Lemborexant and Daridorexant for the Treatment of Insomnia: An Indirect Comparison Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed

Abstract

Objective: To determine if there are differences in the number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH) between lemborexant and daridorexant and to compare lemborexant with daridorexant indirectly.

Methods: Dichotomous efficacy and tolerability outcomes reported for Phase 3 daridorexant trials (conducted May 29, 2018-May 14, 2020) for months 1 and 3 were identified from published literature and regulatory documents. Analogous data were extracted for lemborexant from Phase 3 studies (conducted May 31, 2016-January 8, 2019). NNT, NNH, and LHH were then calculated.

Results: Lemborexant 5 mg and 10 mg had clinically relevant therapeutic effect sizes, evidenced by most NNT values versus placebo < 10 for Insomnia Severity Index [ISI], subjective total sleep time [sTST], and polysomnography outcomes. NNH values for adverse events (AEs) were > 10, suggesting relative tolerability. Somnolence was the most common AE. Discontinuation rates of lemborexant because of an AE were low, including for somnolence. Efficacy outcomes for daridorexant 25-mg and 50-mg doses pooled resulted in most NNT values versus placebo ≥ 10, with more robust NNT estimates for the 50-mg dose than for the 25-mg dose. Discontinuation rate because of an AE at month 3 was higher for placebo than for daridorexant, rendering favorable LHH calculations. Daridorexant evidenced low rates of somnolence or fatigue.

Conclusions: In Phase 3 trials, the benefit-risk ratios for both lemborexant and daridorexant were favorable as measured by NNT, NNH, and LHH. Indirect comparisons of lemborexant with daridorexant suggest an efficacy advantage for lemborexant and a tolerability advantage for daridorexant.

Clinical Trials Registration: NCT02783729, NCT02952820, NCT03545191, NCT03575104.