A Multicenter Open-label Pilot Study Evaluating Next-Dose Transition From Zolpidem to Lemborexant: Subgroup Analysis of Older Adults

Abstract

<h3>Introduction</h3> Treatment for insomnia often includes prescription medication but some commonly prescribed insomnia drugs, such as the GABA-ergic agonist zolpidem (ZOL), are associated with safety concerns in older adults. Studies examining methods for transitioning patients between insomnia medications of different drug classes are needed. Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) that is approved in the US, Canada, and Japan for the treatment of insomnia in adults. Study E2006-A001-312 (Study 312; NCT04009577) was a pilot study designed to examine pre-planned dosing approaches for directly transitioning from ZOL (immediate [IR] or extended release [ER] formulations) to LEM (5mg [LEM5] or 10mg [LEM10]). Here we present a post hoc analysis of outcomes in subjects aged ≥60y from Study 312. <h3>Methods</h3> The design of Study 312 comprised a 3-week Screening Period (SCR; subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (INT; 3-4 nights/week) or frequent (FREQ; ≥5 nights/week) users of ZOL-IR or ZOL-ER participated. Cohort 1 included INT ZOL users and subjects with one week each of INT and FREQ ZOL usage; subjects began TITR with LEM5. Cohort 2 included FREQ ZOL users who were randomized 1:1 to LEM5 (Cohort 2A) or LEM10 (Cohort 2B). Subjects who successfully transitioned to LEM could choose to enter EXT. Subjects could change LEM dose during TITR (one dose change allowed) and EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. <h3>Results</h3> Of the 53 subjects in the Full Analysis Set (Cohort 1, n=10; Cohort 2, n=43), 30 subjects were age ≥60y (Cohort 1, n=6; Cohort 2, n=24); mean (SD) age was 67.5 (4.9) years and 76.7% were female. During SCR, 63.3% of these 30 subjects reported that waking too early was their main sleep complaint, followed by difficulty staying asleep (30.0%) and difficulty falling asleep (6.7%). Overall, 23/30 (76.7%) transitioned to LEM after TITR. In Cohort 1, 5/6 (83.3%) transitioned, with 3 ending TITR on LEM5, and 2 on LEM10. In Cohort 2A (LEM5), 7/8 (87.5%) transitioned; with 3 ending TITR on LEM5 and 4 on LEM10. In Cohort 2B (LEM10), 11/16 (68.8%) transitioned; 1 ending TITR on LEM5 and 10 on LEM10. For the 7 subjects who discontinued during TITR, 1 subject (on LEM5) opted to discontinue and 6 subjects discontinued due to treatment-emergent adverse events (TEAEs; 1 each of intentional overdose, hemiparalysis, nausea, over-sedation, paralysis, and diarrhea; 2 were on LEM5 and 4 were on LEM10 at the time of the TEAE). The hemiparalysis and paralysis were not adjudicated as cataplexy. All 23 subjects who transitioned to LEM chose to continue in EXT. One subject discontinued during EXT and 22/30 (73.3%) subjects completed the study. Based on modal dose (defined as most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 15 days and 55 days for LEM5 and LEM10, respectively. Across the study (TITR and EXT), TEAEs occurred more frequently with LEM10 than with LEM5; the most common TEAEs (in 2 or more subjects) for either LEM dose were abnormal dreams (n=4) and somnolence (n=2). All TEAEs were mild to moderate in severity. <h3>Conclusions</h3> The majority of older subjects from Study 312 successfully transitioned from INT or FREQ ZOL-IR or ZOL-ER use to LEM, and completed the study. LEM was generally well tolerated with a safety profile that was consistent with that observed in Phase 3 clinical development. <h3>Funding</h3> Eisai Inc.