Based on European patient demographics and disease characteristics, background immunosuppressive therapy varies with geographic region among patients receiving lenabasum for diffuse cutaneous systemic sclerosis (dcSSc), according to study results presented at the European League Against Rheumatism (EULAR) 2020 E-Congress, held online from June 3 to 6, 2020.

In phase 2 of the RESOLVE-1 trial (ClinicalTrials.gov Identifier: NCT03398837), selective cannabinoid receptor type 2 (CB2) agonist lenabasum was indicated to be safe and well tolerated, and associated with improvements in American College of Rheumatology (ACR) Combined Response Index Systemic Sclerosis (CRISS) score and other secondary efficacy outcomes.

In this study, to assess variability by geographic region, using phase 3 trial data from background standard of care and baseline disease characteristics of patients with dcSSc who received lenabasum, the researchers included 365 patients from different geographic locations (30.1% from Europe). Adult patients with dcSSc who had a disease duration ≤6 years receiving stable background immunosuppressive therapy were included in the study. Eligibility criteria also included baseline modified Rodnan skin score ≥15 if disease duration was >3 to ≤6 years at enrollment.

The European patients (n=110; mean age, 51±11.7 years; 75% women; 91.8% white) were enrolled in the study for 12 months and received ≥1 dose of lenabasum at 20 sites in 7 countries in Europe. A total of 80% of European patients received immunosuppressive therapy, with 30% receiving methotrexate, 46% receiving mycophenolate/mycophenolic acid, and 43% receiving ≥2 concurrent immunosuppressive drugs.


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Overall, results of the study showed that there were regional differences with background immunosuppressive therapy; methotrexate, mycophenolate/mycophenolic acid, and corticosteroid use were highest in Europe, North America, and Asia, respectively.

To get further insight into this research and the role of lenabasum in SSc, we spoke with study lead author Christopher Denton, PhD FRCP, head of center and consultant rheumatologist at University College London Division of Medicine and Royal Free London NHS Foundation Trust.

Could you tell us more about the findings of this study presented at EULAR 2020?

Systemic sclerosis (scleroderma) is a rare disease with a high unmet need, severity, and mortality. We present the characteristics a large number of cases (n=365) of patients with SSc enrolled into an international phase 3 clinical trial testing the efficacy of lenabasum in SSc.

This [study] is important since we indicate that the cases reflect those seen in everyday clinical practice and define the typical treatment of these patients across many different countries and healthcare systems. We also show that these [patients] have significant disease with reduced function (assessed by the Health Assessment Questionnaire disability index) and substantial skin fibrosis (overall skin score average, >22/51). We show that >80% of cases are being treated with immunosuppression, most often with mycophenolate mofetil, which is not approved therapy but widely used in practice, especially in the United Kingdom and the United States. 

Thus, if the outcomes of the trial are positive, lenabasum [may] add value to standard immunosuppressive [therapy] in a population of patients with [severe] disease.

Also, this is the first phase 3 trial to test the Composite Response Index for Systemic Sclerosis (CRISS) as a primary end point.

Can you briefly describe the mechanism of lenabasum in SSc?

Lenabasum is a synthetic drug that stimulates the CB2 cannabinoid receptor in the immune system and fibroblasts that cause fibrosis. These receptors normally suppress inflammation and appear to promote the resolution of fibrosis. So, this is a novel mechanism of action as it aims to promote natural processes to improve fibrosis, not simply turn off the divers of scarring.

Cannabinoids have been associated with the reduction of pain and inflammation, especially in rheumatic disease; however, being psychoactive, these compounds may have long-term adverse effects. Is there anything known in terms of safety about the long-term outcomes and effects of lenabasum in SSc?

It is unlikely that lenabasum will cause problems with psychoactivity because it works on the CB2 receptor and not the CB1 receptor that is in the brain. There were no major safety concerns in the completed phase 2 trial of lenabasum in SSc, and also in the long-term open-label extension; however, the current phase 3 trial will provide more complete safety information. During the phase 3 study, there [will be] careful safety monitoring; no significant problems have been observed yet, but safety and tolerability will be an important part of the trial results when they are available later in 2020.

Can this study be extended to other inflammatory and fibrotic diseases?

In theory, there are many diseases where tissue inflammation and scarring occur and so it is possible that lenabasum could benefit other conditions. It is currently being tested in cystic fibrosis and dermatomyositis in clinical trials that will assess this broader benefit.

Is there any further research in the pipeline for this drug?

As outlined above, other trials are ongoing and if the drug is effective overall in SSc in the current RESOLVE-1 trial, then it is likely to be investigated further in related diseases where fibrosis and inflammation occurs. In addition, studies to explore the mechanism of action in more detail are also underway.

Disclosure: Dr Denton declared affiliations with the pharmaceutical industry.

Reference

Denton C, Bloom B, Dgetluck N, White B, Spiera R on behalf of RESOLVE-1 Study Investigators. Baseline European patient demographics and disease characteristics in a phase 3 study of safety and efficacy of lenabasum, a CB2 agonist, in diffuse cutaneous systemic sclerosis. Presented at: EULAR 2020 E-Congress; June 3-6, 2020. Abstract AB0568.

This article originally appeared on Rheumatology Advisor