Daridorexant, a dual orexin receptor antagonist approved by the FDA in January 2022 for sleep disorders, improved sleep outcomes at doses of 25 mg or 50 mg with a favorable safety profile, two phase III studies have 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 from Lancet Neurology.
“Improvements in sleep variables were achieved without excessive morning sleepiness, and improvements in daytime functioning were observed,” the researchers wrote. “The improvement in sleep perceived by participants in these studies was consistent with that measured objectively by polysomnography.”
Compared to placebo, daridorexant 50 mg and 25 mg improved outcomes at months 1 and 3, Mignot and co-authors wrote. The greatest effect was observed at the highest dose tested in the studies (50 mg), followed by the 25 mg dose. The 10 mg dose had no significant effect.
The two phase III studies had a similar design. In Study 1, 930 participants were randomized between June 2018 and February 2020 to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310). In Study 2, 924 subjects were randomized to daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) between May 2018 and May 2020.
After screening and a single-blind placebo run-in phase, the double-blind treatment duration was 3 months. Primary endpoints were the change from baseline at months 1 and 3 in wake time after sleep onset (WASO), defined as time in minutes spent awake from the onset of sustained sleep to the lights being turned on, and latency to sustained Sleep (LPS), defined as the time in minutes from lights off to onset as measured by polysomnography.
Daily functioning was assessed using a novel validated instrument, the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). “This secondary endpoint was based on a participant’s daily self-ratings of how energetic, mentally and physically tired, or how sleepy they felt, but it was not an objective measure of sleepiness (like the multiple sleep latency test),” Mignot and co-authors wrote. “With this new patient-reported outcomes tool, study participants were able to report daily how they felt across the three IDSIQ domains of sleepiness, mood, and alertness/cognition.”
Most participants were female (67% in Study 1 and 69% in Study 2). In each study, 39% of the participants were 65 years or older. Overall, 89% of the participants were White and 8% were Black or African American.
In Study 1, WASO and LPS were significantly reduced in participants in the daridorexant 50 mg group at Month 1 compared to placebo, with a 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 -11.7 min.
The 50 mg group had improved self-reported total sleep time at month 1 (mean difference 22.1 min) and month 3 (mean difference 19.8 min) compared to placebo. On the IDSIQ, sleepiness domain scores 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 compared to placebo, with a mean difference of −12.2 min and −8.3 min, respectively. At Month 3, the mean WASO difference -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) versus placebo. The IDSIQ scores for the area of sleepiness did not differ between the groups.
In Study 2, WASO was reduced in participants in the 25 mg group compared to placebo, with a mean difference of -11.6 min at Month 1 and -10.3 min at Month 3. There were none at Month 1 or 3 significant differences in LPS observed for the 25 mg group. No significant differences were found between the 10 mg group and 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). The IDSIQ scores for the area of sleepiness did not differ between the groups. The 10 mg group showed no significant differences compared to placebo in self-reported total sleep time or IDSIQ scores for sleepiness at 1 or 3 months. In both studies, the prevalence of adverse events was similar and consistent in adults younger than 65 years and older adults. Overall, nasopharyngitis and headache were the most common adverse events.
“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),” noted Dr. Kai Spiegelhalder from 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 results indicate that daridorexant is a viable treatment for insomnia, “future studies should provide essential data not only on long-term effects, but also on the impact on patient-centered outcomes that are directly related to the core symptoms of insomnia. Further work is also needed to determine how daridorexant fits into current treatment pathways – e.g. after failing to respond to CBT-I,” the editorials added.
In addition, “Daridorexant exceeded placebo by less than 2 points on the Insomnia Severity Index in both reported studies, calling into question the clinical significance of the study results from the patient’s perspective,” they wrote.
Study limitations include a study population with moderate-to-severe insomnia that was mostly white and had relatively few comorbidities that might limit generalizability, Mignot and co-authors acknowledged.
In addition, the IDSIQ instrument is novel and is being used prospectively in these studies for the first time, the researchers noted. “Therefore, the effects of daridorexant observed with IDSIQ cannot be compared to those of any other therapeutic intervention,” they wrote.
FDA approval for daridorexant was for the 25 mg and 50 mg doses, and the agency has recommended that daridorexant be considered 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 consulting fees or speaker conference reimbursements from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem and Takeda.
Spiegelhalder declared no competing interests.
Paul Smyth, MD, Contributing Author, BreakingMED™
Kaiser Health News
Kaiser Health News is a non-profit health news service. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.