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Psychiatry Research Review

Sanjay Gupta, MD
Released: December 22, 2021

Lemborexant: A New Option for the Treatment of Insomnia

Citrome L, et al. J Clin Psychiatry. 2021;82:20m13795.

Background
When considering treatment options for insomnia, measures of effect size such as the number needed to treat (NNT), number needed to harm (NNH), and the likelihood to be helped or harmed (LHH) are important considerations. This study was done to determine the NNT, NNH, and LHH for the dual orexin receptor antagonist (DORA) lemborexant, which is approved by the FDA for the treatment of insomnia.

Methods
This study evaluated data from the global phase III SUNRISE 1 and SUNRISE 2 trials of lemborexant conducted between 2016 and 2018. In both trials, the efficacy of lemborexant was measured categorically, and tolerability was assessed by AEs. In the SUNRISE 1 trial, some patients received extended-release zolpidem, allowing for direct comparison with lemborexant. Indirect comparisons were made with other hypnotic agents, including doxepin, ramelteon, and select benzodiazepines.

Results
Lemborexant was effective and tolerable, with NNT as low as 3 and NNH ≥10 vs placebo. The most common AE with lemborexant was somnolence, with NNH = 28 with 5 mg (95% CI: 18-61) and NNH = 15 with 10 mg (95% CI: 11-22). AE-related discontinuation rates ranged from 1.4% with the 5-mg dose of lemborexant to 2.6% with the 10-mg dose, leading to LHH values ranging from 13-54. The NNT was lower with lemborexant vs extended-release zolpidem for several outcomes, including polysomnography and sleep diary, but other hypnotics had NNTs comparable with lemborexant.

Conclusions
The efficacy and tolerability for lemborexant were favorable in the phase III SUNRISE 1 and SUNRISE 2 trials as measured by NNT, NNH, and LHH.

Clinical Commentary
Lemborexant is an FDA-approved DORA for the treatment of sleep-onset insomnia and sleep maintenance insomnia. DORAs attenuate wakefulness signaling rather than augment sleep signaling like other hypnotic agents. In this study, a combined analysis of 2 phase III premarketing trials was done to determine the NNT, NNH, and LHH of lemborexant compared with other available hypnotics.

NNT and NNH are measures of effect size that indicate how many patients would need to receive one drug vs another for there to be 1 additional response or AE (eg somnolence), respectively. It is desirable for a drug’s NNT to be <10 and NNH ≥10. LHH is the ratio of NNH to NNT, so LHH >1 means patients are more likely to have a therapeutic response than an AE. As mentioned above, the LHH for efficacy to AE-related discontinuation ranged from 13-54, meaning patients were 13-54 times more likely to have a therapeutic response than discontinue treatment because of an AE.

Clinical Insights

  • Lemborexant was more likely to result in a therapeutic response than discontinuation from AEs at the 5-mg and 10-mg FDA-recommended doses.
  • Both doses of lemborexant were superior to 6.25-mg extended-release zolpidem, but data were not provided for a comparison with 12.5-mg extended-release zolpidem.
  • Lemborexant was similar to the other hypnotics in indirect comparisons, but no head-to-head data were available.
  • The most common AE among patients receiving lemborexant was somnolence.

Summary
In my opinion, it is useful to have a second FDA-approved agent to treat insomnia by attenuating the wakefulness cycle. In this trial, lemborexant was more likely to result in a therapeutic effect than an AE, but there was not a clear clinical benefit compared with most other hypnotic agents. Head-to-head studies and additional clinical experience are needed with lemborexant.

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