A randomised, double-blind, placebo-controlled phase 3 study of lenabasum in diffuse cutaneous systemic sclerosis: RESOLVE-1 design and rationale

OBJECTIVES: The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs). METHODS: RESOLVE-1 is a Phase 3, randomised, double-blind, placebo-controlled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score. RESULTS: The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019. CONCLUSIONS: RESOLVE-1 is the first Phase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis

Objective This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). Results The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was −6.7 versus −8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. Conclusion A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care

OP0171 PHASE 3 TRIAL OF LENABASUM, A CB2 AGONIST, FOR THE TREATMENT OF DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (DCSSC)

Background:Lenabasum is an oral CB2 agonist that attenuates inflammation and fibrosis in SSc animal models and showed clinical benefit with acceptable safety in a Phase 2 trial in dcSSc.Objectives:Test efficacy and safety of lenabasum in a Phase 3 trial in dcSSc.Methods:Subjects ≥18 years old with disease duration ≤ 6 years were randomized 1:1:1 to lenabasum 5 mg, 20 mg, or placebo (PBO), all BID, with stable background immunosuppressant therapy (IST) allowed. The primary efficacy endpoint was ACR CRISS score, and secondary endpoints were ΔmRSS, ΔHAQ-DI, and ΔFVC, all at Week 52 for lenabasum 20 mg vs PBO.Results:363 adults were dosed; 37 (10%) stopped study drug early, with only 1 subject (PBO cohort) stopping due to adverse event (AE). Baseline demographics were similar among groups. Disease duration was ≤ 3 years in 60% and 66%, mean mRSS score was 22.0 and 23.3, and background IST was used by 89% and 84% of lenabasum 20 mg and PBO groups, respectively.Safety results showed serious AEs and severe AEs occurred in 9.2% and 5.8% vs 14.6% and 13.0%, respectively, of lenabasum 20 mg and PBO groups.Efficacy results (Table) demonstrated:Table 1.Primary and secondary efficacy endpoints and post-hoc analyses, Week 52Group, by IST treatmentCohortNΔmRSS, mean (SD)ΔFVC% mean (SD)ΔFVC, mL mean (SD)ΔHAQ-DI mean (SD)ACR CRISS medianmITT population, MMRM primary analysis methodAllPlacebo123-8.1 (7.72)-1.0 (8.68)-51 (317)-0.13 (0.468)0.887Lenabasum 20 mg120-6.7 (6.59)-1.6 (6.91)-78 (265)-0.13 (0.436)0.888Placebo subjects, per protocol completers, LOCFNo ISTPlacebo16-2.3 (9.4)-2.8 (7.4)-97 (244)0.12 (0.34)0.417All ISTPlacebo97-8.9 (7.07)-1.0 (9.2)-43 (330)-0.17 (0.474)0.936MMF, no other ISTPlacebo29-10.7 (8.1)-0.58 (7.1)-37 (235)-0.12 (0.456)0.935MMF ≤ 2 years, no other ISTPlacebo23-11.7 (8.1)-0.3 (6.0)-41 (197)-0.13 (0.495)0.935Non-MMF ≤ 2 yearsPlacebo24-6.7 (6.2)-1.4 (7.87)-52 (281)-0.15 (0.357)0.931Post-hoc comparisons, per protocol completers, LOCFNo ISTPlacebo16-2.3 (9.4)-2.8 (7.4)-97 (244)0.12 (0.34)0.417Lenabasum 20 mg10-6.3 (6.02)-2.3 (5.58)-99 (209)-0.06 (0.498)0.811Established IST1Placebo26-6.1 (5.35)-4.6 (10.11)-170 (350)-0.17 (0.445)0.619Lenabasum 20 mg38-7.4 (5.08)-0.4 (5.70)2-21 (233)3-0.07 (0.357)0.941Established IST, subjects with ILDPlacebo22-5.9 (5.28)-3.7 (5.43)-133 (206)-0.10 (0.372)0.553Lenabasum 20 mg33-7.2 (5.70)-1.0 (10.5)-47 (365)-0.06 (0.391)0.8192 P = 0.0386 two-sample t-test; 3 P = 0.0481 two-sample t-test; other comparisons were not significant• No significant differences were seen in primary and secondary efficacy endpoints. Primary MMRM analyses with treatment-by-time-by-subgroup interactions showed that background mycophenolate (MMF) significantly influenced the outcome•oSubjects on no IST with disease duration ≤3 years were only 7% of PBO subjects and showed little improvement on PBO, in line with other dcSSc trials in which IST was restricted. Post-hoc subgroup analyses of these subjects on no IST suggested improvement in ΔmRSS and ΔHAQ-DI, for lenabasum 20 mg vs PBO•uUnexpectedly high improvement occurred in PBO subjects receiving IST, notably those on MMF started within 2 years of baseline•nPost-hoc analyses of subjects on established IST (MMF or, if no MMF, ≥ 1 non-MMF IST started > 2 years before baseline) suggested improvement in ΔFVC% (nominal P = 0.0386) and ΔFVC mL (nominal P = 0.0481) for lenabasum 20 mg vs PBO. Improvement in FVC was also seen in subjects on established IST who had ILD at baseline, lenabasum 20 mg vs PBO•mACR CRISS score demonstrated a ceiling effect and correlated most highly with ΔmRSS (r = -0.739) and moderately with MDGA (-0.432), HAQ-DI (-0.362), FVC% (0.366), and PtGA (-0.288)Conclusion:Lenabasum was safely used in this study. Unexpectedly high improvement on background IST, especially MMF, has not been previously reported at this level. The primary endpoint was not met. Post-hoc analyses showed greater improvement in lenabasum- vs PBO-treated subjects who were not on background IST and those on established IST, including subjects with ILD.Disclosure of Interests:Robert Spiera Consultant of: Abbvie, Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Formation Biologics, Mitsubishi Tanabe, Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Sanofi, Inflarx, Astra Zeneca, Kadmon, Masataka Kuwana Speakers bureau: Boehringer-Ingelheim, Chugai, Janssen, Consultant of: Boehringer-Ingelheim, Chugai, Corbus, Grant/research support from: Boehringer-Ingelheim, Chugai, MBL, Ono Pharmaceuticals, Tanabe-Mitsubishi, Dinesh Khanna Shareholder of: Eicos Sciences, Inc (less than 5%). Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc, Consultant of: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics, Grant/research support from: NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Laura Hummers Consultant of: CSL Behring, Boehringer Ingelheim, Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals. Corbus, Boehringer Ingelheim, Medpace, Kadmon, Cumberland, CSL Behring, Tracy Frech Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Wendy Stevens Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Jessica Gordon Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals. Research funding for EICOS Pharmaceuticals and Cumberland Pharmaceuticals., Suzanne Kafaja Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Marco Matucci-Cerinic Consultant of: Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Oliver Distler Consultant of: Consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB., Eun Bong Lee Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Yair Levy Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Jae-Bum Jun Consultant of: Consultant to Boehringer Ingelheim Korea, Jeil Pharma, Dae Woong Pharma, Kwangdong Pharma, and Sama Pharma., Grant/research support from: Investigator for study sponsored by Corbus Pharmaceuticals, Scott Constantine Employee of: Employee of Corbus Pharmaceuticals, Nancy Dgetluck Employee of: Employee of Corbus Pharmaceuticals, Barbara White Employee of: Employee and stockholder of Corbus Pharmaceuticals, Daniel Furst Consultant of: Corbus, Galapagos, Pfizer, CSL Behring, Mitsubishi Tanabi, Actelion, Amgen, Novartis, Roche/Genentech, Gilead, Talaris, and Boehringer Ingelheim., Grant/research support from: grants from Corbus, Galapagos, GSK, Pfizer, Talaris, CSL Behring, Mitsubishi Tanabi, Christopher Denton Consultant of: Consultancy fees and/or honoraria from Corbus, Actelion, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Inventiva, Boehringer Ingelheim, Roche, CSL Behring, Acceleron, Horizon, Arxx Therapeutic

Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with cystic fibrosis

Background. Few therapies specifically address the chronic airway inflammation in cystic fibrosis (CF) that contributes to progressive destruction of lung tissue and loss of lung function. Lenabasum is a cannabinoid type 2 receptor (CB2) agonist that resolves inflammation in a number of in vitro and in vivo models. Methods. A Phase 2 double-blind, randomized, placebo-controlled study assessed the safety and tolerability of lenabasum in adults with CF. Subjects with FEV1% (ppFEV1) 6540% predicted were randomized to lenabasum 1 or 5 mg or placebo once daily (QD) (Weeks 1\u20134), then 20 mg QD, 20 mg twice daily (BID) or placebo (Weeks 5\u201312), with follow-up at Week 16. Pulmonary exacerbations (PEx) were recorded and biomarkers of blood and lung inflammation were measured. Results. Of 89 subjects randomized, 51 lenabasum and 23 placebo-only subjects completed the study. No deaths or serious or severe adverse events (AE) were considered related to lenabasum. Most AEs were mild/moderate, and the most common were PEx, hemoptysis, dry mouth, and upper respiratory infection. Three lenabasum and one placebo-only subjects discontinued the study for a treatment related AE. New PEx were treated with intravenous antibiotics in 4.0% of lenabasum-treated vs. 11.4% of placebo-treated subjects, during Weeks 1\u20134 and 5.2% compared to 13.0% during Weeks 5\u201312 (p<0.2). No significant differences in ppFEV1 were observed between treatment groups. Sputum neutrophils, eosinophils, and neutrophil elastase were numerically reduced, and significant (p<0.05) reductions in IL-8 and immunoglobulin G levels occurred with lenabasum. Conclusions. The safety findings of lenabasum, coupled with biomarker data, support further testing in a larger study with a longer duration