Lenabasum fails efficacy outcomes in diffuse cutaneous systemic sclerosis, may improve FVC
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Although lenabasum failed to meet its efficacy endpoint in a trial of patients with diffuse cutaneous systemic sclerosis, a post-hoc analysis suggests an impact on forced vital capacity, according to a speaker at the EULAR 2021 Congress.
“Lenabasum is an oral, non-immunosuppressive preferential cannabinoid-2 agonist that activates resolution of innate immune responses,” Robert Spiera, MD, of the Hospital for Special Surgery, in New York, told attendees during the virtual meeting. “Lenabasum is active in animal models of bleomycin-induced skin and lung fibrosis.”
“In a previously reported 16-week, phase 2 study of lenabasum in patients with diffuse cutaneous systemic sclerosis, treatment with lenabasum was safe, well-tolerated, and was associated with greater improvement in the [American College of Rheumatology Combined Response Index in diffuse cutaneous systemic sclerosis (ACR CRISS)] score, and improved histology and biomarkers in the skin, than treatment with placebo,” he added.
RESOLVE-1 Trial
To examine the efficacy, safety and tolerability of lenabasum (Corbus Pharmaceuticals) among patients with diffuse cutaneous SSc, compared with placebo, Spiera and colleagues conducted the double-blind, randomized, phase-3 RESOLVE-1 trial. A total of 375 adults with a disease duration of 6 years or less — those with a duration of 3 to 6 years were required to have a modified Rodnan Skin Score (mRSS) of at least 15 — randomized across 76 sites in North America, Europe and Asia. In all, 125 received 20 mg of lenabasum twice daily, 124 were treated with 5 mg of lenabasum twice daily, and 126 received placebo.
The researchers allowed participants to receive background immunosuppressive therapies if they were stable for at least 8 weeks prior to screening, and if corticosteroids did not exceed 10 mg of prednisone per day, or equivalent.
“The decision to allow immunosuppressive therapies was to be similar to what is being done, and reflects real-world clinical practice in the treatment of systemic sclerosis,” Spiera said.
In all, 89.2%, 78.3% and 83.7% of participants in the 20 mg, 5 mg and placebo groups, respectively, were on immunosuppressive therapy. Among these, 52.5%, 47.5% and 52.8% were using mycophenolate.
Among the randomized participants, 365 were actually dosed and included in the safety population. In addition, two participants in the 5 mg lenabasum cohort had no efficacy follow-up and were excluded from that analysis. The primary efficacy endpoint was ACR CRISS score in patients who received 20 mg of lenabasum, compared with placebo at week 52. Secondary endpoints included changes in mRSS, Health Assessment Questionnaire Disability Index (HAQ-DI), and forced vital capacity for lenabasum 20 mg compared with placebo, also at week 52.
In all, 10% of the 363 dosed participants with efficacy follow-ups stopped the study drug early, with one patient in the placebo group withdrawing due to an adverse event.
According to the Spiera, there were no significant differences between the three groups in the primary and secondary endpoints.
Mycophenolate Impacted Outcomes
However, in a pre-specified analysis, the researchers found that baseline use of mycophenolate was linked to a greater likelihood of demonstrating a greater improvement in ACR CRISS score. The pre-specified analysis also demonstrated that background mycophenolate had a statistically significant effect on forced vital capacity.
“Patients who entered the trial on mycophenolate were more likely to have a more favorable response with regard to FVC, whereas other features, including the region they came from or disease duration did not,” Spiera said. “Baseline FVC also came up statistically significant in this model.”
In a post-hoc analysis, Spiera and colleagues reported that participants who received no immunosuppressive therapy only demonstrated a roughly 35% ACR CRISS response — lower than all groups who received immunosuppressants. They also found that participants who received mycophenolate for more than 2 years prior to enrollment demonstrated “a somewhat less robust improvement in the ACR CRISS,” than those who had initiated the drug more recently.
The post-hoc analysis also found that patients with no immunosuppressive treatment had a decline in forced vital capacity. Meanwhile, all-comers who received mycophenolate demonstrated less of a decline in forced vital capacity. However, similar to the skin scores, this impact was less pronounced in patients who had received mycophenolate for longer periods.
Lastly, the post-hoc analysis demonstrated that participants in the 20 mg lenabasum group who also received immunosuppressive therapy had stable forced vital capacity, compared with those treated with placebo and immunosuppressives.
“Looking at it a different way, you were more likely to have declined if you were on placebo, and more likely to have improved or stayed stable if you were on lenabasum, if you were a patient on more than 2 years of immunomodulatory therapy at trial entry,” Spiera said.
Regarding safety, the researchers deemed the study drug safe and well-tolerated, noting that adverse events and severe adverse events occurred in 9.2% and 5.8% of those in the 20 mg lenabasum group, respectively, compared with 14.6% and 13%, respectively, for the placebo group.
Future Potential for Systemic Sclerosis
“The primary analysis of this study did not demonstrate efficacy for lenabasum in diffuse cutaneous SSc patient receiving standard treatments, including immunosuppressive therapies,” Spiera said. “Efficacy outcomes in the placebo rate far exceeded what was expected. Mycophenolate significantly affected the results, with greater improvement in subjects who received mycophenolate, and less improvement from mycophenolate if the duration of that mycophenolate therapy was greater than 2 years at baseline.
“Evidence for an effect of lenabasum on forced vital capacity was suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes,” he added. “Results from the post-hoc analyses will require confirmation in additional studies to determine the potential of lenabasum for treating patients with systemic sclerosis. Treatment with lenabasum was safe and well-tolerated in this study.”
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