Corbus Pharmaceuticals’ (NASDAQ:CRBP) Phase II
study of anabasum in skin-predominant dermatomyositis could miss its co-primary
endpoint based on its small sample size and the disease’s heterogeneous nature,
some experts said. However, others noted a narrow focus on a particular aspect
of the disease may actually lead to a strong outcome, considering the sensitive
measure used.
Whilst some experts said the 22-patient Phase
II, double-blind, randomized, placebo-controlled study (NCT02466243) to
investigate anabasum (formerly known as JBT-101/resunab) has a reasonable
co-primary endpoint for efficacy, another said it is not as fully validated as
older scales.
The mechanistic rationale behind treating
dermatomyositis with anabasum is based on the drug’s effect on the cytokine
interferon-alpha (IFN-alpha), which has shown positive results in similar
studies, according to an analyst report. However, experts this news service
interviewed said dermatomyositis is more closely linked to interferon-beta
(IFN-beta), another of the drug’s targets.
Positive results in previous trials against
scleroderma and cystic fibrosis have given experts confidence in the drug’s
safety profile in dermatomyositis patients, but one cautioned efficacy can’t be
extrapolated. Experts said mechanistically it should have fewer side effects
than treatments currently in use. Dermatomyositis is a rare inflammatory
disease with variable symptoms which can include a skin rash, muscle weakness
and muscle inflammation.
Data is expected in 4Q17, the analyst report
stated. Principal investigator Dr. Victoria Werth, professor of Dermatology,
The Hospital of The University of Pennsylvania, added data is expected in the next
few months, possibly at a dermatology or rheumatology meeting. The analyst
report also predicted USD 575M in peak sales for the drug, though it stated
dermatomyositis is the smallest contributor to this valuation.
Small sample
size but a limited focus increases optimism
Experts had divided opinions on how the co-primary
endpoint may pan out given the small number of patients. The efficacy
co-primary endpoint is the Cutaneous Dermatomyositis Disease Area and Severity
Index (CDASI) at 84 days for Part A and 364 days for Part B, according to
ClinicalTrials.gov. Safety and tolerability is the study’s other primary
endpoint.
Dr. Chester Oddis, director, Myositis Center,
University of Pittsburgh School of Medicine, Pennsylvania, said 22 patients is
adequate for a proof-of-concept-trial. But Dr. Paul Plotz, scientist emeritus,
National Institute of Arthritis and Musculoskeletal and Skin Diseases and
medical advisor to the Myositis Association, and Dr. Dana Ascherman, specialist
in idiopathic inflammatory myopathy, University of Miami, Florida, countered
that 22 could be too small to see a statistically significant effect
considering the disease heterogeneity. That said, 22 patients could be enough
if anabasum affects a pretty dramatic response and may still show a good
side-effect profile and tolerability data, Ascherman said.
A Corbus spokesperson said the study is not
formally powered for efficacy. But if the study does show a statistically
significant benefit, that would be profound, she noted. Whilst anabasum, may
benefit other disease aspects, the focus on skin was a requirement for
government study funding, she said.
Focusing just on the skin in this Phase II
actually makes sense considering the disease heterogeneity, Werth and Ascherman
noted.
Testing the drug’s impact on skin-predominant
disease allows for a sensitive, easily measurable outcome that doesn’t require
many patients, they said. But Dr. Fred Miller, chief, Environmental
Autoimmunity Group, National Institutes of Health, said 22 patients may still
not be enough, adding “the skin many not be more responsive than any other
organ.”
CDASI
reasonable for skin evaluation
Not all interviewed experts were familiar with
the CDASI scale, but those who were said it was a reasonable measure for
analyzing the severity of the skin rash in dermatomyositis patients. The
spokesperson said the CDASI endpoint is the best measure for skin disease in
the indication.
The CDASI scale is helpful for distinguishing
between past activity and ongoing disease when looking at the skin rash,
Ascherman noted. Werth, who designed the index, said it’s been validated
including a study comparing CDASI measures to genetic signatures for IFN-beta
(Huard, C. et al. Br J Dermatol. 2017 May;176(5):1224- 1230). However, Miller
said it hasn’t been as fully validated or accepted as older scales such as the
IMACS outcome (Aggarwal, R. et al. Ann Rheum Dis. 2017 May;76(5):792-801) which
measures the whole disease including the muscle and the skin.
The analyst report noted a 5-point change is
indicative of clinical benefit, and Ascherman said this is achievable and
clinically valuable. The number would encourage patient adoption, he added,
especially with a favorable side-effect profile.
Anabasum has been tested in Phase II trials in
scleroderma (NCT02465437) and cystic fibrosis (NCT02465450), and according to
Corbus presentations, these trials had good safety results as well as
improvements in efficacy end points and disease-related biomarkers. Scleroderma
is more closely linked to dermatomyositis than cystic fibrosis, Oddis and
Ascherman noted but Werth said she could not extrapolate from the scleroderma
results to say anabasum might work in dermatomyositis.
Sound
scientific rationale though different from lupus
Although the detailed mechanisms involved are
not fully known, experts said the trial is merited by the evidence linking
interferon and dermatomyositis. However, Werth said it is a different
interferon to that involved in lupus, contrary to the previous analyst report.
In a recent study co-authored by Werth (Robinson, ES. et al. J Invest Dermatol.
2017 Jun 23. pii: S0022-202X (17)31668-8), anabasum was shown to reduce the
level of several cytokines in the cells of dermatomyositis patients in-vitro:
IFN-alpha, IFN-beta and TNF-beta. These three cytokines are known to mediate
inflammation, according to Werth.
The analyst report stated the theory behind treating
dermatomyositis with anabasum is based on the IFN-alpha reduction, which has
shown clinical benefit in lupus studies, but Werth said lupus and
dermatomyositis are not the same in this respect. She explained that it is in
fact IFN-beta that appears to be more important in dermatomyositis (Wong, D. et
al. PLoS One. 2012;7(1): e29161).
The challenge is working out the detailed
mechanism, noted Ascherman. Any drug that has the potential to attack the
autoimmune mechanism has a possibility of working, Plotz said. Miller and Oddis
agreed the evidence for a drug targeting IFN is more compelling than the
evidence for a drug targeting TNF (Arshanpalli A. et al. Cytokine. 2015 June;
73(2):319-25), adding this mechanism could treat the disease’s muscular aspects
as well as the skin.
Corbus continues to explore the various
etiologies behind dermatomyositis, the spokesperson said.
Safety is
promising
Past trials have promising evidence for
safety, and mechanistically anabasum shows more promise than treatments
currently in use, experts said. However, one expert noted there is a risk of
negative impact on other aspects of dermatomyositis.
Safety success in the scleroderma trial, where
there was no serious or severe drug treatment-emergent adverse events, is reassuring
for demonstrating safety given they are both autoimmune diseases, said Werth,
Ascherman and Miller. The side effects listed in Corbus’ trial presentations,
such as dizziness and fatigue in the scleroderma trial and dry-mouth in the
cystic fibrosis trial, were not a cause for concern, added Werth and Ascherman.
These are common in myositis, so it might be difficult to assess if they are
drug-related or not, Miller said.
However, Miller noted there haven’t been
extensive in vitro or animal model studies, which is somewhat concerning for
safety. He also said that in his experience, many agents used in
dermatomyositis can help some disease aspects whilst making other worse, and so
the trial should measure muscle strength, lung and cardiac function as well as
assessing the skin rash. Oddis also said there have been some anecdotal reports
that anti-TNF therapy might worsen muscle disease. Ascherman added he does not
think focusing on the skin presents a safety risk, and he expects future trials
will assess other disease aspects.
Part of the appeal of anabasum is that it is
not a global immune-suppressing drug, Ascherman said, so it should have far
fewer risks than therapies in use. There were no trial drop-outs due to adverse
events, Werth said.
Hannah Wilgar
Reporter, London
Prior to working for BioPharm Insight, Hannah
investigated and wrote public engagement articles for the Wellcome Genome
Campus, part of the Wellcome Trust. She has a BSc in Genetics from the
University of Sheffield and an MSc in Developmental Cell Biology from the
University of Sussex. After graduating, Hannah taught science and wrote and
developed biomedical training materials for a broad range of clients, from
Roche Pharmaceuticals to the World Health Organization. While Hannah’s primary
area of expertise are genetics, oncology and personalized medicine, she has
experience writing about a broad range of topics including universal healthcare
policy, stem cells and infectious disease.