Biopharmaceutical Report I
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 coprimary 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.
"Positive results in previous trials against scleroderma and cystic fibrosis have given experts confidence in the drug’s safety profile in dermatomyositis patients"
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 spokeperson 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.
"Past trials have promising evidence for safety, and mechanistically anabasum shows more promise than treatments currently in use"
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.
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.