Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Study Objectives</jats:title> <jats:p>To assess long-term efficacy and safety of lemborexant (LEM), a novel dual orexin receptor antagonist, versus placebo in adults with insomnia disorder.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>This was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (reported separately). A total of 949 participants with insomnia (age ≥18 years) were randomized, received treatment with an oral dose of placebo or LEM (5 mg [LEM5] or 10 mg [LEM10]) and were analyzed. Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored throughout the study.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Decreases from baseline in patient-reported (subjective) sleep onset latency and subjective wake after sleep onset, and increases from baseline in subjective sleep efficiency, were significantly greater with LEM5 and LEM10 versus placebo. Significant benefits over placebo were observed at the end of month 6, and at most time points assessed over the 6-month period, indicating long-term sustained efficacy of LEM. A significantly greater percentage of sleep onset responders and sleep maintenance responders were observed with LEM treatment versus placebo. Participants treated with LEM reported a significant improvement in quality of sleep after 6 months versus placebo. The majority of TEAEs were mild or moderate. There was a low rate of serious TEAEs and no deaths.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>LEM5 and LEM10 provided significant benefit on sleep onset and sleep maintenance in individuals with insomnia disorder versus placebo, and was well tolerated.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical trial registration</jats:title> <jats:p>ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39</jats:p> </jats:sec>

Effect of gastric acid‐reducing agents on the pharmacokinetics and efficacy of lemborexant

“…Consistent with findings from other Phase 1 clinical studies 9 and Studies 303 and 304, 7,8 lemborexant was found to be well tolerated in the current Phase 1 study. In conclusion, the results from these analyses indicate that lemborexant can be coadministered with ARAs (H 2 antagonists, PPIs, and antacids) and does not warrant dose modifications, which is supported by the lack of restrictive language in the US and Japanese prescribing information.…”

“…gastric acid, insomnia, lemborexant, orexin receptor antagonists, pharmacokinetics placebo at 1 month (Study 304) and through 12 months (Study 303), and was well tolerated. 7,8 Lemborexant is a Biopharmaceutics Classification System Class II molecule and exhibits pH-dependent solubility. Specifically, in vitro dissolution studies have shown that lemborexant exhibits delayed dissolution in weak acid and neutral conditions compared with dissolution at lower pH ( Figure S1).…”

Lemborexant for insomnia

“…The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3 1,10 ). At the end of 6 months, there were significantly more sleeponset responders and sleep-maintenance…”

“…• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights 9 • Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults. 10 Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant,…”

“…In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months. 10 Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF).…”