Nonclinical Studies of Abuse Potential With Dual Orexin Receptor Antagonists: Concordance With Real-World Use

Authors:  Moline M, Cheng JY, Henningfield J, Sembower M, Pype S, Buchhalter AR

Background: Drugs acting on the central nervous system are subject to a determination of abuse potential prior to regulatory approval in the United States (US). Since the dual orexin antagonists (DORAs) are hypnotics, each approved drug (lemborexant, suvorexant, daridorexant) underwent a comprehensive assessment. Per FDA guidance, self-administration and drug-discrimination studies in nonhuman primates and rats are valid and reliable predictors of the abuse potential of a substance. These studies evaluate whether the drug (1) has rewarding or reinforcing properties or (2) has similar effects to drugs with known abuse potential, respectively. The results of the nonclinical studies are then considered with data from clinical trials, including studies in the target patient population and in subjects with a history of abuse of drugs with similar indications. In a self-administration study in rhesus monkeys, lemborexant did not demonstrate a positive reinforcing effect. In a rat drug-discrimination study, lemborexant did not engender zolpidem-like responses in animals trained to discriminate between zolpidem and vehicle. More recently, daridorexant did not elicit any signs indicative of abuse or physical dependence potential in the 3 well-established models (self-administration, drug discrimination, and physical dependence/withdrawal) employed at exposures comparable to or exceeding human exposure, which is similar to previous results with suvorexant and lemborexant. These nonclinical data do not indicate potential for abuse of any of the 3 DORAs in humans. However, based on the human abuse potential studies (HAP), the 3 DORAs were ultimately placed into controlled Schedule 4 (CIV), the same class as GABAergic hypnotics. The HAP studies showed no difference in drug liking between the DORAs and the active comparator zolpidem in recreational sedative users who were able to recognize and like zolpidem (suvorexant) or both zolpidem and suvorexant (lemborexant and daridorexant). This is despite the recognition that HAP studies may not always predict real-world abuse-potential risk and may overestimate the risk of abuse, as has been suggested for drugs that did not demonstrate abuse potential in nonclinical testing or in the community. At the time of their approvals, although there were insufficient postmarketing data from the community for consideration in the scheduling decisions, more than 8 years of postmarketing data across the 3 approved DORAs are now available and indicate lower abuse and other safety risks compared with other CIV hypnotics.

Methods: Adverse events with the preferred terms (PTs) drug withdrawal syndrome, drug abuse, and drug dependence were evaluated from 2 sources: (1) ongoing Eisai’s global postmarketing safety surveillance system (20 Dec 2019 through 23 Sep 2022), and (2) FDA Adverse Event Reporting System (FAERS) from suspect cases (Jan 1, 2015, through Dec 31, 2022). The DORAs were compared with the 3 most currently prescribed benzodiazepines for patients with insomnia (estazolam, temazepam, and triazolam) and with zolpidem reported in FAERS.

Results: Since the time of lemborexant’s marketing approval, there have been a small number of the 3 PT adverse events received from the US, Canada, and Japan. Given the number of patients exposed postmarketing (approximately 460 million patient days), and the number of reports (51), the calculated reporting rate corresponds to 0.11 cases per million patient days of global exposure. This poster will include new evaluations of FAERS and other  surveillance data. For example, of the total number of reports submitted to FAERS based on each drug or drug class, there were relatively low percentages reported for the queried terms for the DORAs. Of 9,722 reports for DORAs, the percentages of reports for PTs of drug withdrawal syndrome, drug abuse, and drug dependence were 0.1%, 0%, and 0.1%, respectively. These data match the findings in the pivotal studies programs for the 3 DORAs, where no dependence was observed in the insomnia patient population. To that end, none of the DORA labels contain a warning about dependence. Conversely, the percentages of reports of those 3 PTs for the benzodiazepines (5,345 reports) were 0.8%, 13.0%, and 3.7% and 1.0%, 8.9%, and 5.3% for zolpidem (17,914 reports).

Conclusions: Data from the community suggest that relying exclusively on HAP studies for scheduling the DORAs appears to overestimate their potential for abuse in the community. These findings are in line with research that suggests abuse potential may be well predicted by the results of the nonclinical studies and national surveillance systems, which also suggest that the DORAs do not pose meaningful abuse potential and related risks.

Sponsor: Eisai, Inc

To be presented at the 62nd Annual Meeting of the American College of Neuropsychopharmacology

Monday, December 4, 2023 at 5 PM – 7 PM