposome
Sensitive to taxane
el/paclitaxel • N inhibitor • Olaparib
After First Line therapy
• TX • G • T+Bevacizumab • Chemo+ PD-1
Treatment • GT • Etoposide • LD inhibitor
HER2-
Systemic • Alibrin/X/N/G • Sacituzumab govitecan- Chemotherapeutic drug
therapies • NP hziy/ Paclitaxel- • LD
After the treatment
• GP albumin/Etoposide • Paclitaxel Liposome
failure of taxane
• NX • Bevacizumab +X • Olaparib
• UTD1+X • Paclitaxel-albumin + • Chemo+ PD-1 inhibitor
Without prior • AI+Abemaciclib/Palbociclib • F • TAM

endocrine therapy • AI • F+CDK4/6 inhibitor
After the treatment • AI+Abemaciclib/Palbociclib/Chid • AI • F+CDK4/6 inhibitor

failure of TAM amide • F
ER+ and/or After the treatment • F+Abemaciclib/Palbocic• SAI+Chidamide/CDK4/ • F/SAI • Progestogen

PR+ failure of NSAI lib/Dalpicilib 6 inhibitor/F/Everolimus • TAM/toremifene
After the treatment • F+Abemaciclib/Dalpicilib/Palboci • F/NSAI • TAM/toremifene

failure of SAI clib • NSAI+CDK4/6 inhibitor • Progestogen
After the treatment • Chidamide+Endocrine therapy Endocrine therapy • Progestogen

failure of CDK4/6 i • Another CDK4/6 inhibitor+ • Toremifene
Notes: H=trastuzumab; L=lapatinib; P=pertuzumab; T=docetaxel, paclitaxel and albumin-bound paclitaxel; X=capecitabine; N=navelbine; Cb=carboplatin;
G=gemcitabine; LD=liposomal doxorubicin; F=fulvestrant; AI=Aromatase inhibitor; TAM=tamoxifen.
Source: CSCO 2020, Frost & Sullivan Analysis

114
Comparison between Breast Cancer Guidelines in US and China
• Currently, the treatment of breast cancer in China generally falls behind that of in US due to either limited accessibility or lag in
innovative targeted drugs investigation. With development of targeted drug and other highly specific therapy catching up, especially for
TNBC, it is expected that in the future, breast cancer treatment will benefit more patient in China.
Advanced /metastasis Advanced /metastasis

Neo adjuvant therapy Adjuvant therapy
1st Line 2nd Line
• AI; F; TAM; SERM;

• TAM •
NCCN
TAM Another endocrine therapy

CDK4/6 inhibitor ; PI3K
ER+ • AI • AI inhibitor regimen
and/or
PR+
Endo-crine • AI
•
Breast Cancer
CSCO
Therapy AI
• AI • AI/F + CDK4/6 • PR
• TAM+AI • TAM
• Systemic therapy with potential targeted therapies, including

• Chemotherapy/ Chemotherapy + PD-1
NCCN
Triple pembrolizumab / sacituzumab govitecan (2L)

(pembrolizumab) • PARP inhibitors for BRCA mutation TNBC
Negative
Breast
Cancer
CSCO
(TNBC) • Chemotherapy
Notes: PR= progesterone receptor; F=fulvestrant; AI=Aromatase inhibitor; TAM=tamoxifen.
• ER+/PR+: For hormone receptor positive treatments, more drugs are approved by FDA compared with China (such as PI3K
inhibitors, etc.), so there are more options for patients in the US.
• TNBC: PD-1 monoclonal antibody, Trop-2 targeting ADC, and PARP inhibitors (for BRCA mutation only) are recommended by
NCCN, while currently no recommendation from CSCO for TNBC.
Source: NCCN 2020 V4, CSCO 2020, Frost & Sullivan Analysis
115
Treatment paradigm for Stage IV breast cancer patients in China
• Breast cancer is one of the most common malignant tumors in women, and its incidence rate ranks first in women's
malignant tumors.
• The main purpose of treatment for advanced breast cancer is not to cure patients, but to improve the quality of life and
prolong the survival time of patients. The treatment methods mainly include chemotherapy and endocrine therapy, and if
necessary, other treatment methods such as surgery or radiation therapy should be considered.
Molecular
Diagnosis Stage IV HER2 + If patient has not used
trastuzumab or meet the re-
use conditions of trastuzumab
• Trastuzumab+Parstuzumab+taxanes
First
• Trastuzumab+taxanes
Line • Trastuzumab ± Parstuzumab
• Trastuzumab+vinorelbine, capecitabine and other
chemotherapy drugs
Disease
Progression If trastuzumab ±
patouzumab
treatment fails
Second
Line • Other anti
HER2 targeted
• Trastuzumab • Pyrrolitinib • Trastuzumab
drugs: • Clinical
Disease emtansine, T- combined with cross line
Initaumab research
Progression DM1 capecitabine therapy
combined with
vinorelbine, etc
Notes: M802 of the company is targeted at HER2+ late-stage breast cancer patients for last-line innovative treatment, so it is not reflected in the treatment
paradigm.

116
Unmet Needs and Future Trends of Breast Cancer (HER2+)
• The clinical practice of HER2-positive breast cancer still has a huge unmet need for treatment, and patients face multiple problems
such as recurrence and drug resistance.
Unmet Needs
Future Trends
Limited treatment Although there are many treatment
options, some patients still develop
choices after BC progression and subsequently
progression Explore new research design on gene level
have very limited treatment options
• The detection techniques of HER2 will be further refined and
the results will be more accurate.
Although trastuzumab remains the
standard treatment in patients with
Resistance to current HER2 overexpressing breast cancer in Find out the key genes that affect the proliferation
treatment neoadjuvant, adjuvant and metastatic and metastasis of breast cancer cells
settings, the presence of acquired and
de novo resistance is a serious concern
• More convenient and valid prediction of prognostic factors will
guide the individualized diagnosis and treatment of HER2-
positive breast cancer.
25% of early HER2-positive breast
High recurrence cancer patients still experience
rates disease recurrence after initial anti- Application of data analysis
HER2 therapy. • Through a large number of data analysis, revealing the law of
efficacy and safety to determine reasonable administration of
regimens.
Brain metastases are common in
patients with HER2-positive mBC; it
Higher risk of
is estimated that brain metastases
complications will ultimately develop in 25–50% of
female patients

117
Future Trends of Breast Cancer Drug Market
• Breast cancer is known to be the most common form of cancer in women around the world.
Influenced by the deteriorating environment and greater pressure for woman, the risk of breast
Increasing Patient
cancer developing is increasing. Early onset of menopause and growing pool of geriatric women
Pool
also increase the patient numbers. In 2020, incidence of breast cancer increased to 2.3 million,
and it is expected to be 2.7 million in 2030.
• Although recent advances in breast cancer treatment such as immunotherapy including PD-
1/PD-L1 has revolutionized the industry, only a certain group of patients can benefit from it.
Advancements Besides, a large proportion of patients will eventually develop resistance through evolving
in R&D resistance pathways such as the PI3K/AKT/mTOR signaling pathway. Together with the growing
breast cancer market, these drives the R&D of novel drug target and mechanism involved in the
cancer development and progression.
• Clinical criteria that include immunohistochemical markers, such as the estrogen receptor (ER),
the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2),
provide a classification of breast cancer. These phenotypes are responsible for directing the
selection of the optimal therapeutic approaches to treatment (i.e. PI3K/AKT/mTOR pathway
Personalized treatment inhibitors, CDK4/6 inhibitors), in determining tumor response to treatments and development of
resistance to therapies. With more advanced genomic techniques, such as RT-PCR, microarrays,
next-generation sequencing, breast cancer diagnostics and targeted treatment is going through a
significant evolution. Together, clinical and molecular criteria can contribute to a more
personalized management of the breast cancer patient.

118
China Market Size of Breast Cancer Drugs, 2018-2030E
• The market size of breast cancer drugs in China is experiencing an accelerated growth. The market size has grown
from RMB 40.1 billion in 2018 to RMB 54.8 billion in 2022, representing a CAGR of 8.1%. It is expected that the market
size will increase to RMB 81.2 billion in 2026 and RMB 114.4 billion in 2030, with a CAGR of 10.3% and 8.9%
respectively.
China Market Size of Breast Cancer, 2018-2030E

Period CAGR
2018-2022 8.1%
2022-2026E 10.3%
2026E-2030E 8.9%
Billion RMB
114.4
105.6
97.3
89.1
74.6 81.2
62.0 68.3
50.7 54.5 54.8
40.1 45.0
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

119
Overview of Gastric Cancer
• Gastric cancer is a type of tumor developing from the lining of the stomach. The cancer may spread from the stomach to
other parts of the body, particularly the liver, lungs, bones, lining of the abdomen and lymph nodes. Most of the time,
stomach cancer develops in stages over years.
• Early symptoms may include heartburn, upper abdominal pain, nausea and loss of appetite. Later signs and symptoms
may include weight loss, yellowing of the skin, etc.
Risk Factors
Gastric Cancer
Infections like Helicobacter
Pylori
95% 5%
Gastrointestinal Stromal
Adenocarcinoma Smoking
Tumors
• Most cancers of the gastric • Gastrointestinal stromal

Diet
cancer are adenocarcinomas. tumors are the most
A stomach cancer or gastric common mesenchymal neo
cancer almost always is an plasms of the
adenocarcinoma. These gastrointestinal tract. GISTs Genetics
cancers develop from the arise in the smooth muscle
cells that form the innermost pacemaker interstitial cell of
lining of the stomach (the Cajal, or similar cells.
mucosa). Others like diabetes
The most relevant factor The least relevant factor

120
China Incidence of Gastric Cancer, 2018-2030E
• Gastric cancer is one of the most frequently occurring cancers in China and there is an obvious geographical distribution.
China new cases of gastric cancer has reached 498.6 thousand in 2022. There are around 23.7% people with gastric
cancer are HER2-positive in China.
• The increased pressure, unhealthy diet will continuously increase the risk of developing gastric cancer in China. It is
expected to be 558.8 thousand in 2026 and 619.6 thousand in 2030, with a CAGR of 2.6% from 2026 to 2030.
China Incidence of Gastric Cancer, 2018-2030E
Period CAGR
2018-2022 3.0%
2022-2026E 2.9%
2026E-2030E 2.6%
Thousand 143.3 146.8

136.0 139.7
128.8 132.4
121.7 125.3
114.7 118.2
108.0 111.3
104.8
589.4 604.6 619.6

543.6 558.8 574.0
498.6 513.5 528.5
455.8 469.6 483.9
442.3
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
HER2+ Gastric Cancer Incidence of Gastric Cancer

121
Treatment Paradigm for Stage IV Gastric Cancer in the U.S.
• Surgery is the main method in treating gastric cancer of stage I-III. However, if the cancer deteriorates to stage IV, the
treatment switches to precision oncology therapies in combination with chemotherapies to alleviate symptoms and
improve the patients’ life quality. Therapies for HER2 negative patients’ treatment are still limited.
GC
Stage IV Early Stage
Molecular HER2 + HER2 -

Diagnosis
• Fluoropyrimidine (fluorouracil or capecitabine) and

First
Line • Trastuzumab + fluoropyrimidine and cisplatin cisplatin
• Trastuzumab + other chemotherapy agents • Fluoropyrimidine (fluorouracil or capecitabine) and
oxaliplatin
Disease
Progression
Second
Line • Ramucirumab + paclitaxel
• Docetaxel/ Paclitaxel / Irinotecan
• Fluorouracil + irinotecan
Disease
Progression
Third • Pembrolizumab
Line • Trifluridine and tipiracil
Source: NCCN, Frost & Sullivan Analysis

122
Treatment Paradigm for Stage IV Gastric Cancer in China
• China is one of the countries with the highest GC incidence. Survival outcomes for gastric cancer are generally quite
poor, as most tumors are already metastasized by the time of diagnosis. Early stage diagnosis may contribute to
recovery after surgery, while advanced metastatic gastric cancer (Stage IV) can only be managed through limited
precision oncology therapy combined with conventional chemotherapy.
Molecular
Diagnosis Stage IV HER2 +
First • Trastuzumab + fluoropyrimidine/ capecitabine +

Line cisplatin
• Trastuzumab + other first-line chemotherapy
regimens
Disease
Progression
If platinum therapy fails and trastuzumab has not been used
Second
Line • Trastuzumab + paclitaxel or
• Trastuzumab + second-line chemotherapy
regimen (excluding anthracyclines)
Disease
Progression
Third Apatinib/ Mono-chemotherapy/ PD-1 monoclonal antibody

Line
Notes: M802 of the company is used as innovative therapy targeted at HER2+ late-stage gastric cancer patients for third-line and above treatment, so it is not
reflected in the treatment paradigm.
Source: National Health Commission of the People's Republic of China, Frost & Sullivan Analysis
123
Unmet Needs and Future Trends of Gastric Cancer Treatment
Disease-related Unmet Needs
• Globally, the onset of gastric caner has reached about 1.1 million in 2019, and the growth momentum is expected to
increase. The symptoms of gastric cancer are often atypical, which makes gastric cancer hard to be diagnosed.
• HER2 overexpression in gastric/GEJ adenocarcinomas tends to be more heterogeneous, both with respect to morphology
and the immunoreactivity of tumor cells to antibodies detecting HER2
Treatment-related Unmet Needs
• Quality control of molecular testing for HER2 is an important issue and standardized protocols are needed to ensure
precise identification of eligible patients
• Although chemotherapy regimens for advanced gastric cancer have made continuous progress in the past 40 years,
including 5-FU based regimens, platinum-containing regimens and novel chemotherapy combination regimens, the
efficacy of first-line chemotherapy for advanced gastric cancer is still considerably low with an ORR of approximately 25%,
a median PFS of approximately from 3 to 6 months and a median OS of approximately from 8 to 13 months.
• To date, trastuzumab, a monoclonal antibody targeting HER2, is the first and only anti-HER2 mAb for gastric cancer
treatment approved by authorities in China and the U.S. Despite the reported efficacy of trastuzumab, its application is
limited by the relatively small portion of HER2 positive gastric cancer, which only accounts for approximately 7.3%-20.2%
of all gastric cancer cases.
Future Trends
• The usage of trastuzamb, a favorable drug for HER2+ gastric cancer, would be expended to later treatment phases, since
the activity of trastuzumab beyond disease progression has been well established in several studies.
• More and more new HER2-targeted therapies are expected to be innovated, since there’s no efficient treatment for
HER2+ patients whose tumors are no longer controlled by trastuzumab.
• More effective systemic therapies are needed as the majority of patients with stage IV disease become refractory to all
available therapies. One area of active research into the disease includes the role of immune therapy.

124
China Market Size of Gastric Cancer Drugs, 2018-2030E
• The market size of gastric cancer drugs in China is experiencing a rapid growth. The market size of gastric cancer drugs
in China has grown from RMB 24.2 billion in 2018 to RMB 33.8 billion in 2022, with a CAGR of 8.7%. The market will
keep growing to RMB 57.2 billion in 2026 and RMB 82.5 billion in 2030, with a CAGR of 14.1% and 9.6% respectively.
China Market Size of Gastric Cancer, 2018-2030E

Period CAGR
2018-2022 8.7%
2022-2026E 14.0%
2026E-2030E 9.6%
Billion RMB
82.5
76.0
69.6
63.2
57.2
51.2
45.4
39.7
29.7 32.3 33.8
24.2 27.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

125
Overview of Ovarian Cancer
Pathological subtypes of ovarian cancer Overview
1 Brief Introduction
• Ovarian cancer develops in the ovaries, which are
Ovarian
the female reproductive glands that produce eggs
epithelial cancer during a woman's reproductive years. Ovarian
cancer develops when cells in the ovaries begin to
grow out of control.
2 Symptom
Ovarian germ
• Early warning signs: Abdominal bloating, indigestion
cell tumors
or nausea, changes in appetite, pressure in the
Ovarian pelvis or lower back, a more frequent or urgent need
cancer to urinate and/or constipation, changes in bowel
movements, increased abdominal girth, tiredness or
low energy, changes in menstruation.
Sex cord-stromal • Advanced: Ovarian cysts, masses or tumors
tumors
Ovarian
sarcoma 3 Diagnosis
• CT scan, MRI, PET/CT scan, Ultrasound (Imaging
tests)
Less common Krukenberg • Advanced genomic testing, nutrition panel, CA-125
tumors test( lab tests); Pelvic exam
types
4 Risk Factors
Ovarian • Age (55&above); Family history
cysts • Genetic mutations (BRCA1&BRCA2)
• Lynch syndrome and Peutz-Jeghers syndrome
• Breast, colorectal or endometrial cancer

126
China Incidence of Ovarian Cancer, 2018-2030E
• In 2018, the incidence of ovarian cancer in China reached 53.0 thousand, and reached 57.0 thousand in 2022 with a
CAGR of 1.8%. It is predicted that the number will continue to grow, and reach 60.0 thousand by the year of 2026, 62.4
thousand by the year of 2030, with CAGR of 1.3% and 1.0% respectively. The rate of HER2 positive ovarian cancer in
China is around 30.8%.
• Ovarian cancer had an estimated annual incidence of 57,000 patients in China in 2022, which is more than double that
of the estimated 19,900 patients each year in the United States, and has seen increasing mortality, according to NCCR,
IARC and ACS.
China Incidence of Ovarian Cancer, 2018-2030E
Period CAGR
2018-2022 1.8%
2022-2026E 1.3%
2026E-2030E 1.0%
Thousand
61.3 61.9 62.4

59.3 60.0 60.7
57.8 58.5
56.2 57.0
55.3
53.0 53.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

127
Treatment Paradigm of Ovarian Cancer in China
• Olaparib, Niraparib and Rucaparib, as PARP-targeted drugs, are recommended for the maintenance treatment of ovarian cancer cancer while Rucaparib hasn’t
been approved in China yet.
• A series of medical evidences show that PARP inhibitors can significantly delay the recurrence time and prolong the PFS time of patients in the maintenance
treatment of ovarian cancer. Especially for patients with BRCA gene mutation/HRD positive, the effect of PARP inhibitors is more significant.
• The previous standard of care in China mainly consists of debulking surgery and platinum-based chemotherapy. Although platinum-based chemotherapy is
effective at inducing an initial response, more than 80% of initially responding tumor will recur, and resistance to platinum-based therapy will eventually emerge.
Stage I (Postoperative adjuvant Platinum-resistant

chemotherapy) relapse
BRCA1/2 mutation
Paclitaxel + Carboplatin Non-platinum single agent +/- Olaparib

Carboplatin + Doxorubicin Bevacizumab Niraparib ± Pembrolizumab
liposome Rucaparib
Ovarian Docetaxel + Carboplatin
Cancer
Platinum-sensitive
Stage II~IV (Postoperative adjuvant relapse
chemotherapy)
Paclitaxel + Carboplatin
Paclitaxel + Carboplatin +/- Carboplatin + Docetaxel BRCA1/2 mutation
Bevacizumab Carboplatin + Gemcitabine
Docetaxel + Carboplatin Carboplatin + Doxorubicin
Carboplatin + Doxorubicin liposome Olaparib
liposome Cisplatin + Gemcitabine Rucaparib
Carboplatin + Albumin bound Fluzoparib
paclitaxel, etc.
Maintenance treatment： Regimens above can combination HRD positive
BRCA1/2 mutation: Olaparib +/- with Bevacizumab
Bevacizumab, Niraparib
Wild type BRCA1/2, HRD positive: Maintenance treatment： Niraparib
Olaparib +/- Bevacizumab, Olaparib
Niraparib Niraparib
Wild type BRCA1/2, HRD negative: Rucaparib
Niraparib
First-line Disease Second-line Disease Subsequent line

chemotherapy after surgery progression chemotherapy progression targeted therapy
Source: Guideline for Diagnosis and Treatment of Ovarian Cancer (2022), Guidelines for Clinical Application of PARP Inhibitors in Ovarian Cancer (2020),
Frost & Sullivan Analysis 128
Comparison between Ovarian Cancer Guidelines in the U.S. and
China
• The medication regimen of the US clinical guidelines makes a more detailed distinction in disease classification, and follow-up
medication plan is based on the application of bevacizumab during primary therapy.
Partly Treatment Paradigm of Ovarian Cancer in U.S.
Recurrence Therapy for Platinum-

Stage I (Primary chemotherapy/primary adjuvant therapy)
Sensitive
Stable disease or
High-grade serous/Endometrioid (grade 2/3)/Clear cell progression Carboplatin/gemcitabine±bevacizu
carcinomad/Carcinosarcomad: Paclitaxel/carboplatin; No
mab
Mucinous carcinoma (stage IC): 5-FU/leucovorin/oxaliplatin, bevacizumab
Carboplatin/liposomal
Capecitabine/oxaliplatin, Paclitaxel/carboplatin; used during
doxorubicin± bevacizumab
Low-grade serous (stage IC)/Grade I endometrioid (stage primary
Carboplatin/paclitaxelf±
IC): Paclitaxel/carboplatin maintenance letrozole or other therapy
Ovarian Cancer
bevacizumab
hormonal therapy, Hormone therapy (aromatase inhibitors: Cisplatin/gemcitabine
anastrozole, letrozole, exemestane) Bevacizumab
Others Niraparib
Olaparib
Stage II~IV (Primary chemotherapy/primary adjuvant

therapy)
Recurrence Therapy for Platinum-

High-grade serous/Endometrioid (grade 2/3)/Clear cell Resistant
carcinomad/Carcinosarcomad: Paclitaxel/carboplatin, Stable disease or
Paclitaxel/carboplatin/bevacizumab + maintenance progression Cytotoxic Therapy
bevacizumab; Cyclophosphamide/bevacizumab,
Mucinous carcinoma: 5-FU/leucovorin/oxaliplatin ± Docetaxel, Etoposide, Gemcitabine,
bevacizumabi, Capecitabine/oxaliplatin ± bevacizumabi, Bevacizumab
Liposomal
Paclitaxel/carboplatin, Paclitaxel/carboplatin/bevacizumab used as part
doxorubicin/+bevacizumab,
+ maintenance bevacizumab; of primary
Paclitaxel/+bevacizumab,
Low-grade serous/Grade I endometrioid: therapy
Topotecan/+bevacizumab;
Paclitaxel/carboplatin ± maintenance letrozole or other Targeted Therapy
hormonal therapy; Paclitaxel/carboplatin/bevacizumab + Others Bevacizumab, Niraparib, Olaparib
maintenance bevacizumab; Hormone therapy
Primary therapy Disease progression Post primary treatment
Source: NCCN Clinical Practice Guidelines in Oncology (2022), Frost & Sullivan Analysis
129
Unmet Needs of Ovarian Cancer in Clinical Treatment
• 70% of patients with ovarian cancer are in advanced stage when they are first
low survival rate of OC diagnosed. Ovarian cancer recurs in most patients, with a 5-year survival rate
less than 30%. Several studies showed that HER2 overexpression in ovarian
cancer patients was significantly associated with worse overall survival rate.
Hard to control the quality • HER2 is overexpressed highly in a variable percentage of epithelial ovarian
of HER2 overexpression cancer (11%-66%) and the degree of overexpression is sensitive to detect
testing approaches, so it’s hard to control the quality of HER2 testing.
• Ovarian cancer is moderately sensitive to chemotherapy, with a response rate of

Limited response rate and 70% - 80% to platinum based chemotherapy, 20% - 30% of the patients did not
high drug resistance of respond to chemotherapy.
chemotherapy • Although ovarian cancer is relatively sensitive to first-line chemotherapy, there
are approximately 70% of patients having drug resistance and recurrence after
initial treatment.
• The clinical efficacy of chemotherapy as first-line treatment is limited, and the PFS
Limited clinical efficacy of
of patients treating with chemotherapy + bevacizumab did not show better result
first-line treatment with
compared with chemotherapy.
chemotherapy +
• The median PFS was 17.4 months for carboplatin plus paclitaxel vs 19.8 months
bevacizumab
for the group of carboplatin, paclitaxel plus bevacizumab.
• It is common that ovarian cancer patients have multiple recurrences, and the time
Limited treatment options
interval of recurrences becomes shorter after each relapse. With the progress of
after ovarian cancer
disease and corresponding treatment lines, effective drugs for subsequent lines
recurrence
of treatments are limited in other chemotherapy plus bevacizumab.

130
Growth Drivers and Future Trends of Ovarian Cancer Drug Market
HER2 serving as • Several meta-statistic studies have shown that HER2 expression is associated with worse
progression outcome of ovarian cancer, implicating HER2 maybe a potential prognostic indicator for ovarian
indicators cancer patients
• The deepening of basic biological research on ovarian cancer disease has brought about the
most profound changes in treatment in this field, leading to the development of new drugs and
drug combinations. Drugs for the treatment of ovarian cancer, especially for patients with
platinum-resistant and recurrent ovarian cancer, are undergoing accelerated research and
clinical trials. Emerging targets for the treatment of recurrent or drug-resistant ovarian cancer,
Increasing Treatment such as AKT, PI3K, TOPI, WEE1, and related drugs are also under clinical development, which
Options will provide ovarian cancer patients with more treatment options and further prolong survival.
• With the increasing number of ovarian cancer patients, the demand for ovarian cancer drugs will
further expand. In addition, with the launch of more drugs for ovarian cancer, especially for
recurrent and platinum-resistant ovarian cancer. Several studies has shown that combination of
a HER2 inhibitor with chemotherapy could improves survival rate, which would boost the
development of combination therapy, the market size will gradually expand.
• Ovarian cancer is not a single disease, but a group of related diseases with unique genetic and
molecular features, some of which respond better to chemotherapy than others. Treatment of
Personalized Treatment
ovarian cancer will be gradually refined to the specific characteristics of each type, and then an
individualized medical plan will be developed for the patient.

131
China Market Size of Ovarian Cancer Drugs, 2018-2030E
• The market size of ovarian cancer drugs in China is experiencing a rapid growth. The market size has grown from RMB
0.5 billion in 2018 to RMB 4.1 billion in 2022, with a CAGR of 69.2%. In the future, the market size will increase into
RMB 17.1 billion in 2026 and RMB 46.4 billion in 2030, with a CAGR of 42.8% and 28.3% respectively.
China Market Size of Ovarian Cancer, 2018-2030E

Period CAGR
2018-2022 69.2%
2022-2026E 42.8%
2026E-2030E 28.3%
Billion RMB
46.4
36.9
29.0
22.6
17.1
12.6
9.2
4.1 6.6
0.5 0.7 1.0 2.8
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

132
Overview of HER2 Target
• HER2 is a ligand-orphan receptor which is expressed in many human tumors, especially in breast cancers. Human
epidermal growth factor receptor (HER2) inhibitors are either tyrosine kinase inhibitors or monoclonal antibodies that
slow down or stop cell growth.
Mechanisms of action of anti HER-2

Drugs
• The HER family of transmembrane tyrosine

ErbB1/EGFR Receptor
kinase receptors is composed of four
members, HER1 to HER4. HER2 is a ligand-
orphan receptor expressed in many human
tumors. ErbB2 (HER2) Receptor
• The humanized Mab has antitumor activity

against HER2-overexpressing human breast
tumor cells and induces HER2 receptor Tyrosine
downmodulation and, as a result, inhibits Kinase
Inhibitors Tyrosine
critical signalling pathways and blocks cell
Kinase
cycle progression by inducing the formation of Inhibitors
p27/Cdk2 complexes.
• The small molecule tyrosine kinase inhibitors

(TKIs) that compete with ATP for binding at Downstream signaling
the HER-2 catalytic kinase domain block transduction pathway
HER-2 signaling.

133
Overview of HER2 x CD3 bispecific antibody
• The bispecific antibody (BsAb) targeting both a T-cell associated antigen and a TAA can bridge T cells and tumor cells to
achieve the concept that the redirecting the cytotoxic activity of the effector T cells to specifically eliminate tumor cells.
• A anti-HER2 × anti-CD3 BsAb recruits and redirects T cells to HER2+ tumor cells through binding to CD3 and HER2,
and further activates T cells to kill the tumor cells.
MOA
The anti-HER2 × anti-CD3 BsAb prevents the dimerization Killing

of the receptor HER2, increases endocytic destruction of the T cell
receptor, and inhibits shedding of the extracellular domain of Tumor cell
HER2. The other target of BsAb, CD3 is the specific surface
antigen of T cells.
Advantage
High effectiveness of the BsAb. TAA(HER2) IAA(CD3)

• The current standard treatment for HER2+ breast cancer is the
anti-HER2 mAb-trastuzumab.
• The comparative in vitro studies showed that the cytotoxicity
activity of M802 (anti-HER2 × anti-CD3 BsAb) was five times
stronger than that of trastuzumab on HER2-positive breast cancer
cells BT-474 killed by PBMCs, and furthermore, M802 displayed
significant cytotoxicity to JIMT-1 (a trastuzumab-resistant breast
cancer cell line) , indicating a new promising therapeutics for BsAb
HER2-positive and/or trastuzumab-resistant breast cancer
patients.
*TAA: tumor-associated antigen; IAA: immune-associated antigen

134
Updated
China Competitive Landscape of HER2 Targeted Drugs
China Marketed Drugs
Drug Approval Price (RMB)

Product Drug Name Company Target Indication Combination Therapy
Type Date in 2021
Gastric Cancer,
Breast Cancer,
Trastuzumab Combination with
Herceptin Roche Pharma HER2 mAb and HER2- 2021/10/22 440mg: 5,500
for Injection trastuzumab
positive
Breast Cancer
Gastric Cancer,
Breast Cancer,
Trastuzumab Shanghai Henlius Combination with
Zercepa HER2 mAb and HER2- 2020/08/12 150mg: 1,688
Injection Biotech, Inc. pertuzumab
positive
Breast Cancer
Sunshine Guojian
Inetetamab Pharmaceutical HER2-positive Combination with
Cipterbin HER2 mAb 2020/06/17 50mg: 590
for Injection (Shanghai) Co., Breast Cancer chemotherapy
Ltd.
Purple shingles in
Trastuzumab
Roche Pharma HER2-positive 100mg: combination
Kadcyla Emtansine for HER2 ADC 2020/01/21
(Schweiz) AG Breast Cancer 19,282 with trastuzumab-based
Injection
neoadjuvant therapy
Pertuzumab Roche Pharma HER2-positive Combination with

Perjeta HER2 mAb 2018/12/17 420mg: 4,955
Injection (Schweiz) AG Breast Cancer pertuzumab

135
Updated
China Competitive Landscape of HER2 Targeted Drugs
China Marketed Drugs
Drug Approval Price (RMB)

Product Drug Name Company Target Indication Combination Therapy
Type Date in 2021
Dextrastuzumab DAIICHI SANKYO HER2-positive

Enhertu HER2 ADC 2023/02/21 100mg: 9,432 N/A
for injection COMPANY Breast Cancer
Hisun
Trastuzumab for Gastric Cancer, Combination with
HS022 Biopharmaceutical HER2 mAb 2023/02/28 150mg:1,588
injection Breast Cancer vinorelbine
Co., Ltd.
Urothelial
carcinoma,
Disitamab
gastric carcinoma, Combination with
RC48 Vedotin for Remegen Co., Ltd. HER2 ADC 2021/06/08 60mg:13,500
gastroesophageal toripalimab
injection
junction
adenocarcinoma

136
China Competitive Landscape of HER2 Targeted BsAbs
China Pipeline
Clinical Phase Date
Advanced HER2-positive breast cancer or
BeiGene,Ltd., Patheon adenocarcinoma of the
Injectable ZW25 Manufacturing Services LLC, HER2 stomach/gastroesophageal junction, III 2021/01/12
BeiGene (Beijing) Co., Ltd. Advanced or metastatic HER2 amplified
carcinoma of the gallbladder
Tislelizumab Baiji Shenzhou (Shanghai)

HER2 Gastroesophageal juction adenocarcinoma III 2021/11/11
Injection Biotechnology Co., Ltd.
Recombinant
Jiangsu Alphamab
humanized HER2/positive gastric cance (including
Biopharmaceuticals Co., Ltd.,
anti/HER2 HER2 adenocarcinoma of gastroesophageal III 2022/01/17
Shanghai GeneMab Biological
bispecific antibody junction)
injection
Recombinant Shanghai Jinmante
humanized anti Biotechnology Co., Ltd.|Jiangsu First line treatment of HER2 positive recurrent
HER2 III 2023/05/12
HER2 bispecific Alphamab Biopharmaceuticals and metastatic breast cancer
antibody injection Co.,Ltd
Jiangsu Alphamab
HER2/positive gastric cance (including
Biopharmaceuticals Co., Ltd.,
KN026 HER2 adenocarcinoma of gastroesophageal II/III 2022/01/17
Shanghai GeneMab Biological
junction)
Shanghai Kanda Biotechnology
Technology Co.,ltd.|Shanghai
KD6001 injection CTLA4,HER2 Advanced malignant tumors II 2023/03/20
Celgen Bio-Pharmaceutical
Co.,Ltd.
• Domain II and domain IV are common antigenic epitopes that HER2 BsAbs target to

137
China Pipeline
Clinical Phase Date
M802 Wuhan YZY Biopharma Co., Ltd. HER2,CD3 HER2/positive advanced solid tumors I 2018/07/26
Recombinant
humanized Locally advanced, inflammatory, or early
bi/functional Beijing Mabworks Biotech Co., stage breast cancer with high HER2
HER2 I 2019/03/25
monoclonal Ltd. expression, metastatic breast cancer,
antibody MBS301 metastatic gastric cancer, etc.
for injection
Innovent Biologics(Suzhou) Co.,

IBI315 PD-1, HER2 Advanced malignant tumors I 2019/11/04
Ltd.

138
China Pipeline

Phase Date
Guangzhou AI Simai Biomedical HER2-positive advanced solid

EX101 Injection HER2, CD3 I 2021/09/15
Technology Co., Ltd. tumors
Sunshine Guojian
Injectable SSGJ/705 PD-1, HER2 Malignant tumors I 2021/11/22
Pharmaceutical(Shanghai) Co., Ltd.
Beijing Xuanzhu Kangming Biotechnology

Co., Ltd., Her2-positive or HER2-expressing
KM257 HER2 I 2022/04/07
Xuanzhu (Shijiazhuang) Biotechnology advanced solid tumors
Co., Ltd.

Injectable TQB2930 Co.,LTD.of Chiatai Tianqing HER2 Advanced malignant tumors I 2022/05/16

139
Global Competitive Landscape of HER2 Targeted BsAbs
Global Pipeline

Clinical Phase Date
Wuhan YZY Biopharma Co., FDA IND

M802 HER2, CD3 HER2+ Solid Tumors \
Ltd. Approval
Sunshine Guojian
Advanced or Metastatic HER2-expressing FDA IND
SSGJ-705 Pharmaceutical (Shanghai) Co., HER2, PD-1 \
Solid Tumors Approval
Ltd.
Zanidatamab
Beigene, Ltd.|Zymeworks Inc. HER2 Salivary gland cancer III 2023/4/11
(ZW25)
Zenocutuzumab Merus N.V. HER2, HER3 Solid Tumours Harboring NRG1 Fusion II 2022/10/20
Yuhan Corporation，BeiGene,
YH32367 HER2, 4-IBB HER2+ Solid Tumor I/II 2022/9/1
Ltd.
Her2+ Solid Tumors，Metastatic Breast

MM-111 Merrimack Pharmaceuticals HER2, HER3 I 2009/6/3
Cancer

140
Global Competitive Landscape of HER2 Targeted BsAbs
Global Pipeline

Clinical Phase Date
Locally Advanced or Metastatic HER2-

AMX 818 Amunix Pharmaceuticals HER2, CD3 I 2022/5/2
Expressing Cancers
Runimotamab
Genentech, Inc. HER2, CD3 Solid Tumor I 2018/2/27
(RG6194)
Beijing Mabworks Biotech Co., HER2+ Recurrent or Metastatic Malignant

MBS301 HER2 I 2019/2/15
Ltd. Solid Tumor
Innovent Biologics (Suzhou)

IBI315 HER2, PD-1 Advanced Solid Tumor I 2019/11/14
Co. Ltd.
Summary of other Clinical-stage HER2 Targeted Biologics:
• Number of fusion proteins: 5

• Number of Multi-specifc antibody: 1
• Number of mAbs: 54
➢ In and above phase III: 19
➢ In phase II or II/II: 11
➢ In and below I/II: 24
• Number of ADC: 40
➢ In and above phase III: 4
➢ In phase II or II/II: 12
➢ In and below I/II: 24

141
Global Competitive Landscape of HER2 x CD3 Targeted Antibodies
Global Pipeline

Type Phase Date
Advanced or Metastatic
Runimotamab
Genentech, Inc. HER2, CD3 BsAb HER2-Expressing Global I 2018/2/27
(RG6194)
Cancers
FDA IND
Wuhan YZY Advanced HER2- Global \
M802 HER2, CD3 BsAb Approval
Biopharma Co., Ltd.. Epressing Solid Tumors
China I 2018/7/26
Guangzhou AI Simai
HER2-positive advanced
EX101 Injection Biomedical HER2, CD3 BsAb China I 2021/9/15
solid tumors
Locally Advanced or
Amunix
AMX 818 HER2, CD3 BsAb Metastatic HER2- Global I 2022/5/2
Pharmaceuticals
Expressing Cancers
Note:
Source: NMPA, CDE, ClinicalTrial.gov, FDA, Frost & Sullivan Analysis

142
Mechanism of Anti-PD-1/PD-L1 Therapy
• Programmed Death-1 (PD-1) is a critical immune checkpoint receptor expressed on T cells upon activation.
Engagement of PD-1 by its ligands, PD-L1 and PD-L2, transduces a signal that inhibits T-cell proliferation, cytokine
production, and cytolytic function. Monoclonal antibody (mAb) inhibitors of immunological and their corresponding
ligands, including PD-1 and PD-L1, have demonstrated significant anti-tumor activity in patients with various solid
tumors.
PD-1 Antibody inhibitors • Antigen(Ag) is capable of

stimulating an immune response.
Antigen-presenting cells (APCs)
can bind to Ag to activate T-cell
T cell
PD-L1
receptor (TCR) and major
APC PD-1
PD-L2 histocompatibility complex(MHC)
Treg
binding. Regulatory T cells(Treg)
PD-L1
create a highly
PD-L2
TCR PD-1 immunosuppressive tumor
environment by maintaining the
expression of PD-1 on its surface.
• When PD-1 binds PD-L1/L2, the
T cell receives an inhibitory
Ag
signal. The inhibition via PD-1
and its ligands lead to T-cell
energy and blockade of a
MHC-Ag PD-L1 productive antitumor immune
PD-L2 PD-L1
Antibody inhibitors response. Anti-PD-1 mAb is
designed to prevent PD-1 binding
Cancer
PD-L1/L2. By this means, the
function of T cell recovers.

143
Development of Anti PD-1/PD-L1 Therapy
Discovery of Anti PD-1/PD-L1 Therapy

• Found PD-1 from mice hybridoma T cell • Malignancies may evade • First anti-PD clinical trial initiated for
2B4.11 which results inactivation for T detection by immune system advanced melanoma, non-small-cell lung
cells. (Ishida) at different points. (Wang RF) cancer(BMS-936558)
1892 1992 2000 2001 2005 2006 2014 2016
• First try in the cancer • B7-H1-PD-1 • Anti-PD-L1 & anti-PD-1 • First anti-PD-1 • First anti-PD-L1 antibody
immunotherapy by interaction, B7-H1 elicits similar anti-tumor antibody approved by approved by FDA.
injecting various renamed PD- activities “Molecular Shield FDA. (Keytruda) (Tecentriq)
antigens into patient L1(Clive Wood and mechanism” (Lieping Chen)
(William B. Coley) Tasuko Honjo)
Therapeutic Advantages
1 Fewer side effects

• Anti-PD-1 is a targeted therapeutic approach. Compared with other
chemotherapy medications, such as docetaxel, in previously treated
advanced NSCLC, grade 3 or higher adverse events were less likely seen
with anti-PD-1 therapy .
2 Variety of indications
• Anti-PD-1 displays impressive anti-tumor activity in multiple types of
cancer. Anti-PD-1 shows high effectiveness on melanoma, NSCLC,
solid tumor, etc.

144144
Overview of TGF-β Pathway
• The transforming growth factor-β (TGF-β) is a family of structurally related proteins that comprises of TGF-β,
activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF-β family control numerous cellular
functions including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and migration.
• TGF-β has a dual action in cancer as a tumor suppressor and a tumor promoter. It can induce cellular growth arrest and
apoptosis at the early stage of cancer as a tumor suppressor. During late stages of tumor progression, it acts as a tumor
promoter and induce tumor cell migration and stimulate epithelial to mesenchymal transition.
Immune evasion
Tumor suppressor role
Treg cell
• TGF-β arrest the late cellular G1 cycle by regulating the
expression of cyclin-dependent kinases (CDK) inhibitors, p21
Cancer cell and c-Myc, to inhibit cell cycle progression. In addition, TGF-β
TGF-β Naïve can induce apoptosis by upregulating apoptotic regulators such
CD4+ T as Bcl-2-like protein 11 (BIM), BCL-2 interacting killer (BIK), and
cell death associated protein kinase (DAPK) .
Antigen Effector
Presenting T cell Tumor promoter role
cell
• In late stage cancer, tumors such as melanomas, gliomas, and

breast cancer have maintained a functional TGF-β
receptor/SMAD pathway, but are resistant to the tumor
(No TGF-β) suppressive effects of TGF-β due to loss of function mutation in
tumor suppressor genes and/or acquiring oncogenic mutations,
such as in the PI3K/AKT, RAS/MAPK pathway components. In
Anti-tumor Immunity Cancer cell this case, cancer cells remain responsive to TGF-β signaling but
become resistant to its cytostatic effects, which then can
promote EMT, thus stimulating cancer cell invasion and
Inhibit Enhance
metastasis.
Source: Literature review, Frost & Sullivan Analysis

145
Mechanism of PD-L1 x TGF-β Targted BsAbs in Tumor Therapy
• TGF-β can promote PD-(L)1 resistance by converting conventional T cells to immunosuppressive Treg cells and
increasing the survival of myeloid progenitors that differentiate to potent myeloid-derived suppressor cells (MDSCs).
Both of these processes result in increased expression of TGF-β, while MDSCs express PD-L1 and drive Treg cell
differentiation.
• Inhibition of TGF-β reduced the number of Treg cells, increased the number of effector T cells, and restored sensitivity to
anti-PD-L1 therapy.
Tumor cells Mesenchymal-like tumor cell
Advantages
NK cell • Blockade of TGF-β signaling
suppresses fibrosis, result in::
Dendritic Tumor angiogenesis Epithelial–mesenchymal transition ➢ enhanced immune
cell Fibroblast cell access to the
tumor
TAM
➢ restored drug access
Cytotoxic to the tumor,
CAF
T cell
TGF-β receptor moiety sequesters ➢ reduced metastatic
Suppression of immune response potential of the tumor.
TGF-β to block downstream signaling Fibrosis and impaired drug access
TGF-β
• Inhibition of angiogenesis
through suppression of TGF-
T cell PD-1 β activity via stromal
PD-L1 modulation and may restore
normal vascular homeostasis,
Tumor cell thereby enhancing drug
Anti-PD-L1 mAb moiety blocks
PD-L1 interactions with PD-1
delivery and T-cell infiltration
into the tumor
Inhibit
microenvironment.
*TAM: Tumor-associated macrophage; CAF: Cancer-associated fibroblast
Source:, Journal for ImmunoTherapy of Cancer, 2022, 10(12): e005543., Molecular oncology, 2022, 16(11): 2117-2134., Antibody Therapeutics, 2020, 3(2): 126-145.,
ADMET and DMPK, 2017, 5(3): 159-172., Frost & Sullivan Analysis
146
Competitive Landscape of PD-L1×TGF-β Targeted Bifunctional
Antibody-Receptor Fusion Proteins
China Pipeline
Clinical Phase Date
Advanced solid tumor
(including, NSCLC,
M7824 Merck & Co., Inc. PD-L1, TGF-β Fusion Protein III 2022/4/21
cholangiocarcinoma,
cervical cancer)
Jiangsu Hengrui Medicine Co Ltd, Advanced solid

Shanghai Hengrui Pharmaceutical tumor(including, NSCLC,
SHR-1701 PD-L1, TGF-β Fusion Protein III 2021/11/17
Co Ltd, Suzhou Suncadia cervical cancer, gastric
Biopharmaceuticals Co Ltd cancer)
Solid tumor;
Wuhan Youzhiyou
Y101D PD-L1，TGFβ BsAb Hepatocellular carcinoma; II 2023/03/17
Biopharmaceutical Co., Ltd
Pancreatic cancer
PM8001 Biotheus Inc. PD-L1, TGF-β Fusion Protein Advanced solid tumor I/II 2020/06/24
Nanjing Jun Xin Pharmaceutical

TQB2858 PD-L1, TGF-β Fusion Protein Advanced malignant tumor I 2021/3/25
Co., Ltd.
Shanghai Junshi Biosciences Co
JS-201 PD-1, TGF-β Fusion Protein Advanced solid tumor I 2021/5/21
Ltd
QLS31901 Qilu Pharmaceutical Co., Ltd. PD-L1, TGF-β Fusion Protein Advanced solid tumor I 2021/6/2
BR102 Hisun Biopharmaceutical Co., Ltd. PD-L1, TGF-β Fusion Protein Advanced malignant tumor I 2021/9/13
LBL-015 Nanjing Leads Biolabs Co., Ltd. PD-1, TGF-β Fusion Protein Advanced solid tumor I 2021/9/22

TQB-2868 Co,Ltdof Chiatai Tianqing PD-1, TGF-β Fusion Protein Advanced malignant tumor I 2022/2/14

147
Competitive Landscape of PD-L1×TGF-β Targeted Bifunctional
Antibody-Receptor Fusion Proteins
China Pipeline
Clinical Phase Date
Boji Biomedical
PD-L1, Advanced solid tumor;
BJ-005 Technology (Hangzhou) Fusion Protein I 2022/3/9
TGF-β advanced lymphadenoma
Co Ltd
Kintor Pharmaceutical PD-L1,

GT-90008 Fusion Protein Advanced solid tumor I 2022/5/31
(Guangdong) Co.,Ltd. TGF-β
Metastatic or locally
Mabspace Biosciences PD-L1,
TST-005 Fusion Protein advanced solid tumors (e.g. I 2022/7/1
(Suzhou)Co,Limited TGF-β
HPV positive, NSCLC)
PD-L1,
HB-0028 Huabo Biopharm Co Ltd Fusion Protein Advanced solid tumor I 2022/8/9
TGF-β
Shandong Boan PD-L1,
LY01019 Fusion Protein Advanced solid tumor I 2022/8/30
Biotechnology Co. Ltd TGF-β
Mabwell (Shanghai) PD-L1,
6MW3511 Fusion Protein Advanced solid tumor I 2022/9/1
Bioscience Co., Ltd. TGF-β
Sales of Nivolumab (OPDIVO®) & Pembrolizumab (KEYTRUDA®) in China, 2020-2021
2021 449 3363

Nivolumab
2020 245 1667 Pembrolizumab
Million RMB
Note:
• “First Posted Date” indicates the date when the study corresponding to the highest clinical phase in China was first available on
148
China Incidence of Liver Cancer, 2018-2030E
• In 2022, liver cancer is the 4th most common happened cancer in China and the incidence of it in China has grown from
400.2 thousand in 2018 to 441.7 thousand in 2022, representing a CAGR of 2.5%. It is expected that the prevalence will
increase to 483.8 thousand in 2026, and 524.7 thousand in 2030, at a CAGR of 2.3% and 2.0%, from 2022 to 2026 and
from 2026 to 2030, respectively.
Incidence of Liver Cancer in China, 2018-2030E

Period CAGR
2018-2022 2.5%
2022-2026E 2.3%
2026E-2030E 2.0%
Thousand
514.8 524.7
494.3 504.6
473.4 483.8
452.3 462.8
431.1 441.7
410.4 420.8
400.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

149
China Market Size of Liver Cancer Therapies, 2018-2030E
• In 2018, the market size of liver cancer therapies reached 4.6 billion RMB, and reached 10.3 billion RMB in 2022 with a
CAGR of 22.2%. It is predicted that the number will continue to grow, and reach 24.6 billion RMB by the year of 2026,
42.0 billion RMB by the year of 2030, with CAGR of 24.4% and 14.2% respectively.
China Market Size of Liver Cancer Therapies, 2018-2030E
Period CAGR
2018-2022 22.2%
2022-2026E 24.4%
2026E-2030E 14.2%
Billion RMB
42.0
37.7
33.3
28.8
24.6
20.7
16.8
13.4
9.9 10.3
4.6 6.9 7.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

150
China Incidence of Pancreatic Cancer, 2018-2030E
• The incidence of pancreatic cancer in China has grown from 104.9 thousand in 2018 to 120.0 thousand in 2022,
representing a CAGR of 3.4%. It is expected that the prevalence will increase to 137.1 thousand in 2026, and 155.2
thousand in 2030, at a CAGR of 3.4% and 3.2%, from 2022 to 2026 and from 2026 to 2030, respectively.
Incidence of Pancreatic Cancer in China , 2018-2030E

Period CAGR
2018-2022 3.4%
2022-2026E 3.4%
2026E-2030E 3.2%
Thousand
146.0 150.6 155.2

132.7 137.1 141.5
120.0 124.1 128.4
108.4 112.0 115.9
104.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

151
China Market Size of Pancreatic Cancer Therapies, 2018-2030E
• In 2018, the market size of pancreatic cancer therapies reached 2.5 billion RMB, and reached 3.2 billion RMB in 2022
China Market Size of Pancreatic Cancer Therapies, 2018-2030E
Period CAGR
2018-2022 5.9%
2022-2026E 32.0%
2026E-2030E 15.2%
Billion RMB
16.9
15.1
13.3
11.5
9.6
7.8
6.1
4.5
2.5 2.7 2.7 3.0 3.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
152
Overview of Age-related Macular Degeneration
• Age-related macular degeneration (AMD) is a major blindness-causing disease in the elderly population, which can be
divided into dry AMD and wet AMD (wAMD) according to its pathological features. Wet AMD is also known as
neovascular AMD (nAMD), and it can lead to irreversible visual impairment and seriously affect the quality of life of
patients. In AMD patients, approximately 10% are wAMD. However, 80%~90% cases of vision loss are from wAMD
patients.
• Although AMD tends to occur in one eye at a time, approximately 50% of patients who have wAMD in one eye will also
develop this condition in their second eye within 5 years.
Category of AMD
Dry AMD Wet (Neovascular ) AMD
• 80%-90% of the AMD patients have dry AMD (also called • wAMD is a less common type of late AMD that usually causes faster
atrophic AMD). This is when the macula gets thinner with age. vision loss, only 10-20% of the AMD patients are diagnosed with
Dry AMD happens in 3 stages: early, intermediate, and late. It wAMD. Any stage of dry AMD can turn into wAMD — but wAMD is
usually progresses slowly over several years. There’s no always late stage at first dignosis. It happens when abnormal blood
treatment for late dry AMD, but patients can take steps to slow its vessels grow in the back of the eye and damage the macula. 90% of
progression such as taking vitamin supplements, having healthy the treatment options are for wAMD, such as anti-VEGF medicines,
diets and stop smoking. photodynamic therapy and photocoagulation.
Risk Factors of AMD
Smoking, Hypertension, and

Cardiovascular Disease Levels of Antioxidants Genetic Factors Aspirin Diet
• Cigarette smoking is the main modifiable risk factor that has been consistently identified in numerous studies. Smoking
cessation is strongly recommended when advising patients who have AMD or are at risk for AMD.
• Additional risk factors include low systemic levels of antioxidants, genetic factors, aspirin use and dietary fat.
153
China Prevalence of Wet Age-related Macular Degeneration, 2018-
2030E
• With increased aging population, the number of patient pool will increase steadily. From 2018 to 2022, the number of
wet age-related macular degeneration patients in China have increased from 3.5 million to 4.0 million, representing a
CAGR of 3.0%. It is estimated that people with wAMD in China will achieve 4.4 million by 2026. and 4.7 million by 2030,
with a CAGR of 1.5% during this period.
Prevalence of Wet Age-related Macular Degeneration in China, 2018-2030E
Period wAMD
2018-2022 3.0%
2022-2026E 2.4%
2026E-2030E 1.5%
Million
4.5 4.6 4.7

4.3 4.4 4.4
4.0 4.1 4.2
3.8 3.9
3.5 3.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Source: NCCR, Frost & Sullivan analysis

154
China Prevalence of Diabetic Macular Edema(DME), 2018-2030E
• From 2018 to 2022, the number of diabetic macular edema patients has increased from 6.5 million to 7.3 million,
representing a CAGR of 2.7%. The total number of China diabetic macular edema patients is forecasted to reach 7.9
million by 2026E, representing a CAGR of 2.3% from 2022 to 2026E, and to 8.5 million by 2030E with a CAGR of 1.8%
from 2026E to 2030E.
Prevalence of Diabetic Macular Edema in China, 2018-2030E
Period CAGR
2018-2022 2.7%
2022-2026E 2.3%
2026E-2030E 1.8%
Million
8.1 8.3 8.4 8.5

7.4 7.6 7.8 7.9
6.7 6.9 7.1 7.3
6.5
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
155
Treatment Paradigm of Diabetic Macular Edema (DME)
China has become the world's largest country in the number of diabetes patients, and the prevalence of DR among
diabetes patients has risen to 34.6% and has not been effectively controlled.
The development of DR assessment technology and the advancement of treatment methods have made rapid progress.
Wide angle fluorescein fundus angiography (FFA), wide angle coherence tomography (OCT), and wide-angle OCT
angiography (OCTA) have improved the diagnosis and evaluation of DR. In particular, the recognition of retinal fluid,
subretinal fluid (SRF), and retinal strong reflex point (HRF) through OCT provides objective biological imaging markers for
disease severity, prognosis, and drug response.
DME
• DME: Diabetic Macular

Edema
I-IV Stage V-VI Stage • CSME: Clinical
Significant Macular
Edema
• VEGF: Vascular
Endothelial Growth
CSME Non-CSME
Factor
Treatment after
diagonis Focused laser Vitrectomy
Photocoagualtion combined Anti-VEGF
With anti-VEGF therapy/Corticosteroids
Therapy/Corticosteroids
Source: IDF, Frost & Sullivan Analysis

156
Treatment Paradigm of Age-Related Macular Degeneration
• In patients with neovascular AMD, early detection and prompt treatment improves the visual outcome. There are different types of
neovascular AMD with CNV based on fluorescein angiography, and their treatments are slightly different.
• Intravitreal injection therapy using anti-VEGF agents is the most effective way to manage neovascular AMD and represents the first
line of treatment. verteporfin PDT and thermal laser photocoagulation surgery remain approved options for the treatment of
subfoveal lesions, and they are usually used in combination therapy with anti-VEGF agents.
Age-Related Macular Degeneration (AMD)
wAMD
(Bleeding, leaking from vessels)

Extrafoveal
Juxtafoveal
CNV
and subfoveal
CNV
• CNV: Choroidal
neovascularization
Lesions • RAP: Retinal angiomatous
Classic CNV Classic CNV proliferation
without classic RAP PCV
Lesions≥50% Lesions<50% • PCV: Polypoidal choroidal
CNV
vasculopathy
• PDT: Photodynamic
Predominantly Minimally therapy
Occult
classic classic
First
Locally
Line First line: anti-VEGF biologics photocoagulati
Disease
Progression anti-VEGF on therapy or
biologics ± anti-VEGF
Second Second line: anti-VEGF biologics + PDT if hardly PDT biologics
Line regular visits in predominantly classic type
Source: CMA, Literature Review, Frost & Sullivan Analysis

157
Treatment Paradigm of Wet Age-related Macular Degeneration and
Unmet Needs
wAMD is one of the broad categories of retinal diseases among common ophthalmic diseases, and the current first-line
treatment for wet AMD is intraocular injection of anti-VEGF drugs, with representative medications such as Ranibizumab,
Compazepam, Aflibercept, and Bevacizumab. In the area of anti-vascular endothelial growth factor inhibitors, ranibizumab
has emerged as one of the leading drugs in the treatment of choroidal neovascularization.
Treatment for wAMD Unmet Needs
Ralizumab is mainly used to treat the disease by blocking

1 Increasing Economic Burdens for Patients
vascular leakage and closing the choroidal vessels, which not • Intraocular injections of anti-VEGF drugs
Ranibizumab only does not cause damage to the choroid and neuroretina, require frequent injections to have a good
but also selectively blocks the neovascularization, effectively therapeutic effect, but frequent dosing
avoiding the formation of dark spots. can add a financial burden to the patient.
Compazepine intravitreal injection for wAMD significantly 2 A High Recurrence Rate after PDT
Compazepam improves visual acuity and reduces CRT thickness, with a • Photodynamic therapy (PDT) may result
First-line Medication
good safety profile. in inadequate choroidal perfusion, a

Compared to Ranibizumab, patients with wAMD treated with significant inflammatory response at the
Aflibercept had six fewer injections over two years, but had treated site and increased VEGF
Aflibercept comparable visual acuity benefits, which could reduce the expression, with a risk of compromising
financial burden on providers and patients' families to some long-term visual prognosis and a high
extent. recurrence rate.
The approved indications for Bevacizumab do not include 3 Limited Effects on Reducing Inflammation
macular degeneration ophthalmic disease, but the drug is
• Frequent injections carry a heavy
mechanistically perfectly suited for the treatment, except that
Bevacizumab therapeutic burden and patients not only
the dosage form used for oncology needs to be diluted 40-100
times, and this makes Bevacizumab for macular degeneration have to overcome fear with each injection
very inexpensive. but also face the risk of infection.
• Anti-VEGF therapy can effectively inhibit
Photodynamic therapy (PDT) for wet AMD is effective in neovascularization but has limited effect
Photodynamic preventing further expansion of the disease, and PDT within
on reducing the inflammation that leads to
Therapy (PDT) the anti-VEGF injections is now one of the main therapies for
wAMD treatment.
wAMD.

158
Mechanism of VEGF×ANG2 Targeted BsAbs and Clinical
Advantages
VEGF (endothelial growth factor) and ANG2 (angiopoietin 2) are important proteins functioning in vasculogenesis,
angiogenesis and cell migration. Abnormally upregulation of those molecules causes inflammation and destabilizes the
endothelial cell layer, which then leads to hypervascular permeability. VEGF/ANG2 bispecific antibody simultaneously
binds to both VEGF and ANG2 and prevents the endothelial barrier from breakdown, diminishes the symptoms of wAMD.
Changes of Eyes
Risk Factors
Mechanism of VEGF/ANG2 bispecific antibody
Source:Biomedicines. 2022 Aug 17;10(8):1996., Cells, 2019, 8(5): 471., Expert Opinion on Investigational Drugs, 2021, 30(3): 193-200., J Ophthalmol.
2012;2012:786870. Frost & Sullivan Analysis 159
China Competitive Landscape of VEGF Targeted Biologics for Eye
Diseases
Marketed Products in China
Approval Time of
Product Drug Name Company Target Drug Type
wAMD
诺适得 Lucentis Ranibizumab Novartis VEGF mAb 2011-12-31
Chengdu Kanghong
朗沐 Conbercept-KH902 VEGF Fusion Protein 2013-11-29
Biotechnology Co., Ltd
艾力雅 Eylea Aflibercept Bayer VEGF Fusion Protein 2018-02-02
China Pipeline
Highest First
Drug
Product Drug Name Company Target Indication Clinical Posted
Type
Phase Date
DME, macular edema secondary to
branch RVO, wAMD, CRVO or
F. Hoffmann-La Roche
Faricimab Injection Faricimab ANG2, VEGF BsAb hemi-retinal vein occlusion III 2021/7/6
Ltd
secondary to macular edema,
polypoidal choroidal vasculopathy
Jiangsu T-mab Bio-
MW02 9MW0211 Pharmaceuticals Co., VEGF mAb wAMD III 2020/12/25
Ltd..
China Novartis Proliferative diabetic retinopathy
Brolucizumab
Brolucizumab Institutes for BioMedical VEGF mAb (DR), wAMD, CRVO, macular III 2019/7/29
Injection
Research Co.,Ltd. edema secondary to branch RVO
TOT
TAB014 Monoclonal Bevacizumab-
Pharmaceutical(Suzhou VEGF mAb wAMD III 2021/5/19
Antibody Injection TAB014
)Co.,Ltd.
Shanghai Henlius
HLX04-O HLX04-O VEGF mAb wAMD III 2021/9/27
Biotech, Inc.

160
Diseases
China Pipeline

Product Drug Name Company Target Drug Type Indication
Clinical Phase Date
Recombinant Anti-VEGF
Bio-Thera
Humanized Monoclonal BAT5906 VEGF mAb wAMD III 2022/5/16
Solutions
Antibody Injection
Diabetic Macular
RC28-E Injection RC28-E RemeGen Co., Ltd. FGF2,VEGF Fusion Protein III 2023-05-25
Edema
Shanghai Henlius
HLX04-O, recombinant anti Biotech, Wet age-related
VEGF humanized Bevacizumab - Inc.|Shanghai macular
VEGF mAb III 2023-04-17
monoclonal antibody eye HLX04-O Henlius degeneration
injection Biopharmaceutical, (nAMD)
Inc.
Recombinant Human
Vascular Endothelial
Huabo Biopharm
Growth Factor Receptor- HB002.1M VEGF Fusion Protein DME, wAMD II 2020/6/9
Co., Ltd.
Antibody Fusion Protein for
Ophthalmic Injection
Efdamrofusp Innovent Biologics VEGF, C4b,
IBI302 Fusion Protien wAMD, DME II 2022/6/7
alfa (Suzhou) Co. Ltd. C3b
Langxin Qisheng
Wet age-related
(Suzhou) Gene
LX102 Injection LX102 VEGF macular II 2023/01
Biopharmaceutical treatment
degeneration
Co., Ltd
Wuhan Youzhiyou wAMD, DME and
Biopharmaceutical other ocular
Y400 Y400 ANG2,VEGF BsAb I/II 2023/04/27
Co., Ltd, neovascularization
CMS Vision related diseases

161
Diseases
China Pipeline

Clinical Phase Date
hPV19 Monoclonal
Affecizx（ Suzhou Stainwei
Antibody Ophthalmic VEGF mAb AMD, DME I 2018/11/1
hPV19） Biotech Inc.
Injection
Innovent Biologics VEGF,

IBI333 IBI333 Fusion Protein wAMD I 2022/10/20
(Suzhou) Co. Ltd. VEGFC
Innovent Biologics VEGF,

IBI324 IBI324 BsAb DME I 2022/6/17
(Suzhou) Co. Ltd. ANG2
Suzhou Aosaikang
ANG2,VEG
ASKG-712 ASKG-712 Biopharmaceutical Fusion Protien wAMD I 2022/7/29
F
Co., Ltd.
Jiangsu Aosaikang Diabetic

ANGPT2,V
ASKG712 Injection ASKG712 Pharmaceutical Fusion Protein Macular I 2023-05-29
EGFA
Co., Ltd. Edema
Wet age-
Chengdu Hongji related
Approved for
KH631 Eye Injection KH631 Biotechnology Co., VEGF Gene treatment macular 2023-02-02
clinical trial
Ltd degeneration
(nAMD)
162
Global Competitive Landscape of VEGF Targeted Biologics for Eye
Diseases
Global Marketed
Approved
Date
wAMD, RVO, DME, DR,

CIMERLI Ranibizumab-eqrn Coherus Biosciences Inc. VEGF mAb Myopic Choroidal 2022/8/2
Neovascularizatio(mCNV)
VABYSMO(Fari
Faricimab-svoa Genetech Inc. ANG2, VEGF BsAb wAMD, DME 2022/1/28
cimab)
SUSVIMO Ranibizumab Genetech Inc. VEGF mAb wAMD 2021/10/22
BYOOVIZ Ranibizumab-nuna Samsung Bioepis Co. Ltd. VEGF mAb wAMD, RVO, mCNV 2021/9/17
BEOVU Brolucizumab-dbll Novartis Pharms Corp. VEGF mAb wAMD, DME 2019/10/7
Antibody-receptor
EYLEA Aflibercept Regeneron Pharmaceuticals VEGF wAMD, RVO, DME, DR 2011/11/18
Fusion Protein
wAMD, RVO, DME, DR,

LUCENTIS Ranibizumab Genetech Inc. VEGF mAb 2006/6/30
mCNV

163
Global Competitive Landscape of VEGF Targeted Biologics for Eye
Diseases
Global Pipeline
Highest
First Posted
Product Drug Name Company Target DrugType Indication Clinical
Date
Phase
Bayer Macular
Pharmaceuticals | edema Approved for
Aflibercept Aflibercept VEGF Fusion Protien 2023/4/28
Regeneron secondary to listing
Pharmaceuticals branch RVO
GR，SMO，ANXA1
Fluocinonide Alimera Sciences | ，ANXA2，ANXA3 Visual Approved for
Faricimab BsAb 2023/4/25
Faricimab Genentech ，ANXA4，ANXA5 impairment listing
ANGPT2，VEGFA
Boehringer
BI 836880 BI 836880 VEGF, ANG2 BsAb wAMD I/II 2019/3/4
Ingelheim
Innovent Biologics
IBI324 IBI324 VEGF, ANG2 BsAb DME I 2022/8/5
(Suzhou) Co. Ltd.
Summary of other Clinical-stage VEGF Targeted Biologics:

• Number of ADC: 1
• Number of fusion proteins: 13
• Number of mAbs: 16

164
China Market Size of Anti-VEGF Agents for Retinal Diseases, 2018-
2030E
• The market size of anti-VEGF agents for retinal disease in China is experiencing a rapid growth. The market size of anti-
VEGF agents for retinal disease in China has grown from RMB 2.0 billion in 2018 to RMB 4.3 billion in 2022, with a
CAGR of 21.0%. The market will keep growing to RMB 10.2 billion in 2026 and RMB 21.7 billion in 2030, with a CAGR
of 18.9% and 20.9% respectively.
China Market Size of Anti-VEGF Agents for Retinal Diseases, 2018-2030E

Period CAGR
2018-2022 21.0%
2022-2026E 18.9%
2026E-2030E 20.9%
Billion RMB
21.7
18.7
15.7
12.8
10.2
8.0
6.3
3.9 4.3 4.9
2.0 2.6 2.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
165
Unmet Needs and Future Trends of wAMD Treatment
• The efficacy of current drugs decreases quickly, most of which must be administered repeatedly, sometimes
High Revisit every month, over a long period of time. As AMD is a chronic disease, patients need to return regularly for
Burden and monitoring and treatment visits. Real-life observational studies show that this burden, along with adherence
Inconvenient aspects, often leads to undertreatment and subsequent visual loss.
Unmet Needs
Method of • At present, most drugs are given by eye ejection and lacking durable treatments intensified this inconvenience,
which means wAMD patients need to have eye injections every one or two months, and this lead to low patient
Administration
compliance.
• Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs has become the common treatment
Inefficiency of for AMD, but its disadvantage is significant. single-target VEGF inhibitors will promote the upregulation of other
angiogenic factors, which impairs the efficacy of treatment.
Current • Studies show that despite optimal individualized treatment, the visual function may slowly deteriorate due to
Treatments other AMD-related disease processes. Additionally, there is not yet a treatment available to slow or halt the
progression of the nonexudative late-stage “dry” manifestation of AMD.
• wAMD is a chronic disease and its incidence increases with aging. With the growth of the aging population,
Enlarged Market the group size of wAMD patients in China would be enlarged and the associated need for effective treatment
Size and is supposed to be increased.
Enhanced • At present, only a few drugs for wAMD are marketed and promoted to the rising need for wAMD treatment
Competition and the expiration of the core patent of the original research drug, more biosimilars will enter the market in the
future, which would intensify the market competition.
Future Trends
Improved • With the development of gene therapy in the wAMD treatment, patients in the future could avoid eye injections
and get various more comfortable and safe methods of administration.
Administration • With more durable drugs generated, the frequency of revisit will decrease which then leads to higher patient
of Drugs compliance.
More Durable • At present, intravitreal injection of anti-VEGF monoclonal antibody drugs is the common treatment for wAMD,
Treatment which is not efficient in inhibiting angiogenesis. Therefore, in the future durable drugs which could block both
Required VEGF and other angiogenic factors are expected to be innovated due to their longer half-life period.

166
Unmet Needs and Future Trends of DME Treatment
Difficulties in • DME is caused by a buildup of fluid in the macula, which damages the optic disc and leads to advanced vision
diagnosis and loss. However, due to its slow progression, few symptoms could be diagnosed in the early stages, which
makes diagnosis difficult, and associated delay in treatment.
adverse caused • DME is a common complication of diabetes and is very sensitive to changes in blood glucose levels. To control
Unmet Needs
by diabetic the complication, patients have to keep taking diabetic medicines, which may lead to some adverse, like
drugs headaches and drug resistance.
• Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs has become the common treatment
Inefficiency of for DME, but its disadvantage is significant. VEGF mAbs will promote the upregulation of other angiogenic
current factors, which impairs the efficacy of treatment. Besides, multiple injections causes heavy economic burdens
treatments for patients，and repeated injections may lead to other complications and lower patient compliance.
• Laser treatment may lead to retinal nerve fiber layer damage.
Innovative • Improving the awareness of the pre-clinical diagnosis benefits early detection and treatment. This goal might
be promoted by the increased trends of digital therapy of DME. Home monitors and Artificial intelligence
diagnostic reading films can detect or monitor central visual field distortion or scotoma in various macular and optic disc
methods diseases, and data collected in this way could assist doctors in more accurate diagnoses.
Future Trends
Develop • Combination therapy can reduce the incidence of certain complications. Small molecule drugs are commonly
combination used as adjuncts to antibody therapy Besides, vitrectomy combined with dexamethasone Mison implants are
therapy proven to be efficient in the treatment of DME.
• Multi-target antibody therapy like Faricimab (BsAb) has higher efficacy than mAbs, which could also help to
New therapies deal with the multi-times injection issue.
• Innovative gene therapy can reduce patient pain, which helps to improve patient compliance.

167
Mechanism and Advantages of VEGF x TGF-β Targetd BsAbs in
Solid Tumor Therapy
Advantages
• The multipronged effects of TGF-β on tumor stroma cells built the TME, including its
capacity to stimulate ECM production, activate CAFs, suppress the immune system, Synergistic Functions
and promote angiogenesis. TGF-β inhibition facilitates restoration of tumor sensitivity
to tumor-specific cellular therapies. • Silencing of tumor-derived VEGF or TGF-β
• VEGF has a dual role in endothelial cell proliferation and vascular permeability. The induced early and pleiotropic up-modulation of
dual inhibition of VEGF and TGF-β may have a stronger anti-angiogenesis effect. immune responses detected in tumor tissue
• Dual effects of Anti-VEFG and anti-TGF-β BsAbs prevent the growth of tumors by transcriptomes. Compared to single inhibitor
limiting immune evasion, fibroblast activation, angiogenesis, etc. treatment, The combination of VEGF and
TGF-β inhibitory drugs is synergistic, which
Mechanism of VEGF x TGF-β Targted BsAbs leads to a substantial spontaneous tumor
eradication rate.
Modulate TME
• VEGF/VEGFR and TGF-β pathways play an
important role in the development and function
of the TME, contributing to the
immunosuppressive status of TME. To inhibit
VEGF/VEGFR and/or TGF-β pathways can
restore TME from immune-suppressive to
immune-supportive status and enhance
sensitivity to anti-PD-(L)1 treatment
Stronger Anti-angiogenesis Effect

• Inhibition of TGFβ signaling renders the
endothelial cells more sensitive to VEGF-
induced sprouting, which might induce
adverse effects including the induction of
tumor angiogenesis. Due to the cross-talk
between VEGF and TGF-β pathways, the dual
inhibition of VEGF and TGF-β may have a
stronger anti-angiogenesis effect.

168
Competitive Landscape of VEGF x TGF-β Targeted Medications
Global Pipeline

Type Phase Date
PD-L1, VEGF, Fusion Advanced Solid

PM8003 Biotheus Inc. China I 2021/7/30
TGF-β Protien Tumors
Suzhou Zelgen FDA IND

Fusion Advanced Solid Global \
ZGGS18 Biopharmaceuticals VEGF, TGF-β Approval
Protien Tumors
Co., Ltd.. China I/II 2022/10/20
Note:

169
Overview of Vaccines
• Vaccines contain substances that resembles disease-causing agents, and works by triggering antigen-specific humoral
and cellular immune responses in the recipient.
• Following entry into recipient, vaccine antigens are recognized by the host immune system. Through intricate signaling
pathways and interplay between different various immune cell types, antigen-specific, long-lasting memory B-
lymphocytes are generated to provide long-term protection.
Description
• Vaccines of are administrated in various methods. Classic means of vaccine

Vaccine administration involves intravenous/intramuscular injection. Recently, other
Administration methods such as skin patches, aerosols via inhalation devices, gene guns are
also being developed.
• Antigens are first non-specifically detected by innate immune system which

distinguishes non-self from self.
• The antigens are endocytosed by macrophages and then delivered to antigen
Immune
presenting cells (APC). The APC process and present the antigens on the cell
Response
membrane to activate T and B cells for adaptive immune responses. B cells
produce antibodies to neutralize pathogens while T cells specifically target
infected/damaged/tumor cells and mediate cytotoxicity.
• After the first immune response, memory T and B cells are generated. When
Long-term the antigens are detected again in the future, memory cells can rapidly elicit an
Protection efficient, antigen-specific immune response to eliminate the invading pathogen
before onset of symptoms, providing protection to the vaccine.

170
General Mechanism of Vaccines
• Vaccines are a type of preventive pharmaceutical product that trains the body’s immune system so that it can fight a
disease it has not come into contact with before.
• Most vaccines are designed to prevent disease, but with the recent developments, therapeutic vaccines are so capable
to treat many diseases.
MOA
• A vaccine works by training the

Vaccines are usually administrated
immune system to recognize
by intramuscular injection. Other
and eliminate pathogens and methods include subcutaneous and
tumor cells. After certain intradermal injection, nasal spray
antigens from the pathogen or and gene gun.
tumor cells are introduced the
immune system then can safely
learn to recognize them as
B cells triggered to produce
hostile invaders, and initiate antigen-specific antibodies while T
immune responses to clean up cells are activated to recognize
these threats. infected or tumor cells.
• When the antigens reappear in
the future, the immune system
will recognize them immediately
and generate sufficient immune
Both humoral and cellular immunity
responses leading to inhibition of are activated to eliminate
pathogen replication and tumor pathogens and tumor cells.
growth which eventually protect
human bodies from diseases.

171
Global Development History of Vaccines
• In the past decades, we have seen the application of molecular genetics in furthering our understanding of immunology, microbiology
and genomics and their integration in vaccine research. Following the outbreak and widespread of COVID-19, traditional vaccine
development and production periods are too long, a more effective and universal vaccine platform is required to contain the pandemic.
The development of mRNA vaccines represents a promising alternative to the conventional approach due to their high potency, short
development period, low cost of manufacture and safe administration. Molecular genetics sets the scene for a bright future for vaccines,
including the development of new vaccine delivery systems and adjuvants.
1700s 1798: Development of first smallpox vaccine Key takeaways

1800s 1885: First live-attenuated vaccine – live-attenuated rabies
1886: First inactivated vaccine – cholera, plague, typhoid • The first smallpox vaccine was developed in 1798. It
1900s 1900s: Toxoid vaccines – diphtheria and tetanus toxoids opened the door for the development of vaccines. In 18th
1932: First use of adjuvants in vaccines – aluminum century, Louis Pasteur’s experiments spearheaded the
1948: First combination vaccines – diphtheria, tetanus and pertussis development of live attenuated cholera vaccine and
1955: Subunit vaccines – Polio (injected, inactivated) vaccine inactivated anthrax vaccines.
1981: First recombinant antigen vaccine - HBV • Adjuvant is a substance that accelerates, prolongs or
enhances antigen-specific immune response when used in
Boom of New Vaccines
combination with vaccine antigens. Aluminum was first
2000-2010 2000: Meningococcal (group C) vaccine used in human vaccines in 1932. Other common adjuvants
2000: Pneumococcal (heptavalent pneumococcal conjugate) vaccine used include AS04, MF59, AS01B and CpG 1018.
2000: First case of reverse vaccinology –
• In the late 1980s and early 1990s, polynucleotides
Serogroup B meningococcus
expressing gene products were tested in gene therapy
2005: Meningococcal (quadrivalent meningococcal conjugate) vaccine
experiments, which induced an immune response in the
2006: Combined Hib vaccine
body and set up a research boom in nucleic acid vaccines.
2008: HPV
2010: PCV13 (13-valent pneumococcal conjugate) • In 2000, Rino Rappuoli led a team that used bioinformatics
2010: First therapeutic vaccine – Provenge for prostate cancer to screen a strain of meningococcus and identify several
novel antigens. This gave a faster and more efficient in
2013 Synthetic biology speeds up vaccine development – avian influenza
silico approach for locating vaccine target.
2013 Shingles: Children’s Influenza Rotavirus
• In 2020, the world’s first mRNA vaccine began its rollout
2015 Meningococcal B: Meningococcal ACWY after being produced at unprecedented speed as part of the
2017 Individualized neoantigen vaccine – malignant melanoma global effort to end the COVID-19 pandemic. The two
mRNA COVID-19 vaccines (made by Pfizer/BioNTech and
2017 Hexavalent: DTaP/IPV/Hib/HepB
Moderna) mark the first time mRNA vaccine technology has
2020 First mRNA vaccine - COVID-19 vaccines, e.g. Pfizer, Moderna been approved for use.

172
Classification of Vaccines
Classification Features Advantages Disadvantages

Virus-based
Vaccines
• Risk of virus infection

Inactivated / Live- Killed or attenuated virus, • Production: Long history with • Limited immunogenicity, usually need
attenuated Virus maintaining antigenicity mature manufacturing technology multiple doses
• Complex virus production process
Protein-based
Vaccines
Purified viral antigens or in vitro • Limited immunogenicity, usually
Purified/Recombinant • Production: Easier for large-scale
synthesized recombinant require adjuvant for stronger immune
production
Protein protein response
• Efficacy: Improved immunogenicity
Structural proteins necessary to • Complex production process, low
Virus-like Particles form a virus particle
than purified/recombinant protein;
production speed
activating innate immune response
Nucleic Acid-
based Vaccines
Development
• Efficacy: Activating innate immune

• More serious side effects
response
Viral Vector Vaccine • Low gene delivery efficiency caused
Nucleic acids • Production: Mature production
by existing immunity to virus vectors
introduced into cells process
• Efficacy: Lower dosage with longer- • Gene integration risk
Antigen time antigen expression • Usually need delivery system
DNA Vaccine • Production: Easier for large-scale
expression • Toxicity of lipid particles and
production impurities
• Efficacy: Lower dosage with longer-
• Easy to degenerate, difficult to store
Immune response time antigen expression, activating
• Short half life, need delivery system
mRNA Vaccine innate immune response
• Toxicity of lipid particles and
• Production: Easier for large-scale
impurities
production, fast update speed

173
Classification of Vaccines
Classification Features Advantages Disadvantages
Subunit Vaccine
• Limited immunogenicity, usually

Purified/Recombinant Protein particles from the virus • Production: Easier for large-scale
require adjuvant for stronger immune
Protein or recombinant virus antigens production
response
• Efficacy: Improved immunogenicity

Structural proteins necessary to • Complex production process, low
Virus-like Particles form a virus particle
than purified/recombinant protein,
production speed
activating innate immune response
Conjugate
Vaccines
made by chemically linking

• Efficacy: improved immune
(conjugating) a protein • Costly to produce
response to the vaccine; helping the
molecule with a tiny amount of • No protection against antigenic
Conjugate vaccines immature immune system react to
variation
the polysaccharide that makes
the coating and develop an immune
up the cell coating of the • May interfere with other vaccines
response
bacterium.
Combination
Vaccines
Development
• Production: less delivery cost of

• Difficulties in preparing and testing
2 or more vaccines given in a vaccines
• The higher the level of combination,
Combination vaccines single dose that protects • Efficacy: Fewer shots, but same
the greater the probability and
against more than 1 disease protection; fewer delays in disease
magnitude of adverse reactions
protection

174
Overview of COVID-19 Outbreak Timeline and Milestone
Dec. 1 Dec. 31 Jan. 8 Jan. 12 Jan. 16 Feb. 10 Mar. 16 Mar. 17
2019 2020
• The first • China officially • Thailand • The first • Researchers from • The COVID- • Moderna‘s • China
patient was reported to the identified their known death German Centre for 19 death toll COVID-19 launched the
reported in WHO of the first COVID-19 from the novel Infection Research surpassed that vaccine, clinical trials
Hubei, possibility of a case, which coronavirus (DZIF) developed a of the SARS, mRNA-1273, for its first
Wuhan new virus with was also the was recorded prototype of the first with 908 commenced coronavirus
symptoms of first recorded • China publicly diagnostic test in reported first human vaccine
pneumonia case outside of shared the the world that could deaths in trials in the
China genetic help in identifying China United States
sequence of COVID-19
COVID-19
Apr. 2 Apr. 7 May. 1 May. 28 Jun. 1 Jun. 7 Jul. 13 Dec. 31 Dec. 31

2021
• Total global • China • FDA granted an • United States • Eli Lilly • The first • The SARS- • Total global • As of Dec. 31,
COVID-19 ended EUA to COVID-19 announced SARS-CoV-2 CoV-2 COVID-19 there were 4
cases lockdown remdesivir after death toll the world's neutralizing neutralizing cases COVID-19
surpassed of Wuhan an NIH trial surpassed first study of antibody antibody Brii- around 80 vaccines in
1 million found the 100,000 an antibody JS016, which 196 entered million the global
treatment treatment, was co- clinical trial market.
accelerated referred to as developed by
recovery in LY-CoV555, Junshi and
individuals with designed to Lilly, entered
advanced fight COVID- the clinical
COVID-19 and 19 stage in China
lung involvement
175
Overview of Coronaviruses and COVID-19
Overview of Coronaviruses
• Coronaviruses are a large family of viruses, which may cause illness in animals or humans. They are widely distributed in many different
species of animals, including bats, cattle, cats, birds, and camels. They are also one of the pathogens that causes respiratory tract
infections in human.
• Coronaviruses are RNA viruses. Their distinctive spike proteins, about 9 to 12 nm, give them the appearance of a solar corona.
• In humans, several coronaviruses are known to cause respiratory infections ranging from the common cold to more severe diseases
such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The mortality rates were 10% for
SARS-CoV and 34.4% for MERS-CoV.
Overview of COVID-19
1 Introduction 3 Transmission
• COVID-19 is the infectious disease caused by the most recently • The disease spreads from person to person mainly through small
discovered coronavirus. It is a beta-coronavirus and is the 7th liquid particles from the nose or mouth, which are expelled when
pathogen identified to cause human respiratory tract infection. an infected coughs, sneezes, or speaks. These particles’ size
• The disease is more likely to infect older people. The Centers for ranges from respiratory droplets to smaller aerosols.
Disease Control and Prevention (CDC) reported that although • COVID-19 could also be transmitted by touching the
individuals older than age 65 comprise 17% of the total population contaminated surface and then touching eyes, nose or mouth.
in the United States, they make up 31% of COVID-19 infections, 4 Complications
45% of hospitalizations, 53% of intensive care unit admissions,
and 80% of deaths caused by these infections. • Complications such as severe pneumonia, hypoxemia, respiratory
failure, ARDS, pulmonary oedema, secondary infection, sepsis,
2 Symptoms septic shock, cardiac injury, and multiple organ failure including
fatal outcomes, have been reported in various studies in China.
• Common symptoms at onset of illness were fever, dry cough,
dyspnea, fatigue, myalgia, and anorexia. 5 Treatment
• Less common symptoms were headache, sore throat, rhinorrhea, • Until now, no specific treatment has been confirmed effective for
dizziness, abdominal pain, diarrhea, nausea, vomiting and treating this emerging coronavirus infection except for meticulous
confusion. supportive care.

176
Analysis of the Spreading Factors of COVID-19
• COVID-19 spreads primarily through droplets generated when an infected person coughs, sneezes or speaks. People
can also become infected by touching a contaminated surface and then touching the eyes, nose or mouth before
washing hands.
COVID-19 COVID-19
Transmission Infectiousness
Droplet Transmission COVID-19 is spreading very easily
The disease spreads primarily from person to person through small droplets and sustainably between people:
from the nose or mouth, which are expelled when a person with COVID-19 • It is reported household
coughs, sneezes, or speaks. People who are in close contact (within 1
contacts and those travelling
meter) with an infected person can catch COVID-19 when those infectious
with a case were at higher risk
droplets get into their mouth, nose or eyes.
of infection than other close
contacts.
Contact Transmission
• The household secondary
People with the virus in their noses and throats may leave infected droplets
attack rate was 11.2% and
on objects and surfaces (called fomites) when they sneeze, cough on, or
touch surfaces, such as tables, doorknobs and handrails. Other people may
children were as likely to be
become infected by touching these objects or surfaces, then touching their infected as adults (infection rate
eyes, noses or mouths before cleaning their hands. 7.4% in children <10
years vs population average of
Aerosol Transmission 6.6%).
Aerosols that remain infectious when suspended in air over long distances • The COVID-19 virus can
and time could be an infectious agent. A recent case study of a dozen survive for up to 72 hours on
passengers infected with COVID-19 after taking a bus suggested that the plastic and stainless steel, less
coronavirus can survive at least 30 minutes and transmit 4.5 meters in a than 4 hours on copper and
closed air-conditioned environment. But further studies are needed to less than 24 hours on
determine their significance for transmission of COVID-19. cardboard

177
Analysis of Variants and Impact on Vaccine Development
• COVID-19 virus is constantly changing through mutations, leading to a number of changes in many aspects of the virus. Most of
the mutations have negligible impact on virus properties or even causing a decrease in pathogenicity. However, mutations in
critical genes, especially in genes coding spike-proteins, are potentially turning the virus more aggressive and infectious. Until now,
there’re 4 variants of concern (VOCs) threatening people across the world.
Features of COVID-19 Variants New Features of Variants
VOCs First Spotted Key Mutations

Mutations have led to many new features including
transmissibility increase, disease severeness
Beta (B.1.351) South Africa, May. 2020 N501Y, K417N, E484K
increase, antibody neutralization reduction,
Alpha (B.1.1.7) UK, Sep. 2020 N501Y, 69-70del, P681H effectiveness reduction of treatments or vaccines,
and diagnostic failures.
“Double Mutant”
Among the 4 mutations, Delta variant has evolved
Delta (B.1.617.2) India, Oct. 2020 several key mutations including
L452R, D6146, P681R, etc. to be more contagious than others with
potential reduction of treatment and vaccination
outcomes.
Gamma (P.1) Brazil, Nov. 2020 N501Y, K417T
Impact on Vaccine Development
Constantly Updating Vaccines Technology Developments
With the mutation of COVID-19 virus, certain changes in virus spike Vaccine manufacturing companies are optimizing the original
protein may end up with a decrease of the vaccine efficacy. technologies, but also seeking opportunities in new vaccine designs to
Manufacturing companies need to update vaccines constantly to catch fight the virus. Many companies are developing innovative vaccines
up with the variants. for larger scale production and broader protection against variants.
Source: WHO, CDC, Frost & Sullivan Analysis

178
Comparison Among 4 Types of COVID-19 Vaccines
• Various technologies are used to generate COVID-19 vaccines, and the following table summarizes the 4 main
approaches broadly investigated around the world.
Mechanism Advantage Limitation Examples
Established technical pathway; Large dose;

Use killed pathogen to Quick and scalable May cause antibody- • Sinovac CoronaVac;
Inactivated Vaccine induce the production of manufacturing; dependent enhancement • Sinopharm (Beijing)
antibodies Effective; (ADE); BBIBP-CorV
Use the spike (S) protein of

Safe and effective;
Recombinant Subunit SARS-CoV-2 as the antigen antigenicity subject to the • Anhui Zhifei Lingcom RBD-
Established technical pathway;
Protein Vaccine to induce the production of expression system Dimer
Scalable manufacturing;
antibodies
Use viral vector that cause Long R&D process;

no harm to human body to May have pre-existing
Safe and effective;
carry the gene of the spike immunity (has infected with • CanSino Ad5-nCoV;
Few side effects;
Viral Vector Vaccine (S) protein into the body, the vector virus before so that • Oxford/AstraZeneca
Easy administration and less
and produce the spike (S) there are neutralizing AZD1222
doses taken;
protein to trigger production antibodies against the vector
of antibodies virus in the body)
Direct injection of the gene Scalable manufacturing

of the spike (S) protein, use No need to express protein or process need optimization;
• Moderna Mrna-1273;
Nucleic Acid Vaccine human cell to produce virus during manufacturing; mRNA is not stable;
• Pfizer/BioNTech BNT162b2
antigen and then trigger Safe Difficult for the vaccine to
production of antibodies enter cells
Source: Literature review, Frost & Sullivan analysis

179
Approved COVID-19 Vaccines Worldwide
Approved
Manufacturer Product Name Platform Type of Vaccine Doses
Regions
Full-length spike protein modified by two
Pfizer / BioNTech BNT162b2 mRNA US, Europe 2
proline mutations
Moderna / NIAID mRNA-1273 mRNA Prefusion stabilized full-length spike protein US, Europe 2
Takeda TAK-919 mRNA Prefusion stabilized full-length spike protein Japan 2
AstraZeneca / Adenoviral vector ChAdOx1 containing

AZD1222 Viral Vector US, Europe 2
University of Oxford SARS-CoV-2 spike protein gene
Covishield (ChAdOx1_nCoV-
Serum Institute of India Viral Vector RBD SARS-CoV-2 HBsAg VLP vaccine India, Brazil 2
19)
Janssen Adenovirus serotype 26 vector containing

Ad26.COV2.S Viral Vector US, Australia 1
Pharmaceutical SARS-CoV-2 spike protein gene
Recombinant adenovirus serotype 26
The Gamaleya National
Sputnik V Viral Vector particles containing the sars-cov-2 protein S Russia, Angola 2
Center
gene
Recombinant serotype 26 adenoviral
The Gamaleya National
Sputnik Light Viral Vector particles containing the sars-cov-2 S protein Russia, Angola 1
Center
gene
Recombinant novel coronavirus vaccine China,
Cansino Ad5-nCoV Viral Vector 1
(adenovirus type 5 vector) Argentina
A DNA plasmid vector pvax1 carrying gene
Zydus Cadila ZyCoV-D DNA expressing spike-s protein of sars-cov-2 India 3
and ige signal peptide
As of March 2023
Source: WHO, Company Website, Frost & Sullivan analysis

180
Approved
Regions
Sinopharm Beijing SARS-CoV-2 Vaccine (Vero
Inactivated Virus Inactivated SARS-CoV-2 HB02 strain China, Brazil 2
Institute Cell), Inactivated (lnCoV)
Sinopharm Wuhan SARS-CoV-2 Vaccine (Vero China,

Inactivated Virus Inactivated SARS-CoV-2 HB02 strain 2
Institute Cell), Inactivated (lnCoV) Philippines
Shenzhen Kangtai SARS-CoV-2 Vaccine (Vero Inactivated SARS-CoV-2 vaccine (Vero China,
Inactivated Virus 2
Biotechnology Cells) cell) Indonesia
Shifa Pharmed COVID-19 Inactivated Inactivated SARS-CoV-2 vaccine (Vero

Inactivated Virus Iran 2
Industrial Co Vaccine cell)
Inactivated SARS-CoV-2 vaccine (Vero Kazakhstan,

Kazakhstan RIBSP QazVac Inactivated Virus 2
cell) Kyrgyzstan
SARS-CoV-2 Vaccine (Vero

Sinovac Inactivated Virus Inactivated SARS-CoV-2 CN2 strain China, Brazil 2
Cell), Inactivated
Whole virion Inactivated SARS-CoV-2

Bharat Biotech BBV152 Inactivated Virus India, Iran 2
Vaccine
Vaxine/CinnaGen Co. COVAX-19 Protein subunit Recombinant spike protein + adjuvant Iran 2
Recombinant Novel
China,
Zhifei Longcom, China Coronavirus Vaccine (CHO Protein subunit Recombinant SARS-CoV-2 RBD protein 3
Indonesia
Cell)
Center for Genetic
Engineering and CIGB-66 Protein subunit CIGB-66 (RBD+aluminium hydroxide) Russia 3
Biotechnology
As of March 2023

181
Manufacturer Product Name Platform Type of Vaccine Approved Regions Doses
Nuvaxovid (NVX- SARS-CoV-2 recombinant spike (40 countries) US,

Novavax Protein subunit 2
CoV2373) protein+lipids+adjuvant Europe, Canada, India
A recombinant receptor-binding
Baqiyatallah University of
Noora Protein subunit domain-based protein subunit Iran 1
Medical Sciences
vaccine
Beijing WANTAI
Del-NS1-2019- A attenuated influenza virus of
Biological/University of Hong viral vector China 2
nCOV recombinant SARS-CoV-2 RBD gene
Kong/Xiamen University
A recombinant replication-deficient
Bharat Biotech BBV154 viral vector
adenovirus vectored vaccine with a India 2
pre-fusion stabilized spike protein
An active yeast-based receptor
Bio Farma Indovac Protein subunit binding domain of the SARS-CoV-2 Indonesia 2
spike protein
Biological E/Baylor College of the Receptor Biding Domain of the
Medicine/Texas Children's Corbevax Protein subunit spike protein + adjuvanted with CpG Botswana, India 2
Hospital 1018 and alum
SARS-CoV-2 strain AYDAR-1
Belarus, Cambodia,
Chumakov Covi-Vac (KoviVac) Inactivated antigen inactivated by beta- 2
Russian Federation
propiolactone
A trimeric form of the SARS-CoV-2
Clover Biopharmaceuticals SCB-2019 Protein subunit spike protein + adjuvants AS03 or China 2
CpG/Alum
Erciyes University Turkovac Inactivated The SARS-CoV-2 inactivated vaccine Turkey 2
Cambodia, Russian
Vector State Research Center Three peptides of the spike protein
EpiVacCorona Protein subunit Federation, Turkmenistan, 2
of Virology and Biotechnology and a chimeric protein
Venezuela
As of March 2023

182
Approved
Regions
Vector State Research Three peptides of the spike protein + viral
Aurora-CoV Russian
Center of Virology and Protein subunit nucleocapsid protein + bacterial maltose- 1
(EpiVacCorona-N) Federation
Biotechnology binding protein
Cuba, Iran,
The SARS-CoV-2 spike protein conjugated
Finlay Soberana 2 Protein subunit Nicaragua, 2
chemically to tetanus toxoid
Venezuela
A vaccine composed of SARS-CoV-2
Finlay Soberana Plus Protein subunit Receptor Binding Domain protein (sequence Belarus, Cuba 1
319-541)
A recombinant adenoviral vector based on
Russian
Gamaleya Research Institute Sputnik M viral vector human adenovirus serotype 26 + serotype 5 2
Federation
carrying the gene for the S-protein
In-vitro a mRNA-based vaccine using Spike
Gennova GEMCOVAC-19 mRNA India 2
(S)-protein of the virus as antigen
Institute of Medical Biology of
IMBCAMS COVID-19
the Chinese Academy of Inactivated Inactivated SARS-CoV-2 vaccine (vero cell) China 2
vaccine (Covidful)
Medical Sciences
Recombinant novel coronavirus fusion protein
Livzon Pharmaceutical V-01 Protein subunit expressed in recombinant CHO cells + China 1
aluminum hydroxide adjuvant
Eswatini,
Paraguay,
Medigen MVC-COV1901 Protein subunit Gene recombinant spinin S-2P+adjuvant 2
Somaliland,
Taiwan
Recombinant COVID-
National Vaccine and Serum The antigens from multiple SARS-CoV-2
19 Vaccine (CHO cell, Protein subunit UAE 1
Institute strains
NVSI-06-08)
Organization of Defensive
FAKHRAVAC Inactivated An inactivated virus-based vaccine Iran 2
Innovation
As and Research
of Dec 2021
As of March 2023

183
Approved
Regions
PT Biotis/Airlangga University Inavac Inactivated Inactivated SARS-CoV-2 vaccine Indonesia 2
Razi Vaccine and Serum A recombinant protein subunit vaccine

Razi Cov Pars Protein subunit Iran 3
Research Institute containing the SARS-CoV-2 spike protein
(30 countries)
Sanofi/GSK VidPrevtyn Beta Protein subunit Spike protein of the Beta variant + adjuvant 1
France, UK
An engineered baculovirus containing a gene for

Serum Institute of India Covovax Protein subunit India 2
a modified SARS-CoV-2 spike protein
Recombinant S trimer protein antigen (Alpha

Sinocelltech SCTV01C Protein subunit China 1
and Beta) + adjuvant
SK Bioscience/Institute for
SKYCovione Protein subunit SARS-CoV-2 Spike protein + adjuvant Korea 1
Protein Design
(10 Countries)
A vaccine (adenovirus type 5 vector) expressing China, Hungary,
Tianjin CanSino CONVIDECIA viral vector 1
the SARS-CoV-2 coronavirus spike protein Indonesia,
Malaysia
A vaccine (adenovirus type 5 vector) expressing
Tianjin CanSino Convidecia Air viral vector China, Morocco 1
the SARS-CoV-2 coronavirus spike protein
Inactivated SARS-CoV-2 + two adjuvants (alum (33 countries)

Valneva/Dynavax VLA2001 Inactivated 2
and CpG 1018) UK, Italy, UAE
mRNA encoding the RBD of the S protein of

Walvax/Suzhou Abogen AWcorna mRNA Indonesia 2
SARS-CoV-2
As of March 2023

184
Approved
Regions
Protein
WestVac Coviccine Recombinant COVID -19 Vaccine (Sf9 cell) China 1
subunit
Virus-like Recombinant spike (S) glycoprotein

Medicago Covifenz Canada 2
particle expressed as virus-like particles (VLPs)
(38 countries)
Ancestral SARS-CoV-2+Omicron Variant
Moderna Spikevax Bivalent (Original/Omicron BA.1) mRNA Australia, 1
(B.1.1.529)
Japan, UK
(33 countries)
Spikevax Bivalent (Original/Omicron Ancestral SARS-CoV-2+Omicron Variant
Moderna mRNA US, Japan, 1
BA.4/BA.5) (BA.4/BA.5)
Canada
Ancestral BNT162b2 + Omicron variant (35 countries)
Pfizer/BioNTech BNT162b2 Bivalent (WT/OMI BA.1) mRNA 1
BNT162b2 Omi (BA.1) Japan, France
Ancestral BNT162b2 + Omicron variant (33 countries)

Pfizer/BioNTech BNT162b2 Bivalent (WT/OMI BA.4/BA.5) mRNA 1
BNT162b2 Omi (BA.4/BA.5) USA, Japan
Protein COVID-19 Alpha/Beta/Delta/Omicron

Sinocelltech SCTV01E China 1
subunit variants S-trimer vaccine
A vaccine covering omicron variant BA.5

CSPC SYS6006 mRNA China 2
strain
As of March 2023

185
Global Historical Accumulated Cases of COVID-19
Global Cumulative Cases of COVID-19, July 2021– July 2022
Thousand
20000000
18000000
16000000
14000000
12000000
10000000
8000000
6000000
4000000
2000000
Note: COVID-19 pandemic is still progressing, the diagram above is updated as of the date August 12th, 2022

186
Global Historical New Cases of COVID-19
Global New Cases of COVID-19, July 2021 – July 2022

Thousand
100000
90000
80000
70000
60000
50000
40000
30000
20000
10000

187
China Historical Accumulated Cases of COVID-19
China Cumulative Cases of COVID-19, July 2021 – July 2022
Thousand
250
200
150
100
50
0
07/21 08/21 09/21 10/21 11/21 12/21 01/22 02/22 03/22 04/22 05/22 06/22 07/22

188
China Historical New Cases of COVID-19
China New Cases of COVID-19, July 2021 – July 2022

Thousand
70
60
50
40
30
20
10
0
07/21 08/21 09/21 10/21 11/21 12/21 01/22 02/22 03/22 04/22 05/22 06/22 07/22

189
Global Historical Accumulated Death of COVID-19
Global Cumulative Death of COVID-19, July 2021– July 2022

Thousand
250000
200000
150000
100000
50000

190
Global Historical New Death of COVID-19
Global New Death of COVID-19, July 2021 – July 2022

Thousand
350
300
250
200
150
100
50

191
China Historical Accumulated Death of COVID-19
China Cumulative Death of COVID-19, July 2021 – July 2022
Thousand
5.3
5.2
5.1
4.9
4.8
4.7
4.6
4.5
4.4
4.3
07/21 08/21 09/21 10/21 11/21 12/21 01/22 02/22 03/22 04/22 05/22 06/22 07/22

192
China Historical New Death of COVID-19
China New Death of COVID-19, July 2021 – July 2022
Thousand
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
07/21 08/21 09/21 10/21 11/21 12/21 01/22 02/22 03/22 04/22 05/22 06/22 07/22

193
Uncertainties of COVID-19 (Long-term Scenarios Analysis)
Infection Fatality Rate and Duration of Acquired Immunity Play an Important Role
Potential Long-term Effect Limited Moderate Severe Infection Fatality Rate

Duration of Acquired Immunity
Long • There are two measures used to assess

(>2 yrs) 1.0% infection the proportion of infected individuals with
0.6% infection 0.2% infection
fatal outcomes. The first is infection fatality
fatality rate with life fatality rate with life fatality rate with life
ratio (IFR), which estimates this proportion
long immunity long immunity long immunity
of deaths among all infected individuals.
The second is case fatality ratio (CFR),
1.0% infection 0.6% infection 0.2% infection which estimates this proportion of deaths
fatality rate with 6 fatality rate with 6 fatality rate with 6 among identified confirmed cases.
Short month immunity month immunity month immunity • It is hard to find out the true infection level
(<6 mons) in some countries, due to the high rates of
asymptomatic cases and limited testing
0.01 Infection Fatality Rate (IFR) 0.002
Duration of Acquired Immunity

• There is no evidence yet that infection of COVID-19 will ensure long-
lasting immunity to re-infection and the protective effect of the
COVID-19 vaccines are still under observation and need more time to
accumulate relevant data.
• Less durable immune response would make COVID-19 a circulating
endemic disease. According to the projection model built by Harvard
scholars, (A) a short duration (40 weeks) of SARS-CoV-2 immunity
could yield annual SARS-CoV-2 outbreaks. (B) Longer-term SARS-
CoV-2 immunity (104 weeks) could yield biennial outbreaks, possibly
with smaller outbreaks in the intervening years. (C) Higher seasonal
variation in transmission would reduce the peak size of the invasion
wave but could lead to more severe wintertime outbreaks thereafter
[compare with (B)]. (D) Long-term immunity (infinity) to SARS-CoV-2
could lead to elimination of the virus.
Source: Literature Research, Frost & Sullivan analysis
194
Overview of Recombinant Protein Vaccine
Recombinant Protein Advantages

Vaccine
Well-established technology
+ adjuvant Scalable manufacturing
Low reactogenicity, suitable for compromised

immunity
Relatively stable, ease of transport and storage,

Technical principle conventional cold chain transportation
Purified immunogenic proteins or peptides Potential Risk

make up subunit vaccines through genetic
engineering technique. The majority of CoV • Expected global excess capacity
subunit vaccines target the Spike protein, Access to capacity (especially for smaller
players) and requirements/timelines for
particularly its receptor binding domain which repurposing could potentially be a barrier to the
is highly immunogenic. Vaccination targets scale-up of capacity ready for COVID-19
include viral structural proteins such as small vaccines production.
envelope protein E, envelope spike protein S, • Antigenicity subject to the expression system
nucleocapsid protein N, and matrix protein M. Probably low expression level.
• Require adjuvant for stronger immune response

195
Overview of Recombinant Protein Vaccine II
Vaccination Procedure Safety
Few clinical adverse reactions
No virus cultivation, avoid the leakage of active

virus
Only contains RBD (receptor-binding domain)

protein, ensure high purity of the vaccines
Effectiveness
After vaccination, nearby cells pick up whole
spike protein of virus or its fragments. Then • Relevant clinical trials shows that after receiving 2
immune system distinguish those exogenous doses of vaccine, the positive transversion of true
proteins from host’s ones by antigenic epitope. virus neutralizing antibodies reached 83%, and after
The adjuvant in vaccine then affiliates to produce 3 doses, the positive transversion of true virus
antibodies and activate other immune cells to neutralizing antibodies reached 97% and the positive
transversion rate of RBD protein-binding antibodies
fight off antigens recognized by immune system. reached 99%.
At the end of the process, memory cells are
generated for future protection.

196
Industry Value Chain of Human Vaccine
• The first stage of vaccines industry value chain is the preparation of raw materials, which include primary cell, Vero
cell, human diploid cell and the serum.
• The virus are grown and cultured during fermentation process, such as the use of bioreactor. After the
fermentation process, the cell cultures harvested and purified, and then vaccine manufacturers completed
formulation, filing and packaging for vaccines.
End User &

Raw Material Fermentation Manufacturing Logistics Vaccination
Payer
Class I
Hospitals/ Primary
Vaccine User
Serum providers Healthcare
(Government
Institutions
Reimbursement)
Vaccine Vaccine Logistic

Bioreactor
Manufacturer Provider
Class II
Cell culture CDC-designated Vaccine User
providers Vaccination Points (Out-of-pocket
money)

197
China R&D of Recombinant Protein Vaccines in China
China Pipeline

Product Company Indication
Phase Date
Recombinant (Hansenula
Walvax Biotechnology Co., Ltd.,
Polymorpha) hepatitis B Hepatitis B Clinically approved 2014-04-03
Yuxi Walvax Biotechnology Co., Ltd.
vaccine
Recombinant Quadrivalent Shenzhen Sanofi Pasteur Biological Application in
Influenza prophylaxis 2019-09-27
Influenza Vaccine Products Co., Ltd. progress
Recombinant hepatitis B
Access to document
vaccine (Hansenula Beijing Minhai Biotechnology Co., Ltd. Hepatitis B 2013-09-18
number
Polymorpha)
Recombinant hepatitis B
Hualan Biological Engineering,Inc., Access to document
vaccine (Hansenula Hepatitis B 2014-01-10
Hualan Biological Bacterin Inc. number
Polymorpha)
Recombinant human HPV 16/18, cervical
Shanghai Zerun BIOTECHNOLOGY Co., Access to document
papillomavirus bivalent intraepithelial neoplasia, cervical 2014-09-26
Ltd. number
(16/18) vaccine (yeast) cancer
Recombinant human
papillomavirus bivalent Xiamen University, Access to document
HPV 16/18, cervical cancer 2015-06-01
(16/18) vaccine (escherichia Xiamen Gongli Yangsheng Hall Co., Ltd. number
coli)
Recombinant B subunit
bivalent O1/O139 cholera Shanghai United Cell Biotechnology Co., Vibrio Cholera O139/O1, Access to document
2015-07-27
vaccine (enteric-coated Ltd. diarrhea number
capsules)
Nine-valent human Yidao Biotechnology(Suzhou)Co., Access to document

Human papillomavirus infection 2023-05-24
papillomavirus vaccine Ltd.|Ab&b Biotechnology number

198
China Pipeline

Phase Date
Shanghai Qingsai Biotechnology Co.,

live attenuated mumps Access to document
Ltd|Beijing Saierfusen Biotechnology Co., Parotitis 2023-04-26
vaccine number
Ltd
Recombinant Hepatitis B CGC theravac Healthcare (Nanjing) Access to document

Hepatitis B 2023-04-03
Vaccine CO.,Ltd. number
Beijing Wantai Biological Pharmacy

Access to document
Hepatitis E vaccine Enterprise Co.,Ltd.|Xiamen Innovax Hepatitis E 2023-02-09
number
Biotech Co.,Ltd.|Xiamen University
Recombinant Staphylococcus Chongqing Yuanlun Biotechnology Co.,

Staphylococcal infection,
aureus vaccine (escherichia Ltd., III 2016-08-15
septicopyemia
coli) Third Military Medical University.
Lanzhou Biological Products Research

Institute Limited Liability
Bivalent recombinant Company.|BEIJING INSTITUTE OF
Gastroenteritis III 2023-05-26
Norovirus vaccine BIOLOGICAL PRODUCTS
CO.,LTD.|NATIONAL VACCINE &
SERUM INSTITUTE

199
China Pipeline

Clinical Phase Date
cervical cancer，
Taizhou Tiande Pharmaceutical Co., HPV 16/18/58 infections, genital
Ltd., disease，including：cervical dysplasia
Recombinant trivalent human
Aihui Import and Export Process For (cervical intraepithelial neoplasia),
papillomavirus vaccine III 2018-04-13
Russia Heihe City Heilongjiang, adenocarcinoma in situ, invasive
16/18/58 (escherichia coli)
Beijing Health Guard Biotechnology cancer, vulvar intraepithelial neoplasia,
INC. vaginal intraepithelial neoplasia, cancer
of vulva, vaginal cancer
cervical cancer，cancer of vulva,
vaginal cancer, precancerous lesions of
Recombinant human
the genitals, indiscriminate damage，
papillomavirus nine-valent
Shanghai Bovax Biotechnology Co., cervical intraepithelial neoplasia 1/2/3,
vaccine III 2018-09-12
Ltd. adenocarcinoma in situ, invasive
(6/11/16/18/31/33/45/52/58)
cancer, vulvar intraepithelial neoplasia
(Hansenula Polymorpha)
1/2/3, vaginal intraepithelial neoplasia
1/2/3, genital warts
Xiamen University，
Recombinant human HPV 6/11, condyloma accuminatum,
Beijing Wantai Biological Pharmacy
papillomavirus nine-valent HPV16/18/31/33/45/52/58, cervical III 2019-01-11
Enterprise Co., Ltd.,
vaccine (escherichia coli) cancer
Xiamen Innovax BIOTECH Co., Ltd.
Recombinant human
papillomavirus vaccine nine-
valent Abzymo Biosciences Co., Ltd.,
HPV-6/11/16/18/31/33/45/52/58 III 2019-01-22
6/11/16/18/31/33/45/52/58 Jiangsu Rec-Biotechnology Co., Ltd.
(Hansenula Polymorpha)

200
China Pipeline
Clinical Phase Date
HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58
human papillomavirus infection and the
resulting cervical cancer and other related
diseases,
prevent persistent infection with HPV types 6,
11, 16, 18, 31, 33, 45, 52 and 58 in men and
Recombinant nine-valent human their resulting genital warts, anal cancer, anal
papillomavirus vaccine Beijing Health Guard intraepithelial neoplasia (AIN1/2/3) and other
III 2019-05-22
(6/11/16/18/31/33/45/52/58) Biotechnology INC. diseases of external genital lesions,
(escherichia coli) prevent persistent infection due to human
papillomavirus (HPV) types 6, 11, 16, 18, 31,
33, 45, 52, 58, and diseases of CIN, VIN, VaIN,
AIN, cervical cancer, vaginal cancer, vulvar
cancer, anal cancer, and genital warts
(condyloma acuminatum) caused by HPV
infection of the above types
Third Military Medical
Recombinant Staphylococcus University,
Staphylococcus aureus infection III 2019-06-03
aureus vaccine(escherichia coli) Chongqing Yuanlun
Biotechnology Co., Ltd.
Xiamen Innovax
BIOTECH Co., Ltd.,
Recombinant bivalent human Human papillomavirus HPV6 and HPV11
Beijing Wantai Biological
papillomavirus vaccine (6/11) infections and the resulting condyloma II 2014-12-03
Pharmacy Enterprise Co.,
(escherichia coli) acuminatum and other diseases
Ltd.,
Xiamen University

201
China Pipeline
Clinical Phase Date
Vaccination with this vaccine stimulates the
body to develop immunity against human
Recombinant quadrivalent human papillomavirus. For the prevention of the
Shanghai Insititute of
papillomavirus (16/18/52/58) virus- following diseases caused by high-risk HPV
Biological Products Co., II 2019-03-08
like particle vaccine (Pichia types 16/18/52/58: (1) cervical cancer (2)
LTD.
pastoris) grade 2 and 3 cervical intraepithelial neoplasia
(CIN2/3) and adenocarcinoma in situ (3) grade
1 cervical intraepithelial neoplasia (CIN1)
Advanced solid tumors,
Recombinant EGF-CRM197 tumor Shanghai Huidun Bio- patients with non-small cell lung cancer who
II 2019-03-19
therapeutic vaccine Technology Co., Ltd. have failed first-line chemotherapy or first-line
chemotherapy with PD-1/PD-L1 inhibitors
Beijing Institute of
Biological Products Co.,
Recombinant norovirus bivalent Ltd., NATIONAL This vaccine is intended for the prevention of
(GI.1/GII.4) vaccine (Hansenula VACCINE & SERUM moderate/severe acute gastroenteritis caused II 2019-11-27
Polymorpha) INSTITUTE, Lanzhou by Norovirus GI.1 and GII.4 infections.
Institute of Biological
Products Co., Ltd.
For the prevention of cervical, vulvar, vaginal
Rescombinant fourteen-valent and anal cancers, intraepithelial neoplasia and
SinoCelltech Ltd.,
human papilloma virus vaccine adenocarcinoma in situ due to HPV 6, 11, 16,
Beijing Nuoning II 2021-05-26
(6,11,16,18,31,33,35,39,45,51,52, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
Biotechnology Co., Ltd.
56,58,59) (insect cells) human papillomavirus infection, as well as
genital warts caused by HPV6 and HPV11.
Recombinant herpes zoster Chengdu Maikekang

Varicella-zoster virus infection II 2023-05-08
vaccine (CHO cells) BioTechnology Co., Ltd.

202
China Pipeline
Clinical Phase Date
Shanghai Maikekang Biotechnology

Recombinant trivalent rotavirus Co., Ltd., For the prevention of rotavirus
II 2021-07-28
subunit vaccine MaxHealth Biotechnology Limited gastroenteritis in infants and children
Liability Company.
Yidao Biotechnology(Suzhou)Co.,
Recombinant herpes zoster
Ltd., Prevent shingles II 2021-10-26
Vaccine (CHO cells)
Ab$B Bio-Tech Co., Ltd.JS
Green Bamboo Biopharmaceutical

Vaccination of this product can
Recombinant herpes zoster (Zhuhai) Co., Ltd.,
prevent the disease caused by II 2022-01-30
Vaccine (CHO cells) Beijing Lvzhu Biological Technology
varicella-zoster virus infection
Co., Ltd.
Recombinant human epidermal Biotech Pharmaceuticals Co., Ltd.,

growth factor (EGF) -conjugated Beijing Jingyitaixiang Technology Advanced non-small cell lung cancer I 2014-12-22
vaccine Development Co., Ltd.
Changchun Institute of Biological

Recombinant HEV vaccine Products Co., Ltd. Prevent viral hepatitis E I 2015-08-07
Southeast University
Patients with HIV/AIDS whose viral

Recombinant Adenovirus AIDS National Institute for Viral Disease
load is controlled after antiretroviral I 2016-03-30
GAG Vaccine (AD5-HIVGAG) Control and Prevention, China CDC
therapy

203
China Pipeline
Clinical Phase Date
Recombinant human Jiangsu Rec-Biotechnology Co., For use in healthy women for the
papillomavirus 16/18 bivalent Ltd., prevention of HPV-16 and/or 18 I 2019-01-04
vaccine (Hansenula Polymorpha) Abzymo Biosciences Co., Ltd. infection and associated lesions
It is intended for use in women aged

9-45 years to induce antibodies to
Recombinant human
HPV types 6, 11, 16, 18, 31, 33, 45,
papillomavirus nine-valent virus-
Shanghai Zerun 52, and 58 to prevent infection with
like particle vaccine（6、11、16、 I 2019-03-08
BIOTECHNOLOGY Co., Ltd. the relevant types of viruses, as well
18、31、33、45、52、58 type L1
as genital warts, cervical, anal,
protein）（pichia pastoris)
vaginal, and vulvar cancers that may
result from infection.
Beijing Kexing Biology Product Co.,

Recombinant(Hansenula
Ltd., Hepatitis B Prevention I 2019-07-02
Polymorpha)hepatitis B vaccine
Sinovac Life Sciences Co., Ltd.
Immunoprophylaxis of Streptococcus
Recombinant pneumococcal
CanSino Biologics Inc. pneumoniae in infants, children and I 2019-09-06
protein vaccine
the elderly
Recombinant human Jiangsu Rec-Biotechnology Co., For use in healthy individuals for the
papillomavirus 6/11 bivalent Ltd., prevention of HPV-6 and/or 11 I 2021-01-22
vaccine (Hansenula Polymorpha) Abzymo Biosciences Co., Ltd. infection and related diseases
Recombinant Group B Beijing Zhifei Luzhu

Infectious diseases I 2023-04-26
Meningococcal Vaccine Biopharmaceutical Co.,Ltd

204
Future Trends of Recombinant Protein Vaccines
Recombinant protein vaccines bring more efficacy for the current vaccine technology
Mechanism of Recombinant Protein Vaccines Efficacy of Recombinant Protein Vaccines
• Recombinant protein vaccines missed out on

Humoral Immune Response Cellular Immune Response the early wave of investments from
government and industry. However, as
CD4*T cell recombinant protein vaccines are effective at
boosting pre-existing responses, emerging
data are suggesting that recombinant protein
Nabs Block CD8*T cell vaccines indeed might offer an advantage or
the binding to complement to the nucleic acid or viral vector
hACE2 vaccines that will likely reach the clinic
faster.
• Therefore, the difficulties ahead might
therefore be reduced for these recombinant
+ Stimulation of Th1 type CD4+ cells when protein vaccines, which could have an
+ Robust and durable B cell response formulated in combination with appropriate
+ High titers of Neutralizing antibodies important role in maintaining immunity
adjuvants
against COVID-19.
The Market is Expected to Grow as the Need for COVID-19 Vaccine Continues to Rise
• The demand for recombinant protein vaccines will grow in the future as the new coronavirus is expected to coexist with humans in
the long term.
• The recurrence of coronaviruses suggests possible future outbreaks and potential to become pandemic and therefore the process
of vaccine development should focus on wide host-range against several of the circulating CoVs to get flexible products within a
short period of time. This necessitates the alliance of recombinant platforms to bring more accuracy and predictable efficacy to the
current vaccine technology.
• Based on current clinical data, most of the COVID-19 vaccine candidates will require a boost injection to increase the cell-
mediated immune response, induce memory cells, and sustain high titers of neutralizing antibodies. This doubles the need for
vaccine supply, and it involves detailed patient follow up and logistical oversight.
205
Growth Drivers and Future Trends of Recombinant Subunit Protein
COVID-19 Vaccines
Supportive polices、unique strengths and unmet needs boost recombinant subunit protein vaccine market
Advantages of Recombinant Subunit
Supportive Polices Unmet Needs
Protein Vaccines
• Without active virus, recombinant

• Implementation of COVID-19 sequential
subunit protein vaccines are more safer
immunization strategy and immunization • Implementation of strengthen
than other types of COVID-19 vaccines
programs for autonomous selection boosts immunization policies creates
• The production process is more simple，
the vaccine market high demands for enhanced
thus mass production is easier to
• Vaccine Administration Law gradually needles in China
achieve
standardized the industry which • Rising aging population
• Recombinant subunit protein COVID-19
encourages the large-scale and intensive generates more demands of
vaccines works well on fighting against
production of vaccines and improved the preventive vaccines in China
both prototype strains and multiple
overall level of whole vaccine industry
variants
More player would be engaged in future market and the advantages of leading companies would be obvious
• Leading companies own various manufacturing pipelines and high-quality
Obvious Advantages of Leading
products , which would reinforce their dominant positions during further market
Companies differentiation in the future.
• With gradual increases of patients education and per capita disposable income
Vaccination as Usual in China , the penetration rate of vaccines would increase which would then
boost the expeditions of vaccine market in non-immunization programs.
• Producing recombinant subunit protein vaccine has lower biosecurity level
requirements for production halls. Besides, massive outputs and higher purity
More Players to Be Involved of productions could be achieved via transgenesis technology. These features
of recombinant subunit protein vaccines decides its higher return on investment,
which would trigger more participants joining in this market

206
Appendix 1
• As a result, additional boosting might be required because of waning immunity to the primary vaccination. Some recent studies
have shown that the antibody concentration declined in the third month after administration of two doses of inactivated vaccines,
and the protection rate of currently approved mRNA vaccines declined to approximately 40% in six months. These indicate a
significantly larger and longer-term market demand for booster shots and re-vaccination of COVID-19 vaccines
• As COVID-19 continues to spread and as new variants emerge, this indicates a great opportunity for Chinese vaccine
manufacturers with stable manufacturing capacity to enter the market
• with around 87% of global COVID-19 vaccines supply being allocated to a few high or upper-middle income countries, whereas
other less developed countries with large populations were only allocated around 0.2%
• As of the Latest Practicable Date, there were [15] COVID-19 vaccines that have been conditionally approved or granted for
emergency use in the PRC, of which [1] were mRNA vaccines, [5] were inactivated vaccines, [3] were recombinant adenovirus
viral vector-based and [6] were recombinant subunit protein vaccines. As of the same date, there were [32] clinical-stage COVID-
19 pipeline candidates in the PRC developed, of which [9] used the recombinant subunit protein route
• Around 45% of the globally marketed and in the clinical stage bispecific antibodies target CD3.
• High concentration rate to support different types of formulations. We are able to produce different types of formulation products,
such as lyophilized powder and injectables. Through the formulation screening and optimization, our BsAb formulations are able
to reach a concentration rate of 140mg/ml with low product viscosity and great stability, exceeding the industry average in China,
according to Frost & Sullivan.
• High expression level in upstream process development and optimization. To improve the production titers of target BsAbs, we
optimize the manufacturing process by adopting the Fed-Batch mode. With the optimized techniques, we are able to achieve the
average expression level for our Check-BODY antibodies and our Nano-YBODY™ antibodies of approximately 6.0g/L and 8.0g/L,
respectively, which are higher than the industry average, according to Frost & Sullivan.
• M802 became the first BsAb to file IND application in China.
• M701 became the second BsAb to file IND application in China.
• M701 is the first and only BsAb for MA treatment which received both FDA IND approval and enter Phase II clinical trials in China.

207
Appendix 2
• With respect to HER2-targeted therapies, there are currently 23 approved antibody drugs worldwide, and over 500 antibody
pipelines are in the clinical phase globally. For ICI mAbs, taking anti-PD-1 mAbs as an example, there are currently 16
approved drugs globally, and over 200 pipelines are in the clinical phase. Globally, there are 6 approved cell therapy products
(excluding genetically modified products) and 14 approved gene therapy products for the treatment of cancer.
• The development trend of China’s BsAb market from 2023 to 2025, having four BsAb products launched in 2023 and a rich
pipeline under development, is comparable to that of China’s anti-PD-1/PD-L1 mAb market from 2018 to 2020. China’s anti-PD-
1/PD-L1 mAb market grew at a CAGR of 278.3% from 2018 to 2020, with four PD-1/PD-L1 products launched in 2018.
• As of the Latest Practicable Date, there were 75 and 22 CD3 targeted antibody drug candidates or fusion proteins for the
treatment of MA, MPE, MM and solid tumors under clinical development globally (excluding China) and in China.
• As of the Latest Practicable Date, there were 65 and 56 PD-1/PD-L1 targeted antibody drug candidates or fusion proteins for
the treatment of solid tumors.
• As of the Latest Practicable Date, there was no TGF- targeted antibody drug or fusion protein approved for the treatment of
solid tumors globally. As of the same date, there were 20 and 16 TGF- targeted antibody drugs or fusion proteins for the
treatment of solid tumors under clinical development globally (excluding China) and in China, respectively.
• As of the Latest Practicable Date, there were 56 and 16 VEGF targeted antibody or fusion protein drug candidates for the
treatment of wAMD and DME under clinical development globally (excluding China) and in China, respectively.

208
Appendix 3
Incidence and market size of Breast Cancer，Gastric Cancer and
Ovarian Cancer in China, 2018-2030E
Incidence of Breast Cancer，Gastric Cancer and Ovarian Cancer in China, 2018-2030E
CAGR Breast Cancer Gastric Cancer Ovarian Cancer
2018-2022 1.5% 3.0% 1.8%
2022-2026E 1.2% 2.9% 1.3%
2026E-2030E 0.9% 2.6% 1.0%
Thousand 61.3 61.9 62.4
59.3 6… 60.7
57.0 57.8 58.5
53.0 53.9 55.3 56.2
543.6 558.8 574.0 589.4 604.6 619.6

455.8 469.6 483.9 498.6 513.5 528.5
442.3
320.7 326.2 331.6 336.3 341.0 345.5 349.8 353.9 357.8 361.4 364.8 367.8 370.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Breast Cancer Gastric Cancer Ovarian Cancer
Note：the epidemiological data for cancer in this stacked graph are non-accumulative
Market Size of Breast Cancer，Gastric Cancer and Ovarian Cancer in China, 2018-2030E
CAGR Breast Cancer Gastric Cancer Ovarian Cancer 46.4
2018-2022 8.1% 8.7% 69.2%
36.9
29.0
2022-2026E 10.3% 14.1% 42.9% 22.6
2026E-2030E 8.9% 9.6% 28.3% 17.1 82.5
76.0
6.6 12.6 69.6
4.1 9.2 63.2
Billion RMB 1.0 2.8 51.2 57.2
0.5 0.7 45.4
39.7
29.7 32.3 33.8
24.2 27.9 105.6 114.4
81.2 89.1 97.3
54.5 54.8 62.0 68.3 74.6
40.1 45.0 50.7
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Note：the market size data for cancer in this stacked graph are non-accumulative
209
Appendix4
China Incidence of Diabetic Macular Edema（DME）, 2017-2030E
• From 2017 to 2021, the number of diabetic macular edema patients has increased from 6.3 million to 7.1 million,
representing a CAGR of 2.8%. The total number of Chinese diabetic macular edema patients is forecasted to reach 7.9
million by 2025E, representing a CAGR of 2.7% from 2021 to 2025E, and to 8.9 million by 2030E with a CAGR of 2.3%
from 2025E to 2030E.
China Incidence of Diabetic Macular Edema（DME）, 2017-2030E
Period CAGR
2021-2021 2.8%
2021-2025E 2.7%
2025E-2030E 2.3%
Million
8.3 8.5 8.7 8.9

7.5 7.7 7.9 8.1
6.7 6.9 7.1 7.3
6.3 6.5
2017 2018 2019 2020 2021 2022E 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
210
Appendix 5
Incidence of Company’s Targeted Cancers in China，2018-2030E
Incidence of Company’s Targeted Cancers in China, 2018-2030E
Wet Age-
Malignant
Breast Gastric Ovarian Multiple Liver Pancreatic related Malignant
Period Pleural
Cancer Cancer Cancer Myeloma Cancer Cancer Macular Ascites
Effusion
Degeneration
2018-2022 1.5% 3.0% 1.8% 2.7% 2.5% 3.4% 3.4% 3.1% 2.6%
2022-2026E 1.2% 2.9% 1.3% 2.8% 2.3% 3.4% 2.4% 2.9% 2.4%
2026E-2030E 0.9% 2.6% 1.0% 2.5% 2.0% 3.2% 1.7% 2.6% 2.2%
4.7
4.6 155.2
Thousand 4.5 150.6
4.4 146.0
4.4 141.5
4.3 137.1
4.2 132.7 524.7
4.1 128.4 514.8
4 124.1 504.6
3.9 120.0 494.3
3.8 115.9 483.8 27.6
3.6 112.0 473.4 27
3.5 108.4 462.8 26.3
104.9 452.3 25.7
441.7 25
431.1 24.4
420.8 23.7
410.4 22.4 23 712.5 726.6
400.2 21.7 697.7
21.1 667.2 682.6
20.1 20.7 651.7
621.9 636.8
591.8 606.9
562.1 576.9
547.6
737.7 756.7 775.4

699.4 718.5
661.5 680.4
624.1 642.7
587.7 605.6
553.1 570.0
60.7 61.3 61.9 62.4
58.5 59.3 60.0
56.2 57.0 57.8
53.0 53.9 55.3
543.6 558.8 574.0 589.4 604.6 619.6
469.6 483.9 498.6 513.5 528.5
442.3 455.8
320.7 326.2 331.6 336.3 341 345.5 349.8 353.9 357.8 361.4 364.8 367.8 370.6
2018 2019 2020 2021 2022E 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
Malignant Pleural Effusion Malignant Ascites Multiple Myeloma
Liver Cancer Pancreatic Cancer Wet Age-related Macular Degeneration
Note：the epidemiological data for cancer in this stacked graph are non-accumulative
211
Appendix 6
Incidence of Hepatocellular Carcinoma (HCC) in China, 2018-2030E
• Due to factors such as alcohol abuse, HBV and HCV infections, the new case of HCC increases to the 397.5 thousand
in 2022 at a CAGR of 2.5% from 2018 to 2022, and is expected to reach 472.3thousand in 2030.
Incidence of HCC in China, 2018-2030E

Period CAGR
2018-2022 2.5%
2022-2026E 2.3%
2026E-2030E 2.0%
Thousand
463.3 472.3
444.8 454.2
426.0 435.5
407.1 416.6
388.0 397.5
369.4 378.7
360.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E

212
Appendix 7
Historical and Forecasted Market Size of China HCC Drug Market,
2018-2030E
• China HCC drug market increased from RMB4.6 billion in 2018 to RMB10.3 billion in 2022 at a CAGR of 22.2%. The
market will reach RMB24.6 billion in 2026, at a CAGR of 24.4% and will finally reach RMB42.0 billion in 2030.
Historical and Forecasted Market Size of China HCC Drug Market, 2018-2030E
Period CAGR
2018-2022 22.2%
2022-2026E 24.4%
2026E-2030E 14.2%
42.0
37.7
33.3
28.8
Billion RMB
24.6
20.7
16.8
13.4
10.3
8.9
6.9 7.2
4.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
213
Appendix 8
Incidence of Hepatocellular Carcinoma (HCC) and Pancreatic
Cancer (PC) in China, 2018-2030E
Incidence of HCC and PC in China, 2018-2030E
Hepatocellular Pancreatic Cancer
CAGR
Carcinoma (HCC) (PC)
2017-2021 2.5% 3.4%
2021-2025E 2.3% 3.4%
2025E-2030E 2.0% 3.2%
463.3 472.3
444.8 454.2
Thousand 426.0 435.5
407.1 416.6
388.0 397.5
369.4 378.7
360.2
146.0 150.6 155.2

132.7 137.1 141.5
120.0 124.1 128.4
108.4 112.0 115.9
104.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
HCC Pancreas
214
Appendix 9
Market Size of Hepatocellular Carcinoma (HCC) and Pancreatic
Cancer (PC) in China, 2018-2030E
Market Size of HCC and PC in China, 2018-2030E

Hepatocellular Pancreatic Cancer
CAGR
Carcinoma (HCC) (PC)
2018-2022 22.2% 5.9%
2022-2026E 24.4% 32.0%
2026E-2030E 14.2% 15.2%
42.0
37.7
Billion RMB
33.3
28.8
24.6
20.7
16.8 16.9
15.1
13.4 13.3
11.5
10.3 9.6
8.9
6.9 7.2 7.8
6.1
4.6 4.5
2.5 2.7 2.7 3.0 3.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E
HCC Pancreas
215
Appendix 10
HCC Treatment Options in China
• In China, HCC is a large economic burden with a huge patient pool, low accessibility, low affordability and ill-educated, providing
new entries with great growth potential.
• China’s HCC treatment options can be classified into locoregional and systemic therapies. Locoregional therapies can be further
categorized into liver resection, liver transplantation, ablation, arterially directed therapies, radiation therapy and
radioimmunotherapy(RAIT). The company’s products belong to the immunotherapy under systemic therapies.
CN HCC Treatment Options
Systemic chemotherapy FOLFOX 4
Molecular targeted drug 1L: Donafeni, Lenvartini, sorafenib
Systemic Therapy
First line:Anti-PD (L) 1 antibodies

（Atezolizumab+bevacizumab,
Sintilimab+bevacizumab analogues）
Immunotherapy
Second line: Regofinib*, Apatinib*, Karelizumab*,
Tirelizumab*
*Drugs that are not yet approved in China.
Source: NHC, Frost & Sullivan analysis

216
Appendix 11
Treatment Paradigm of Pancreatic Cancer in China
• The treatment of pancreatic cancer mainly includes surgical treatment, radiotherapy, chemotherapy, interventional
therapy, ERCP related treatment and TCM treatment. Currently, the option of targeted therapies is quite limited. Several
targeted therapies besides erlotinib have been assessed in combination with gemcitabine, but none has been shown to
significantly impact outcomes.
Pancreatic Cancer
Resectable Pancreatic
Cancer
Unresectable Local Progression or Distant Metastasis
Borderline Resectable Pancreatic Cancer
Pancreatic Cancer
Good Physical Fitness Poor Physical Fitness
• FOLFIRINOX
• mFOLFIRINOX
• Gemcitabine+Erlotinib/Capecitabine/Tegio/Cisplatin/Albumin-
bound paclitaxel
First Line • Tegio
• Olaparib maintenance therapy • Gemcitabine
• CapeOx • Fluorouracil monotherapy
• 5-FU/LV
• FOLFIRI
Disease • Nanoliposome irinotecan+5-FU/LV
Progression • Pemborolizumab (Only patients with microsatellite instability)
• Nanoliposome irinotecan+5-Fu/LV
• FOLFIRI
Second Line • FOLFIRINOX/GP/mFOLFIRINOX
• CapeOX
• FOLFOX
• Pemborolizumab (Only patients with microsatellite instability)
Source: NHC, Diagnosis and treatment of pancreatic cancer (2018), Frost & Sullivan analysis
217
Appendix 12
Competitive Landscape of EpCAM and CD3 Targeted Drugs
Global Pipeline

Phase Date
A-337 ITabMed Ltd. EpCAM, CD3 BsAb Solid Tumors China I 2023/08/02
Advanced
BA3182 BioAtla EpCAM, CD3 BsAb United States I 2023/04/01
Adenocarcinoma
Wuhan YZY
M701 EpCAM, CD3 BsAb MA, MPE, Solid Tumor China I/II 2022/09/30
Biopharma Co., Ltd.
Stomach Neoplasms
Advanced Gastric
III 2020/07/17
LintonPharm Co., Carcinoma With
Catumaxomab EpCAM, CD3 BsAb China
Ltd. Peritoneal Metastasis
Non-Muscle-Invasive
I/II 2021/04/12
Bladder Cancer
Urinary Bladder
Catumaxomab LINDIS Biotech EpCAM, CD3 BsAb Germany I 2020/07/07
Neoplasms
AcadeMab
AM-928 EpCAM mAB Solid Tumors United States I 2023/01/07
Biomedical
Qilu Antibody
Non-Muscle Invasive
VB4-845 Pharmaceutical Co., EpCAM fusion China III 2021/04/13
Bladder Cancer
Ltd. protein
TM4SF1- positive chimeric
Shanghai
antigen receptor T-cell
Biomedunion EpCAM,
therapy,EpCAM- positive CAR-T Solid Tumors China NA 2019/10/29
Biotechnology Co., TM4SF1
chimeric antigen
Ltd.
receptor T-cell therapy
218
Appendix 13
Addressable MA Patients of M701 in China
Addressable MA Patients of
Unit 2030E
M701 in China
Incidence of MA Thousand 726.6
Treatment Rate % 82.3
Local Therapy Rate % 90.0
Addressable Patients Thousand 538.4
219
Appendix 14
Addressable MPE Patients of M701 in China
Addressable MPE Patients of

Unit 2030E
M701 in China
Incidence of MA Thousand 775.4
Local Therapy Rate % 90.0
220
Appendix 15
Addressable rrMM Patients of Y150 in China
Addressable rrMM Patients of

Unit 2030E
Y150 in China
Incidence of MM Thousand 27.6
rrMM Prevalence Thousand 83.6
2nd-Line Treatment Rate % 83.5
221
Appendix 16
Addressable Breast Cancer Patients of M802 in China
Addressable Breast Cancer Patients of

Unit 2030E
M802 in China
Breast Cancer Incidence Thousand 370.6
Total Late Stage HER2+ Breast Cancer

Thousand 49.6
Patients*
3rd-Line Treatment Rate % 48.0
222
Appendix 17
Addressable Gastric Cancer Patients of M802 in China
Addressable Gastric Cancer Patients of

Unit 2030E
M802 in China
Gastric Cancer Incidence Thousand 619.6
Total Late Stage HER2+ Gastric Cancer

Thousand 109.0
Patients
3rd-Line Treatment Rate % 61.0
223
Appendix 18
Addressable HCC Patients of Y101D in China
Addressable HCC Patients of

Unit 2030E
Y101D in China
Incidence of HCC Thousand 472.3
Late Stage HCC Patients Thousand 236.1
1st-Line Treatment Rate % 94.0
224
Appendix 19
Addressable Pancreatic Cancer Patients of Y101D in China
Addressable Pancreatic Cancer Patients of

Unit 2030E
Y101D in China
Incidence of Pancreatic Cancer Thousand 155.2
Late Stage Pancreatic Cancer Patients Thousand 124.1
1st-Line Treatment Rate % 84.0
225
Appendix 20
Addressable DME and wAMD Patients of Y400 in China
Addressable DME Patients of

Unit 2030E
Y400 in China
Prevalence of DME Thousand 8,548.8
Treatment rate % 30.0
Addressable wAMD Patients of

Unit 2030E
Y400 in China
Prevalence of wAMD Thousand 4,702.4
Treatment rate % 70.0
226

Market Study of Innovative Biologics: Independent Market Research Report

Uploaded by

Copyright:

Available Formats

Market Study of Innovative Biologics: Independent Market Research Report

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Market Study of Innovative Biologics: Independent Market Research Report

Uploaded by

Copyright:

Available Formats

Market Study of Innovative Biologics

Independent Market Research Report

Frost & Sullivan

China Aging Population Trend, 2018-2030E

Source: NBSC, Frost & Sullivan Analysis

China Healthcare Expenditure, 2017-2030E

Source: NHC, Frost & Sullivan Analysis

1. Discovery 2. Pre-clinical 3. Clinical and Registration

Source: Frost & Sullivan Analysis

5. Commercialization 6. Terminal Consumption

Source: Frost & Sullivan Analysis

China R&D Expenditure, 2017-2030E

Source: Frost & Sullivan Analysis

Global Pharmaceutical Market, 2018-2030E

1,209.3 1,230.9 1,248.4 1,264.1 1,279.2 1,293.7 1,307.6

China Pharmaceutical Market, 2018-2030E

Chemical Drugs Traditional Chinese Medicine Biologics

Segmentation of Biologics Market

Antibodies therapy is a form The vast majority of

Source: Literature Review, Frost & Sullivan Analysis

Marketing Authorization Holder (MAH)

Dynamic Adjustment of NRDL via Price Negotiation

Source: Government Website, Frost & Sullivan Analysis

• Lengthy review and • Priority review and enable

• A drug must be in a Phase II • Accepting foreign clinical data

Source: Government Website, Frost & Sullivan Analysis

R&D Evolution of MAH System in China

Preclinical & Clinical Trials

Commercialization Commercialization Manufacture

Distribution & Retailing

Source: Government Website, Frost & Sullivan Analysis

Manufacturing CMO Some wholesalers act as

Contract with Commission CSO

Source: Government Website, Frost & Sullivan Analysis

• Deepening review and approval system reforms. Establishing a more

Source: Government Website, Frost & Sullivan Analysis

Source: Government Website, Frost & Sullivan Analysis

Announcement on the Release of Quality

Source: Government Website, Frost & Sullivan Analysis

• Drug research and development institutions or scientific research

Source: Government Website, Frost & Sullivan Analysis

Source: Government Website, Frost & Sullivan Analysis

Source: Government Website, Frost & Sullivan Analysis

• In order to encourage the development of pharmaceutical industry,

Source: Government Website, Frost & Sullivan Analysis

Guidance from the National Health

• According to the policy, the 2022 medical insurance catalog

Source: Government Website, Frost & Sullivan Analysis

Unit: Million People 2015 2016 2017 2018 2019 2020

URBMIS 376.9 448.6 873.6 897.4 1025.1 1016.8

UEBMIS 288.9 295.3 303.2 316.8 329.3 344.6

NRCMIS* 670.0 275.0 133.0 130.0 \ \

Population in China 1,374.6 1,382.7 1,390.0 1,395.4 1,400.1 1,411.8

Coverage Rate 92.3% 73.7% 94.2% 96.4% 96.7% 96.4%

Progression of NRDL Recent Progression of 6th NRDL Keep Implication

Source: Official Website, Frost & Sullivan Analysis

Annual Novel Drug Approvals by NMPA, 2016- 2021

Not in National Reimbursement Drug List(NRDL)