Lenabasum Encouraging in Systemic Sclerosis Save

The oral cannabinoid receptor type 2 (CB2) agonist lenabasum showed promising results for systemic sclerosis (SSc) in a phase II study.

At week 16, the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) increased to 0.33 among patients given lenabasum compared with 0.00 for those receiving placebo (P=0.04 on 1-sided mixed model repeated measures analysis [MMRM] and P=0.07 on 2-sided MMRM), according to Robert Spiera, MD, of Weill Cornell Medical College in New York City, and colleagues.

"These results are encouraging and support the potential for lenabasum to be an effective treatment for diffuse cutaneous SSc," the team wrote in the study online in Arthritis & Rheumatology.

Improvements also were seen in measures of cutaneous involvement and underlying disease pathology such as gene expression in inflammatory pathways, and in patient-reported outcomes, the researchers reported.

Current treatments for SSc -- a multisystem autoimmune disorder characterized by fibrotic changes, inflammation, and damage to the small vessels -- have only modest efficacy and are hampered by adverse effects, and there remains a major unmet need for more effective and safer treatments.

Lenabasum "modulates the endocannabinoid system to activate the resolution phase of innate immune responses," directly affecting fibroblasts to limit fibrotic processes, Spiera and co-authors explained. Among the varied activities relevant to SSc are inhibition of adenylyl cyclase, reduction of toll-like receptor signaling, inhibition of the production of inflammatory cytokines, and reduction in activation of the NLRP3 inflammasome. In animal studies, lenabasum has demonstrated an ability to alleviate inflammation and fibrosis in the skin and lungs.

To explore the possibility of lenabasum as a treatment for SSc, Spiera and colleagues enrolled 41 patients with diffuse cutaneous disease from nine U.S. specialized clinics from 2015 to 2016. Stable doses of immunosuppressive medications were permitted.

For the initial 4 weeks, participants were randomized to receive 5 mg oral lenabasum and placebo each once daily, 20 mg plus placebo once daily, 20 mg twice daily, or placebo alone. All patients receiving the active treatment then were given 20 mg twice daily for the subsequent 8 weeks.

The primary outcome of change from baseline on CRISS encompasses total Rodnan skin scores, Health Assessment Questionnaire-Disability Index (HAQ-DI), physician global assessment, patient global assessment, and forced vital capacity percent predicted.

The sample size was not powered for efficacy but was estimated to be sufficient to detect efficacy and safety signals, the researchers noted.

Patients' mean age was 48, the majority were white women, and mean disease duration was 34 months. Approximately 90% were on concomitant immunosuppressive medications, most commonly mycophenolate.

At week 16, the treatment difference on patient global assessment was -1.2 (P=0.04 and P=0.08 for 1-sided and 2-sided MMRM, respectively). On the modified Rodnan skin score, the mean improvement at week 16 was -4.6 points, which is within the reported range of a minimally important difference of -3.2 to -5.3 in a previous study.

There also were improvements on HAQ-DI as early as week 2, which was "noteworthy," since HAQ-DI scores typically either remain stable or show worsening during clinical studies, according to the authors. By week 12, the treatment difference versus placebo was -0.32 (P=0.006 and P=0.01 on 1-sided and 2-sided MMRM, respectively).

Skin biopsies of samples collected at baseline showed more than 1,900 genes that were differentially expressed across the treatment groups, including genes associated with fibrosis and inflammation, metabolism of collagen, angiogenesis, and inflammation. Histologic evaluations revealed greater improvements on fibrosis and inflammation in the patients receiving the active treatment.

Among the common adverse events were dizziness, reported in 22% of the lenabasum group and 13% of the placebo group, fatigue in 19% vs 7%, and headache in 11% vs 7%. Most of these toxicities were mild, with only one patient in each group reporting moderate dizziness.

Dizziness and fatigue have been previously reported with endocannabinoid receptor agonists, the investigators noted, adding that there were no severe adverse events associated with the treatment.

"Further evaluation of lenabasum, a CB2 agonist, as a treatment for SSc and other inflammatory and fibrotic diseases is warranted," the investigators concluded. They noted that the drug has also shown preliminary benefits in a phase II trial for dermatomyositis.

A limitation of their study, Spiera and co-authors said, was its small size and short duration.

The study was funded by Corbus Pharmaceuticals, Inc. The authors reported financial support from Corbus Pharmaceuticals, and several are employees of the company.

Primary Source - Arthritis & Rheumatology.  Spiera R, et al "Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with systemic sclerosis" Arthritis Rheum 2020; DOI: 10.1002/art.41294.