Enpatoran Dose-Finding Trial Falls Short on Primary Lupus Endpoint

Key Takeaways

• Higher week 24 BICLA responses were observed with each enpatoran dose than with placebo, while the prespecified dose-response objective was not met.
• Week 24 response rates remained numerically above placebo across active groups, without a statistically significant dose-response relationship.
• Diarrhea was the most common treatment-emergent adverse event, serious adverse events were uncommon across groups, and investigators described enpatoran as well tolerated.

In Cohort B of the WILLOW phase 2 trial, adults with active moderate-to-severe SLE had higher week 24 BICLA response rates with enpatoran than with placebo across all twice-daily doses. The multicenter study tested oral enpatoran in a randomized, placebo-controlled, double-blind, basket, dose-finding setting over 24 weeks. The highest observed response rate was 58% with enpatoran 25 mg twice daily, compared with 39% with placebo.

The study enrolled adults aged 18 to 75 years with moderate-to-severe SLE, with or without cutaneous manifestations, who were taking stable background medication before screening. Investigators screened 715 participants, randomized 354 into the safety population, and included 353 in the efficacy analysis after one placebo-assigned participant was excluded for ineligibility. Recruitment took place at 132 centres in 22 countries. Part 1 used 1:2 randomization to placebo or enpatoran 100 mg twice daily, and Part 2 used 1:1:1:1 assignment to 25 mg, 50 mg, 100 mg, or placebo twice daily for 24 weeks. The prespecified endpoint was a dose-response analysis of week 24 BICLA response using MCP-Mod, and that analysis was negative.

The primary objective was not met statistically, with p=0.14 for the dose-response analysis based on week 24 BICLA response. Response rates at week 24 were 58% (41/71) with 25 mg, 49% (36/74) with 50 mg, 49% (56/114) with 100 mg, and 39% (37/94) with placebo. The corresponding odds ratios versus placebo were 2.2 (95% CI 1.1-4.0), 1.5 (0.8-2.8), and 1.6 (0.9-2.8) for the 25 mg, 50 mg, and 100 mg groups. Across groups, week 24 response rates were numerically higher with each enpatoran dose than with placebo, even though the formal dose-response test was negative.

Diarrhoea was the most common treatment-emergent adverse event, occurring in 4/71 (6%), 2/74 (3%), 2/114 (2%), and 7/95 (7%) participants in the 25 mg, 50 mg, 100 mg, and placebo groups. Serious adverse events occurred in 1/71 (1%), 3/74 (4%), 5/114 (4%), and 3/95 (3%) participants, respectively.