medwireNews: The cannabinoid receptor type 2 agonist lenabasum may improve clinical outcomes and underlying disease pathology in patients with diffuse cutaneous systemic sclerosis (dcSSc), show the results of a first-in-human study.
Writing in Arthritis & Rheumatology, Robert Spiera (Weill Cornell Medical College, New York, USA) and co-investigators say their “results are encouraging and support the potential for lenabasum to be an effective treatment for dcSSc.”
The multicenter phase 2 study included 42 individuals with dcSSc of up to 6 years duration who were on stable background immunosuppression. The participants were randomly assigned to treatment with oral lenabasum 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, each followed by 20 mg twice daily for a further 8 weeks (n=27), or to placebo for 12 weeks (n=15).
The researchers found that, at week 16, the median Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score had reached 0.33 points among individuals in the lenabasum arm, whereas it remained unchanged, at 0 points, among those in the placebo group.
And although the study was not powered to test statistically significant differences in efficacy, a one-sided mixed effect model repeated measures test suggested that the difference between the two groups was indeed significant.
The Physician Global Assessment of Overall Patient Health and Patient Global Assessment of Health measures also showed improvements with lenabasum relative to placebo up to week 16.
“Combined, these three outcomes suggest lenabasum may provide treatment benefit on overall disease in dcSSc patients,” Spiera et al remark.
The team also found that lenabasum treatment resulted in significantly greater improvements in patient-reported SSc skin symptom questionnaire score and in 5-D itch score versus placebo at week 12, and a nonsignificant improvement in modified Rodnan Skin Score.
In line with these findings, an analysis of gene expression in skin biopsies collected at baseline and at week 12 identified 1937 genes that were differentially expressed between the treatment groups. Genes involved in inflammation and fibrosis were among those that had decreased expression following treatment with lenabasum.
Histologic examination of skin biopsies also showed a significant reduction in inflammation and fibrosis among the patients who received lenabasum relative to those given placebo, the researchers report.
Adverse events occurred at a similar rate in the lenabasum and placebo groups (63 vs 60%), and most commonly included dizziness (22 vs 13%), fatigue (19 vs 7%), headache (11 vs 7%), arthralgia (11 vs 7%), and upper respiratory tract infection (11 vs 0%). There were no deaths and no serious or severe adverse events related to lenabasum.
“Overall, the results of this Phase 2 study indicate potential efficacy in lenabasum in dcSSc patients, with consistent improvement in multiple physician- and patient-reported outcomes and apparent improvement in underlying disease mechanisms as shown in skin biopsies,” Spiera and co-authors conclude.
They add: “Further evaluation of lenabasum […] as a treatment for SSc and other inflammatory and fibrotic diseases is warranted.”
In an accompanying editorial, Monique Hinchcliff, from Yale School of Medicine in New Haven, Connecticut, USA, comments that the study “exemplifies how translational research using tissues from patients with systemic sclerosis […] can provide scientific rationale for clinical trials.”
She says: “If lenabasum is shown to significantly improve skin fibrosis and possibly gastrointestinal motility and Raynaud phenomenon, then [it] could emerge as [a] first-[line] treatment for SSc patients.”
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Arthritis Rheumatol 2020; doi:10.1002/ART.41294
Arthritis Rheumatol 2020; doi:10.1002/ART.41302