Cannabinoid receptor 2 agonist, lenabasum, for the treatment of pulmonary exacerbations in cystic fibrosis.

Background: Lenabasum is a cannabinoid receptor 2 (CB2) agonist under development for cystic fibrosis (CF), targeting inflammation. We evaluated the efficacy and safety of lenabasum in people with CF (pwCF).

Methods: We conducted a global, 28-week, randomized, double-blind, placebo-controlled Phase 2b trial. PwCF were ≥12 years old with 2-3 pulmonary exacerbations (PEx) treated with intravenous (IV) antibiotics (or 1 PEx treated with IV and ≥1 PEx treated with oral antibiotics) in the past year. Subjects were randomized 2:1:2 to lenabasum 20 mg BID, lenabasum 5 mg BID, or placebo BID. Primary endpoint was rate of PEx, comparing lenabasum 20 mg BID to placebo.

Results: Among 447 subjects from 21 countries, mean age was 26.9 (10.3 SD) years, 53.6% were female, 45.2% homozygous for F508del, and 24.9% received CFTR modulators. Highest ppFEV1 in the previous year was 69.2% with the majority having 1-2 PEx treated with IV antibiotics (2-7 PEx treated with either IV or oral antibiotics). PEx incidence over 28 weeks was 0.84 for placebo, 0.75 for lenabasum 5 mg BID, and 0.91 for lenabasum 20 mg BID; rates were not lower relative to placebo in the 5 mg (incidence rate ratio (IRR)=0.89, 95% CI 0.66 to 1.19, p = 0.44) or the 20 mg group (IRR 1.08, 95% CI 0.86 to 1.37, p = 0.51). PEx occurred less frequently in participants from Eastern Europe, but there was no evidence of regional variation in treatment efficacy. Lenabasum was well tolerated, without safety signals.

Conclusions: Lenabasum did not improve key clinical outcomes in this Phase 2b study in pwCF.