ACR 2017 | Daily Highlights
A Phase 2 Study of Safety and Efficacy of Anabasum (JBT-101), a Cannabinoid Receptor Type 2 Agonist, in Diffuse Cutaneous Systemic Sclerosis
Authors: Robert F. Spiera1, Laura K. Hummers2, Lorinda Chung3, Tracy M. Frech4, Robyn T. Domsic5, Vivien Hsu6, Daniel E. Furst7, Jessica K. Gordon1, Maureen D. Mayes8, Robert W. Simms9, Scott Constantine10 and Barbara White10, 1Rheumatology, Hospital for Special Surgery, New York, NY, 2Medical and Rheumatology, Johns Hopkins University, Baltimore, MD, 3Rheumatology, Stanford University Medical Center, Palo Alto, CA, 4Division of Rheumatology, University of Utah, Salt Lake City, UT, 5Rheumatology, University of Pittsburgh, Pittsburgh, PA, 6Rheumatology, Robert Wood Johnson University Scleroderma Program, New Brunswick, NJ, 7David Geffen School of Medicine at UCLA, Los Angeles, CA, 8University of Texas McGovern Medical School, Houston, TX, 9Rheumatology, Boston University School of Medicine, Boston, MA, 10Corbus Pharmaceuticals, Inc., Norwood, MA
Systemic sclerosis (SSc) is characterized in part by chronic activation of the innate immune system with fibrosis. Anabasum is a non-immunosuppressive, synthetic, orally administered selective CB2 agonist that activates resolution of innate immune responses in animal models of SSc and healthy humans. This study evaluated safety and efficacy of anabasum in diffuse cutaneous SSc (dcSSc).
A double-blind, randomized placebo (PBO)-controlled 16-week Phase 2 trial (JBT101-SSc-001) enrolled subjects with dcSSc ? 6 years duration on stable medications including immunosuppressive drugs. Subjects received anabasum 5 mg QD, 20 mg QD, or 20 mg BID x 4 weeks, then 20 mg BID x 8 weeks, or PBO x 12 weeks. Subjects were followed off study drug x 4 weeks. The primary efficacy outcome was ACR Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS).
Forty-two subjects received study drug: anabasum N = 27 and PBO N = 15. Baseline patient characteristics were similar in both groups. There were no serious, severe or unexpected adverse events (AEs) related to anabasum. Severity and relationship of AEs to study drug were similar in both groups. AEs in ? 10% of anabasum subjects were dizziness and fatigue. Anabasum subjects had greater improvement in ACR CRISS scores than PBO subjects over 16 weeks (Fig. 1, p = 0.044, 1-sided, mixed model repeated measures included baseline mRSS and disease duration). Anabasum subjects had greater improvement and less worsening in individual CRISS core measures including modified Rodnan Skin Score (mRSS), Patient Global Assessment (PtGA), Physician Global Assessment (MDGA), and HAQ-DI (Fig. 2).
Figure 1. CRISS Scores
Figure 2. CRISS Core Measures
There were strong correlations of CRISS scores with change from baseline in mRSS (r = -0.894, p < 0.0001) and MDGA (r =-0.591, P < 0.0001) with weaker correlations with FVC % predicted (r = 0.280, P = 0.0006), PtGA (r = -0.270, P = 0.0008), and HAQ-DI (r = -0.294, P = 0.0003). Patient-reported outcomes of SSc skin symptoms, itch, and PROMIS-29 physical function, pain interference, and sleep also improved (P < 0.05 for all). Evaluation of gene transcripts in skin biopsies showed anabasum but not placebo reduced expression of key genes implicated in SSc and gene ontology pathways associated with inflammation and fibrosis.
Anabasum had acceptable safety and tolerability in this Phase 2 trial in dcSSc and demonstrated consistent evidence of clinical benefit. Changes in gene expression were consistent with biologic effects of anabasum on pathways relevant to SSc. Further evaluation of anabasum in treatment of dcSSc is warranted.
R. F. Spiera, Roche-Genetech, 2,GSK, 2,BMS, 2,Boehringer Ingelheim, 2,Cytori, 2,Chemocentryx, 2,Corbus Pharmaceuticals, 2,Prism, 2,Roche-Genetech, 5,GSK, 5,Boehringer Ingelheim, 5; L. K. Hummers, None; L. Chung, Cytori, Actelion, Reata, 5; T. M. Frech, None; R. T. Domsic, None; V. Hsu, None; D. E. Furst, Grant/Research Support: Amgen,BMS Novartis, Pfizer, Roche/Genentech,Corbus. Consultant:AbbVie, Amgen, BMS, Corbus, Cytori, , Novartis, Pfizer, Roche/Genentech,. Speakers Bureau(CME or non-promotional only): BMS, Abbvie NO stocks, royalties, direct fina, 2,see above, 5,see above, 8; J. K. Gordon, Corbus Pharmaceuticals, 2,Cumberland Pharmaceuticals, 2,Bayer Pharmaceuticals, 2; M. D. Mayes, None; R. W. Simms, None; S. Constantine, Corbus Pharmaceuticals, Inc., 1,Corbus Pharmaceuticals, Inc., 3; B. White, Corbus Pharmaceuticals, 1,Corbus Pharmaceuticals, 3.
This study adds to the larger number of targeted therapies currently in advanced testing for systemic sclerosis. There is good preclinical, translational evidence that activation of the Cannabinoid receptor 2 inhibits skin and organ fibrosis. The current phase 2 proof of concept study showed promising results on skin fibrosis as measured by the modified Rodnan skin score (mRSS) as well as on the new combined response index CRISS, which includes in addition to the mRSS measures for lung (FVC), quality of life and patient and physician reported visual analogue scales. The positive results of this study have led to a phase study program, which is currently launched. If the larger phase 3 study confirms the initial results, it is likely that this will lead to registration of Anabasum (JBT-101) the for the indication “systemic sclerosis”. Limitations of the current study include the small sample size in particular in the control group, their heterogeneity in important baseline parameters and the short study duration for an anti-fibrotic trial.
Prof. Dr. Oliver Distler