Daridorexant, a dual orexin receptor antagonist approved by the FDA in January 2022 for insomnia disorders, improved sleep outcomes at doses of 25 mg or 50 mg with a favorable safety profile, two phase III trials found.
In addition, the 50 mg dose significantly reduced patient-reported daytime sleepiness, reported Emmanuel Mignot, MD, of the Stanford Center for Sleep Research and Medicine in Palo Alto, and co-authors in Lancet Neurology.
“Improvements in sleep variables were achieved without excess sleepiness the following morning, and improvements in daytime functioning were observed,” the researchers wrote. “The improvement in sleep perceived by participants in these studies was consistent with that objectively measured by polysomnography.”
Compared with placebo, daridorexant 50 mg and 25 mg improved outcomes at months 1 and 3, Mignot and co-authors wrote. The largest effect was seen with the highest dose (50 mg) tested in the trials, followed by the 25 mg dose. The 10 mg dose did not have a significant effect.
The two phase III trials shared a similar design. In Study 1, 930 participants were randomized between June 2018 and February 2020 to daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310). In Study 2, 924 people were randomized between May 2018 and May 2020 to daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308).
Following screening and a single-blind placebo run-in period, the double-blind treatment period was 3 months. Primary endpoints were change from baseline at months 1 and 3 in wake time after sleep onset (WASO) defined as time in minutes spent awake after onset of persistent sleep until lights on and latency to persistent sleep (LPS) defined as duration of time in minutes from lights off to persistent sleep onset measured by polysomnography.
Daytime functioning was assessed with a novel validated instrument, the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). “This secondary endpoint was based on a participant’s daily self-assessment of how energetic, mentally and physically tired, or how sleepy they felt, but it was not an objective measure of sleepiness (such as the multiple sleep latency test),” Mignot and co-authors wrote. “Using this new patient-reported outcome instrument, participants in the studies could report daily how they felt with regard to the three IDSIQ domains of sleepiness, mood, and alert/cognition.”
Most participants were female (67% in Study 1 and 69% in Study 2). In each study, 39% of participants were age 65 or older. Overall, 89% of particpants were White and 8% were Black or African American.
In Study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group at month 1 compared with placebo, with least squares mean difference of −22.8 min and –11.4 min, respectively. At month 3, the mean difference in WASO was −18.3 min and in LPS was −11.7 min.
The 50 mg group had improved self-reported total sleep time versus placebo at month 1 (mean difference 22.1 min) and month 3 (mean difference 19.8 min). On the IDSIQ, sleepiness domain scores were improved in the 50 mg group at month 1 (mean difference –1.8) and month 3 (mean difference –1.9).
Study 1 also showed that WASO and LPS were significantly reduced in the 25 mg group at month 1 versus placebo, with a mean difference of −12.2 min and –8.3 min, respectively. At month 3, the mean difference in WASO was −11.9 min; in LPS, it was −7.6 min.
The 25 mg group also had significantly improved self-reported total sleep time at month 1 (mean difference 12.6 min) and month 3 (mean difference 9.9 min) over placebo. IDSIQ sleepiness domain scores did not differ between groups.
In Study 2, WASO was reduced among participants in the 25 mg group versus placebo, with a mean difference of −11.6 min at month 1 and −10.3 min at month 3. No significant differences in LPS were seen at month 1 or 3 for the 25 mg group. No significant differences were seen for the 10 mg group versus placebo for WASO or LPS at months 1 or 3.
The 25 mg group had improved self-reported total sleep time at month 1 (mean difference 16.1 min) and month 3 (mean difference 19.1 min). IDSIQ sleepiness domain scores did not differ between groups. The 10 mg group showed no significant differences versus placebo on self-reported total sleep time or IDSIQ sleepiness domain scores at 1 or 3 months. In both studies, the prevalence of adverse events was similar and consistent across adults younger than age 65 and older adults. Nasopharyngitis and headache were the most common adverse events overall.
“According to the guidelines of the American College of Physicians and the European Sleep Research Society, the first-line treatment for the disorder is cognitive behavioral therapy for insomnia (CBT-I),” observed Kai Spiegelhalder, PhD, of the University of Freiburg in Germany, and co-authors in an accompanying editorial. “This treatment is safe and effective but not widely available.”
While the findings show daridorexant is a viable treatment for insomnia disorder, “future studies should provide essential data not only on long-term effects but also on the effects on patient-centered outcomes that are directly related to the core symptoms of insomnia. More work is also needed to establish how daridorexant will fit within current treatment pathways — e.g., after non-response to CBT-I,” the editorialists added.
In addition, “daridorexant out-performed placebo by less than 2 points on the Insomnia Severity Index in both reported trials, questioning the clinical importance of the study findings from the patients’ perspective,” they wrote.
Study limitations include a trial population with moderate to severe insomnia that was mostly White and had relatively few co-morbidities which may limit generalizability, Mignot and co-authors acknowledged.
In addition, the IDSIQ instrument is novel and used prospectively for the first time in these studies, the researchers noted. “Therefore, the effects of daridorexant observed with IDSIQ cannot be benchmarked with those of any other therapeutic intervention,” they wrote.
The FDA approval for daridorexant was for the 25 mg and the 50 mg dose, and the agency has recommended that daridorexant be classified as a controlled substance.
This study was funded by Idorsia Pharmaceuticals.
Mignot reported research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda and consultancy fees or speaker’s conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda.
Spiegelhalder declared no competing interests.
Paul Smyth, MD, Contributing Writer, BreakingMED™
Kaiser Health News
Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.