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Why Is Development of New Treatments Necessary For Myasthenia Gravis? Recent Advances in Clinical Trials
Why Is Development of New Treatments Necessary For Myasthenia Gravis? Recent Advances in Clinical Trials
DOI: 10.1111/ncn3.12301
REVIEW ARTICLE
Tomihiro Imai
KEYWORDS
eculizumab, myasthenia gravis, neonatal Fc receptor antibody, rituximab, thymectomy
Neurol Clin Neurosci. 2019;7:161–165. © 2019 Japanese Society of Neurology and John | 161
wileyonlinelibrary.com/journal/ncn3
Wiley & Sons Australia, Ltd
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162 IMAI
maintaining health‐related quality of life (QOL) and mental health.6 from baseline. Disease exacerbation, need for rescue medications,
The recent international consensus guidance for management of MG and hospital admission decreased in patients receiving eculizumab
proposes minimal manifestation (MM) status or better as a goal for compared with placebo. The most common adverse side effects
MG treatment.9 Japanese clinical guidelines for MG has also pro‐ were headache, upper respiratory tract infections, and nasopharyn‐
posed that “MM status or better with prednisolone (PSL) 5 mg/day gitis. Since eculizumab has been known to place patients at a 1000‐
or lower” (MM‐or‐better‐5 mg) may be a more practical treatment to 2000‐fold greater risk for meningococcal diseases, vaccination
goal than CSR and more achievable by more patients, and that this against Neisseria meningitides is absolutely needed prior to starting
goal yields patient satisfaction essentially equivalent to CSR based the medication.
on patients’ QOL.6
The latest Japanese cross‐sectional survey concluded that a low‐
dose PSL regimen with early combination of other treatment options 3 | R AV U LIZU M A B ( A L X N1210 )
may ensure earlier achievement of the treatment target “MM‐or‐
better‐5 mg” in generalized MG.10 One suggested new strategy for Ravulizumab is derived by introducing four unique amino acid sub‐
increasing the success rates of MM‐or‐better‐5 mg is early fast‐act‐ stitutions into the heavy chain of eculizumab. By these substitutions,
ing treatment (EFT) using reduced oral corticosteroid dose and early ravulizumab provides longer serum terminal elimination half‐life
combination with calcineurin inhibitors, then using plasma exchange and prolonged duration of pharmacological activity compared with
(PE)/plasmapheresis (PP) and/or intravenous immunoglobulin (IVIg) eculizumab. Extension of the dosing interval may allow administra‐
and/or intravenous methylprednisolone pulse therapy to resolve tion every 8 weeks.16 A phase 3 study of ravulizumab in generalized
11
remaining symptoms quickly. However, Japanese studies also AChR‐MG is currently being developed.
showed a considerable population (40%‐50%) of generalized MG pa‐
tients who had difficulty controlling disease progression even with
the new treatment strategy.10,12 These patients failed to respond to 4 | N EO N ATA L FC R EC E P TO R (FC R N)
adequate doses and durations of conventional immunotherapies and A NTI B O D I E S
required excessive fast‐acting treatments such as PE/PP and IVIg.
In this short review, the author describes further development of Neonatal Fc receptor (FcRn) is known to play an important role in
treatment options for these difficult‐to‐control patients. rescuing serum IgGs in circulation from lysosomal degradation and
replacing them into recycling pathways. Therefore, an FcRn mono‐
clonal antibody that inhibits the function of FcRn would be a rational
2 | EC U LIZU M A B therapeutic agent to reduce the levels of pathogenic autoantibodies
with IgG isotypes relevant in MG. Several FcRn antibodies such as
Eculizumab is a C5 monoclonal antibody directed at the complement efgartigimod (ARGX‐113)17‐19 and rozanolixizumab (UCB7665)20 are
protein C5 to block the formation of the terminal complement com‐ currently in the pipeline and are in different stages of clinical trial.
plex, C5b‐9. It has been used to treat paroxysmal nocturnal hemo‐
globinuria and atypical hemolytic uremic syndromes. The rationale
4.1 | Efgartigimod (ARGX‐113)
for MG treatment is based on both human and animal studies show‐
ing complement‐mediated damage at the endplate of the neuromus‐ The FcRn monoclonal antibody efgartigimod recently completed its
cular junction in MG.13,14 In 2017, eculizumab was approved for MG phase 2 trial to evaluate the safety, efficacy, and pharmacokinet‐
15
treatment on the basis of a phase 3 trial (REGAIN, NCT01997229). ics of the drug for the treatment of generalized MG. The phase 2
Patients aged 18 years or older with refractory generalized anti‐ trial showed that 75% of subjects treated with efgartigimod had im‐
AChR antibody‐positive MG (AChR‐MG) were enrolled in this dou‐ provement in MG‐activities of daily living (MG‐ADL) scores in the
ble‐blind placebo‐controlled study if they had impaired ADL defined 6‐week study period compared with 25% of those given placebo,
as a MG‐ADL score of 6 or higher, and class II‐IV disease accord‐ with reduction in total IgG levels and adequate tolerability. No se‐
ing to the MGFA classification.7 Despite the absence of a standard vere adverse events were reported during the study period.18 The
definition, refractory MG in this study was defined as MG without aim of the ongoing phase 3 trial is to confirm the safety, efficacy,
symptom control for 12 months after treatment with two or more and tolerability of the drug in generalized MG patients classified as
immunosuppressive therapies, or with at least one immunosuppres‐ MGFA class II‐IVb, and thereby validating the concept of serum IgG
sive therapy with IVIg, or PE given at least four times per year. The reduction as a therapeutic modality in MG.
study observed significant differences in changes from baseline in
eculizumab‐treated patients compared with placebo‐treated con‐
4.2 | Rozanolixizumab (UCB7665)
trols at week 26, both in patient‐administered QOL and ADL surveys
as well as physician‐administered scoring systems. The MG‐QOL15 Rozanolixizumab is another FcRn monoclonal antibody designed
and Quantitative Myasthenia Gravis (QMG) scores were signifi‐ to reduce the levels of pathogenic IgGs in serum. The safety,
cantly different between two groups although all scores improved tolerability, pharmacokinetics (movement in the body), and
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pharmacodynamics (effect on the body) of the drug were evaluated were reported at the American Academy of Neurology in 2018.18
in a placebo‐controlled phase 1 clinical trial in 41 healthy adult vol‐ Fifty‐two participants with AChR antibody were randomly assigned
unteers (NCT02220153). 20 A multicenter, randomized, double‐blind, to receive either rituximab or placebo (in addition to the patients’
placebo‐controlled phase 2 study has been started to examine the baseline immunotherapy regimen) for evaluating safety and useful‐
effectiveness, safety, and tolerability of rozanolixizumab in patients ness of rituximab. Primary outcome measures were steroid require‐
with moderate‐to‐severe MG (NCT03052751). ment over the 52‐week period in addition to the safety profile of the
drug. No significant differences in primary endpoints were found in
this study. Final publication of the results of this study is pending.
5 | R IT U X I M A B
Although several prospective trials, retrospective studies, and case 6 | M O N A R S E N (E N101)
series have reported a good response of MG to rituximab, a CD20 +
B‐cell depleting monoclonal antibody, these studies had small num‐ Monarsen is an antisense oligonucleotide that induces a reduction
bers of patients and lacked a randomized and blinded design. These in production of acetylcholinesterase by intermixing with mRNA
investigations differ in inclusion criteria, outcome measures, and encoding for the enzyme. In 2007, a non‐placebo‐controlled, open‐
treatment regimens and are therefore not easily comparable.1 In label, phase 1b study showed that monarsen improved QMG score
2017, Tanden et al21 reviewed the efficacy and safety of rituxi‐ in 87% of the participants, with no major adverse events. 23 Later, a
mab in 169 MG patients from case reports and series. Antibodies phase 2 study also showed improvement in QMG score while on the
to AChR were present in 59%, and MuSK in 34% of the patients drug in 31 patients. 24 Although death due to cerebral hemorrhage
studied. Among a rituximab responder subset, 26% of AChR‐MG and several adverse events were reported during the clinical trial,
and 82% of MuSK‐MG patients showed decreased antibody titers the investigators concluded no causal relation between these ad‐
after treatment. A meta‐analysis identified MuSK‐MG, less severe verse events and the drug. There is no plan for further studies at this
disease, and younger age at treatment as predictors of a favorable time. The future of monarsen is currently unknown.
response to rituximab. They also concluded that rituximab was gen‐
erally well tolerated in MG patients. 21 Another large multicenter
blinded review was published in 2017, comparing 24 MuSK‐MG 7 | AU TO LO G O U S H E M O P O I E TI C S TE M
patients who received rituximab (rituximab‐treated group) with C E LL TR A N S PL A NTATI O N
31 MuSK‐MG patients who received other immunosuppressive
medications (control group). 22 With Myasthenia Gravis Status and The efficacy of autologous hemopoietic stem cell transplanta‐
Treatment Intensity (MGSTI) as primary endpoint, the rituximab‐ tion for severe refractory MG has been reported. Bryant et al25
treated group achieved an MGSTI score of 2 or higher, which was reported achievement of drug‐free remission after autologous
statistically significant when compared with the control group. A hemopoietic stem cell transplantation in seven non‐respond‐
limitation of this review may be retrospective collection of data. ers to conventional treatments. Håkansson et al26 also reported
For AChR‐MG, preliminary data of a randomized, double‐blind, a successful case in which a patient with refractory MG showed
placebo‐controlled phase 2 clinical trial (BeatMG, NCT02110706) significant improvement without supplementary therapies after
Eculizumab C5 monoclonal antibody Block formation of the mem‐ A phase 3 study (REGAIN study) reported significant
brane‐attacking complex on improvement of MG‐QOL15 and QMG scores
postsynaptic membrane
Ravulizumab C5 monoclonal antibody Same as eculizumab, but A phase 3 study is in pipeline
long‐acting
Efgartigimod FcRn monoclonal antibody Reduction in pathogenic autoan‐ A phase 2 study reported efficacy without severe
tibodies with IgG isotypes adverse effects. A phase 3 study is in pipeline
Rozanolixizumab FcRn monoclonal antibody Same as efgartigimod A phase 1 study reported safety, tolerability, pharma‐
cokinetics, and pharmacodynamics. A phase 2 study
is in pipeline
Rituximab CD20+ B‐cell depleting Reduction in pathogenic A meta‐analysis and blinded review showed favorable
monoclonal antibody autoantibodies effects for MuSK‐MG. A phase 2 study failed to dem‐
onstrate significance changes in primary endpoints
for AChR‐MG
autologous hemopoietic stem cell transplantation, although immu‐ autoantibodies in blood (Table 1). Recent development of the bio‐
nosuppressive therapies with rituximab, sirolimus, and bortezomib logics is promising new treatment options for MG. Thymectomy is
had failed. another option in selected MG patients. Clinical trials in the pipeline
are anticipated to generate further evidence leading to the develop‐
ment of additional treatment options for MG.
8 | TH Y M EC TO M Y
C O N FL I C T O F I N T E R E S T
AChR‐MG is commonly associated with thymus changes, as both
thymus follicular hyperplasia and thymoma play a role in pathogen‐ No conflict of interest.
esis. The rationale for thymectomy in patients without thymoma is
based on the acknowledged roles of thymus follicular hyperplasia in
ORCID
sensitization against AChR and as a source of specific antibodies.27
Thymectomy has been used for MG treatment since the 1940s, but Tomihiro Imai https://orcid.org/0000-0002-3601-0564
1
the evidence toward its efficacy has been based on uncontrolled data.
In 2016, the long‐awaited results of the MG thymectomy (MGTX)
study was published, which was the first randomized trial comparing REFERENCES
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