Exscientia’s Post

RNAi-based drug design: Synthetic siRNAs, which trigger RNAi, hold immense promise for specifically silencing virtually any therapeutic target with exceptional potency and long-lasting effects. However, delivering these innovative therapeutics to patients presents significant challenges, with delivery being a paramount concern. While various siRNA drug classes are undergoing clinical trials, and several have been FDA-approved for hepatic diseases, their effectiveness in treating diseases outside the liver remains limited, necessitating ongoing innovation. This review explores key considerations and future directions for designing therapeutic siRNAs, focusing particularly on the critical interplay between siRNA chemistry, informatics-driven approaches, delivery strategies, and meticulous target selection – all of which influence therapeutic success. https://lnkd.in/eqTERxwr #genetics #genomics #precisionmedicine #genomicmedicine #rnai #rna #vaccines #immunology #immunity #drugdesign #drugdevelopment #therapeutics #clinicaltrial #clinicalresearch #pharmacology #biotechnology #innovation #reseach #science #sciencecommunication

Biotech firms are facing challenges in treating viral liver infections, particularly the transition from addressing hepatitis C to tackling hepatitis B, according to Fierce Biotech. Despite some recent advancements in hepatitis B treatments, economic constraints and historical under-prioritization of hepatitis B pose obstacles. Recent industry developments, such as strategic acquisitions and positive data from clinical trials, suggest a renewed focus on hepatitis B research, even as investor attention appears to be shifting toward other liver diseases such as nonalcoholic steatohepatitis. Check out this and 4 other top news stories from the week: https://bit.ly/47DKoZf Other stories: - FDA’s oncology office uses advisory committee to spotlight timely accelerated approval confirmation - New study shows one in five experience rebound COVID after antiviral drug - Exodus of life sciences researchers from academia to industry and the impact on scientific progress - Study details revived debate over GLP-1 impact on devices

An Exciting Update in TB Drug Development! Ganfeborole Shows Promise in Phase 2 Clinical Trial We are proud to share a summary of our research as highlighted in a recent article published in Nature Medicine, with Prof. Andreas Diacon, the founding member of TASK, as lead author, and Dr. Veronique de Jager as study Principal Investigator. A phase 2 clinical trial conducted at TASK and in partnership with the AnTBiotic Consortium, has shown evidence of a significant anti-tuberculosis (TB) effect for the novel drug Ganfeborole, developed by GSK. The study showed the ability of Ganfeborole to reduce the burden of Mycobacterium tuberculosis, the bacteria that cause TB, in participants with TB affecting the lungs who received Ganfeborole daily over 2 weeks. Ganfeborole was well-tolerated, with study participants experiencing mostly mild side effects. Findings from this study support further development of Ganfeborole as a potential candidate for future TB therapies. The innovative use of advanced imaging and transcriptional profiling has provided valuable insights into how Ganfeborole works, offering hope for new methods of evaluating novel medicines to develop effective and safer TB treatments. The collaboration between institutions within the AnTBiotic Consortium exemplifies how partnership and expertise can drive forward medical research, bringing us closer to better solutions for TB, a global health challenge. For access to reading the full article, click here: https://lnkd.in/ecMhG-dX

Our paper published today in the British Journal of Clinical Pharmacology, has shown for the first time that: 1. COVID-19 severity gradient is associated with the dysregulation of drug processing genes, particularly, drug metabolizing enzymes and membrane transporters 2. this dysregulation is driven by an imbalance in COVID-19-associated inflammatory and anti-inflammatory processes that correlate with disease severity 3. three distinct biomarkers may be useful for the identification of outpatients, non-ICU, and ICU patients at risk of COVID-19-mediated interactions with drug metabolizing enzymes and membrane transporters 4. nasopharyngeal swab samples express clinically relevant drug metabolizing enzymes and membrane transporters, unraveling potential utility for drug disposition studies and diagnosis of disease-drug interactions 5. COVID-19-mediated interactions with drug metabolizing enzymes and membrane transporters are tissue-specific I thank all of the collaborators who worked with us on this very important work. Enjoy your reading! #personalizedmedicine #COVID-19 #clinicalpharmacology https://lnkd.in/eNjhVN2X

At the end of 2021, I wrote on my personal blog of the "Madness of #molnupiravir" - a drug designed to treat #COVID via "lethal mutagenesis". The trouble was, and continues to be, that the mutagenesis induced by the drug is *not* necessarily "lethal" to the virus, which at scale means that the use of this drug encourages the emergence of escape mutants, i.e., variants of the virus that escape our immunity against it - all the while rendering much safer drugs like #paxlovid (a drug that works via the non-mutagenic mechanism of action that is protease inhibition) potentially ineffective down the road. Nearly 2 years later, this view is increasingly being supported by empirical findings such as those summarised in the journal Nature this week: - Sanderson et al. "developed a genomic 'fingerprinting' technique to scan millions of SARS-CoV-2 genome sequences for telltale signs of molnupiravir-induced mutations. Their analysis showed that thousands of viruses with many mutations - sometimes more than 100 - had apparently survived molnupiravir treatment". You can find the Sanderson paper here: https://lnkd.in/d6fc6b-X - The authors of "Anti-COVID drug accelerates viral evolution" continue to explain that these highly mutated viruses, catalysed by the drug under discussion, have in fact been transmitted between individuals and had continued to be viable - which is a "startling finding, because previous studies of such drugs have assumed that highly mutated viruses would not be viable". Source: https://lnkd.in/dgrEg2_i The authors conclude that "continued widespread administration of molnupiravir seems inadvisable". Nearly 2 years prior, my own conclusion had been that "the world should abstain from playing Russian roulette with the mutagen molnupiravir" and that "there is absolutely no sound reason for rushing [it] through the regulatory process". Alas, rushed through it was, and we are now living with the increasingly demonstrable, dangerous consequences of a drug that should never have been approved. Cf. my late-2021 blog post for more context: https://lnkd.in/dZpZpwuU

I'm editing a new Special Issue from Viruses MDPI that is focused on Pharmacology of Antiviral Drugs (https://lnkd.in/g_mqWVK5). The Special Issue invites submissions that include molecular interactions between drugs and viral targets, pharmacokinetics, pharmacodynamics, and the influence of host factors on drug efficacy. We are also interested in exploring how issues such as drug resistance, novel drug delivery approaches, and advancements in medicinal chemistry factor in to impact the efficacy and safety of antiviral treatments in humans and animals. #viruses #pharmacology

SanegeneBio siRNA drug targeting C3 has been approved for Phase I clinical trial in New Zealand Sanegene Bio Inc. (SanegeneBio) announced that its siRNA drug SGB-9768 for the treatment of complement mediated diseases has recently been approved by the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) and the Health and Disability Ethics Committee (HDEC) to conduct Phase I clinical trial in New Zealand. SGB-9768 is a RNAi drug targeting the complement C3 (C3) protein, and is SanegeneBio's second siRNA drug to enter into clinical development. SGB-9768, an siRNA-N-acetylgalactosamine (GalNAc) conjugate targeting C3, is delivered to liver using SanegeneBio's novel LEAD™ GalNAc platform to reduce production of complement component 3 through RNA interference. The advantages of GalNAc platform have been also fully verified, including safety, effectiveness, and stability. SGB-9768 can be administered every 3 or 6 months, with the advantages of low dosing frequency, good patient compliance, and long-term efficacy. SGB-9768 can continuously reduce C3 synthesis and has been shown in preclinical studies with superior efficacy than benchmark compounds, , showing its potential to be the best-in-class siRNA drug targeting C3. The Phase I, randomized, double-blind, placebo-controlled, and single-dose escalation study is designed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of SGB-9768 in adult healthy volunteers. "SGB-9768 is SanegeneBio’s first siRNA drug in the field of immune related diseases to enter into the clinical development, using our proprietary LEAD™ GalNAc delivery platform, and has demonstrated excellent potency, duration, and safety in the preclinical studies. We will accelerate the phase I clinical trial of SGB-9768 and look forward to the verification and demonstration of the excellent compound in clinical as soon as possible. At the same time, SanegeneBio will continue to deeply explore the full potential of C3 program, push forward its development in various complement mediated diseases, and provide more and better treatment options for patients with immune related diseases." said Dr. Weimin Wang, Founder and Chief Executive Officer of SanegeneBio.

05 New Drug Approval Focus in 2024 Alzheimer's disease will be a hot topic in 2024. Eli Lilly is eagerly awaiting approval of its asset, donanemab. Once Donanemab is launched, it will become a direct competitor of Eisai and Biogen's Leqembi, which is already on the U.S. market. Madrigal’s MASH (Metabolicdysfunction-associated steatohepatitis, formerly known as nonalcoholic steatohepatitis, NASH) asset Resmetirom is attracting attention, and it is expected to become the first #MASH drug approved by the FDA in history , to fill the gap in which this disease has no cure. Moderna is working to bring its third RSV (respiratory syncytial virus) vaccine to the market, MRNA-1345. Previously, RSV vaccines from GlaxoSmithKline and Pfizer were already on the market. AstraZeneca and Daiichi Sankyo’s #Datopotamabderuxtecan will add another fuel to the hot ADC development. Datopotamab, a drug that targets Trop2, has made progress in lung and breast cancer. Another ADC drug, patritumab deruxtecan, which Daiichi sold to Merck in 2023, may also be launched in 2024. Whether the transthyretin stabilizer Acoramidis can be approved in 2024 is also one of the topics of concern to the industry for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM).

There are several other FMTs and LBPs which have either completed Phase I & II clinical trials or being initiated. 'Controlling LBP dosing, measurement and host responses will be key to clinical success. The FMT era has been productive, but now it’s time to rally together as an industry to accelerate next-generation LBP drug discovery, development and FDA approval. To do so, we must be able to control and eventually standardize the dosing of the LBP drug material in question, the measurement of that drug material (PK) and the host response (PD) – and do so with the same precision of antibody or small molecule drug development. Funding will continue to be constrained until the LBP field has a breakthrough, so we must prioritize creating value via small clinical studies that don’t require massive financial resources, but demonstrate the unique capabilities of LBP therapeutics.' Abbreviations: FMTs: Fecal microbiota transplants LBPs: Live Biotherapeutic Products https://lnkd.in/g8_bmc8j

SanegeneBio siRNA drug targeting C3 has been approved for Phase I clinical trial in New Zealand Sanegene Bio Inc. (SanegeneBio) announced that its siRNA drug SGB-9768 for the treatment of complement mediated diseases has recently been approved by the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) and the Health and Disability Ethics Committee (HDEC) to conduct Phase I clinical trial in New Zealand. SGB-9768 is a RNAi drug targeting the complement C3 (C3) protein, and is SanegeneBio's second siRNA drug to enter into clinical development. SGB-9768, an siRNA-N-acetylgalactosamine (GalNAc) conjugate targeting C3, is delivered to liver using SanegeneBio's novel LEAD™ GalNAc platform to reduce production of complement component 3 through RNA interference. The advantages of GalNAc platform have been also fully verified, including safety, effectiveness, and stability. SGB-9768 can be administered every 3 or 6 months, with the advantages of low dosing frequency, good patient compliance, and long-term efficacy. SGB-9768 can continuously reduce C3 synthesis and has been shown in preclinical studies with superior efficacy than benchmark compounds, , showing its potential to be the best-in-class siRNA drug targeting C3. The Phase I, randomized, double-blind, placebo-controlled, and single-dose escalation study is designed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of SGB-9768 in adult healthy volunteers. "SGB-9768 is SanegeneBio’s first siRNA drug in the field of immune related diseases to enter into the clinical development, using our proprietary LEAD™ GalNAc delivery platform, and has demonstrated excellent potency, duration, and safety in the preclinical studies. We will accelerate the phase I clinical trial of SGB-9768 and look forward to the verification and demonstration of the excellent compound in clinical as soon as possible. At the same time, SanegeneBio will continue to deeply explore the full potential of C3 program, push forward its development in various complement mediated diseases, and provide more and better treatment options for patients with immune related diseases." said Dr. Weimin Wang, Founder and Chief Executive Officer of SanegeneBio.