Phase 2 findings
The single-center phase 2 trial of lenabasum for DM enrolled 22 adults with minimal muscle involvement as evidenced by normal maximal resistance on muscle testing at entry and throughout the study. Most were taking immunosuppressant medication, and all had CDASI scores of at least 20, with mean scores in the severe range (> 26). Symptoms registered on patient-reported outcome measures were moderate to severe.
Patients received a half-dose of lenabasum (20 mg daily) for 1 month and a full dose (20 mg twice daily) for 2 months, or placebo, and were followed for an additional month without dosing.
Starting at day 43 – approximately 2 weeks after the dose was increased – there was “a trend for the change from baseline CDASI to be greater” in the lenabasum group, compared with those on placebo, Dr. Werth and colleagues reported. The differences reached statistical significance on day 113 (P = .038), a month after patients discontinued lenabasum, “suggesting that the modulation of the inflammatory response by lenabasum continued beyond its last dose.”
Five of the 11 patients treated with lenabasum (45%), and none of those on placebo, achieved at least a 40% reduction in the CDASI activity score by the end of the study.
Patients in the lenabasum group also had greater improvement in the Skindex-29 Symptoms scores – an objective measure of itch – and improvements in other secondary efficacy outcomes, including pain, though these did not reach statistical significance.
Skin biopsies before and after treatment showed significant reductions in inflammatory cytokines relevant to DM pathogenesis. Patients treated with the CB2 agonist had a downward trend in the CD4+ T cell population, which correlated with decreased CDASI activity scores, for instance, and a decrease in IL-31 protein expression, which correlated with decreased Skindex-29 Symptoms scores, the investigators reported.
There were no serious adverse events related to the CB2 agonist, and no treatment discontinuations.
The main part of the phase 2 trial, conducted from 2015 to 2017, was followed by a 3-year, open-label extension, in which 20 of the 22 patients took lenabasum 20 mg twice a day. The drug continued to be safe and well tolerated, and the CDASI activity score and other outcomes improved through year 1 and remained stable thereafter, according to a poster presented by Dr. Werth at the 2021 EULAR meeting.
After 1 year in the open-label extension, 60%-70% of patients had achieved mild skin disease, and 75% had achieved at least a 40% reduction in CDASI activity.
“A lot of patients, even if they weren’t completely cleared, were much happier in terms of their itch,” said Dr. Werth, also chief of dermatology, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia. “It’s been difficult for a lot of them now that they’re off the long-term extension ... a lot of them are flaring.”
The future
In the lab, with funding from the National Institutes of Health, Dr. Werth is continuing to investigate how lenabasum may be working in DM. A paper just published in the open access journal Arthritis Research & Therapy describes CB2 receptor distribution and up-regulation on key immune cells in the skin and blood, and how, in DM skin, its highest expression is on dendritic cells.
Through both mechanistic and more clinical research, “it’s important to understand the characteristics of the people [lenabasum] worked in or didn’t work in,” she said.
And in clinical trials, it’s important to capture meaningful improvement from the patient perspective. “It may be,” she noted, “that more global, systemic assessments are not the way to go for autoimmune skin disease.”
For dcSSc, Dr. Spiera said, it’s possible that a CB2 agonist may be helpful for patients who have been on immunosuppressants, particularly mycophenolate, for more than 6 months “and are still struggling.”
The phase 2 trial in DM was funded by the National Institutes of Health, the Department of Veterans Affairs, and Corbus Pharmaceuticals. The phase 3 trials in DM and in dcSSc were funded by Corbus. Dr. Werth disclosed grant support from Corbus and several other pharmaceutical companies. Dr. Spiera disclosed that he has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, and several other pharmaceutical companies.
A version of this article first appeared on Medscape.com.