0375 A Novel Dual Orexin Receptor Antagonist (ACT-541468) to Treat Insomnia: A Randomized, Double-Blind, Placebo-Controlled, Active-Reference Phase 2 Study

Abstract

Introduction: Orexins are involved in the regulation of sleep and wakefulness. The primary objective of this Phase 2 study was to investigate the dose‐response relationship of ACT‐541468 on sleep variables in subjects with insomnia disorder. Methods: Eligible adults (≤64 years) with insomnia disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria) were randomized (1:1:1:1:1:1) to receive, 5, 10, 25, and 50 mg ACT‐541468, placebo or 10 mg zolpidem for 4 weeks. Main efficacy endpoints were the change from baseline (placebo run‐in) to Days1&2 for wake after sleep onset (WASO; primary) and latency to persistent sleep (LPS; secondary). The dose‐response of ACT‐541468 was evaluated using MCP‐Mod methodology. Results: Of 1005 subjects screened, 360 (median age 47 [range, 36‐53]; 64% female) were randomized. A significant dose‐response of ACT‐541468 was demonstrated for WASO (p≤0.0007). Observed mean reductions from baseline to Days 1&2 for WASO were ‐28.99, ‐33.75, ‐39.64, and ‐45.49 min for ascending ACT‐541468 doses (placebo, ‐20.98 min; zolpidem, ‐31.23 min) and were sustained at Days28&29 (‐37.76, ‐43.74, ‐39.84, ‐46.97 min for ascending ACT‐541468 doses [placebo, ‐33.80 min; zolpidem, ‐37.08 min]). A significant dose‐response for LPS at doses 10 mg and above was detected (p<0.05). Observed changes in mean LPS from baseline to Days1&2 were ‐26.88, ‐29.31, ‐36.14, and ‐36.41 min for ascending ACT‐541468 doses (placebo, ‐22.02 min; zolpidem, ‐45.12 min). Reductions in LPS were sustained at Days28&29. ACT‐541468 treatment was well‐tolerated at all doses, with no evidence of dose‐dependent adverse effects. Treatment‐emergent adverse events (TEAEs) were reported in 35%, 38%, 38%, and 34% subjects treated with 5, 10, 25, and 50 mg ACT‐541468, respectively (30% for placebo; 40% for zolpidem). The main TEAEs across all groups were headache, somnolence, and nasopharyngitis. No signs of next‐day residual effects or rebound insomnia were observed. Conclusion: ACT‐541468 demonstrated a significant dose‐response for WASO and LPS compared with placebo and was well‐tolerated without dose‐dependent safety concerns or residual negative nextday effects. Phase 3 evaluation of ACT‐541468 in adults with insomnia is ongoing.