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

Abstract

ObjectiveThis 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).MethodsA 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).ResultsThe 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.ConclusionA 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.

Cannabinoids for the treatment of autoimmune and inflammatory skin diseases: A systematic review

“…In the phase 2 study (NCT02465437) of lenabasum in SSc, the most common AE attributed to lenabasum was dizziness (22% for lenabasum vs. 13% for placebo), which led to the study discontinuation in one lenabasum‐treated patient 95 . In the phase 3 trial (NCT03398837) of lenabasum in dcSSc, no serious AEs related to lenabasum were observed and the safety profiles were similar to those reported in the phase 2 trial 98 . In the phase 2 trial of lenabasum for DM, no serious or severe AEs occurred in the treatment groups.…”

“…95 In the phase 3 trial (NCT03398837) of lenabasum in dcSSc, no serious AEs related to lenabasum were observed and the safety profiles were similar to those reported in the phase 2 trial. 98 In the phase 2 trial of lenabasum for DM, no serious or severe AEs occurred in the treatment groups. The most common AEs in the study were mild dizziness (45% for lenabasum vs. 18% for placebo), mild or moderate fatigue (27% vs. 27%), mild dry mouth (36% vs. 18%) and mild diarrhoea (27% vs. 9%).…”

“…95 With the favourable results of the phase 2 trial, the phase 3 trial was undertaken to investigate the safety, efficacy and tolerability of lenabasum in dcSSc (NCT03398837). 98 In this study, 365 patients with dcSSc were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg or placebo, each twice daily while receiving stable medication including immunosuppressants. The primary endpoint of the ACR CRISS score was not met (0.888 for lenabasum 20 mg vs. 0.887 for placebo at Week 52; p = 0.497 by mixed-effects model repeated-measures analysis).…”

“…Although promising results were obtained from the phase 2 trials, the phase 3 trials failed to meet the primary endpoint in both diseases, which are attributed to the confounding effect of background immunosuppressants in SSc and the change of primary endpoint from CDASI to Total Improvement Score in DM. 98,109 Nonetheless, subgroup analysis suggested that lenabasum was associated with the improvement of several secondary endpoints in both phase 3 trials. In Pso and AD, the included studies, although limited, support the potential therapeutic benefit of topical cannabinoids.…”

“…With the favourable results of the phase 2 trial, the phase 3 trial was undertaken to investigate the safety, efficacy and tolerability of lenabasum in dcSSc (NCT03398837) 98 . In this study, 365 patients with dcSSc were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg or placebo, each twice daily while receiving stable medication including immunosuppressants.…”