Regulatory Decision Summary for Belsomra

The efficacy of suvorexant in insomnia was evaluated in two Phase 3, randomised, double-blind, placebo-controlled studies.

In these studies, suvorexant was evaluated at a high dose level (HD; 30 mg in elderly and 40 mg in non-elderly adults) and a low dose level (LD; 15 mg in elderly and 20 mg in non-elderly adults). Efficacy was evaluated by both objective (polysomnography) and subjective (patient diaries) parameters of sleep onset (latency to sleep) and of sleep maintenance (total sleep time or wake time after sleep onset). Assessments were conducted at Night 1 (polysomnography)/Week 1 (patient diaries), Month 1 and Month 3 of treatment.

The HD was significantly better than placebo for both subjective and objective outcomes for sleep onset and for sleep maintenance parameters. The suvorexant LD was statistically better than placebo for objective and subjective sleep maintenance parameters for all time points, and for the objective sleep onset parameter at Month 1, as per multiplicity testing procedure in one study. Similar results favouring the LD were seen in the second study, however, the analyses for the LD were exploratory and statistical inferences were not allowed. The efficacy of suvorexant 10 mg was evaluated in a Phase 2 study, with significant results for an objective sleep maintenance outcome. Although this evidence is not robust, it indicates that the 10 mg dose is efficacious at least for some patients, and its use as initial dose is justified as a risk minimisation strategy for some important dose-dependent events associated with suvorexant.

For the evaluation of safety, the overall exposure to suvorexant in the clinical program included 922 subjects (healthy volunteers and special populations) in 32 Phase 1 trials, and 2,027 primary insomnia patients in 4 Phase 2/3 trials. In the Phase 3 trials combined, a total of 1784 patients received suvorexant daily, with 1218 patients treated for at least 3 months (290 with LD and 927 with HD), 507 patients for 6 months or longer (42 with LD and 464 with HD), and 160 patients for 12 months or longer (all with HD).

Suvorexant targets the orexinergic system by blocking the wake-promoting effects of orexins. Antagonism of orexin receptors could potentially cause symptoms associated with narcolepsy, such as excessive daytime sleepiness (EDS), recurrent intrusions of elements of rapid eye movement (REM) sleep into sleep-wake transition periods (hypnagogic or hypnopompic hallucinations; sleep paralysis), and cataplexy (a sudden involuntary skeletal muscle weakness or paralysis during wakefulness, typically triggered by strong emotions, commonly laughter). Residual effects associated with the therapeutic effect, i.e., next-day somnolence/sedation and psychomotor impairment, are a concern with any hypnotic. All hypnotics approved in Canada also have a class warning on Complex Sleep-related Behaviours (CSBs), which are behaviours that patients show after they get up from bed while not completely awake, such as cooking, eating, having sex, and driving, and for which they typically have no memory. Potential safety issues related to suvorexant mechanism of action, and other risks identified for marketed hypnotics were evaluated in the clinical program for suvorexant in insomnia.

The most common adverse event with incidence higher in suvorexant compared to placebo in clinical trials was somnolence (during the day). Suvorexant was also associated with dose-related events of suicidal ideation and EDS. Sleep paralysis and hypnagogic/hypnopompic hallucinations were reported infrequently in the suvorexant groups, with no events in the placebo group. Two events of CSB were reported in the HD group (0.2%). There was also one event of muscular weakness in the legs triggered by laughter in the suvorexant HD group (0.1%). This event was determined not to be cataplexy by a blinded independent expert adjudication committee.

There was no evidence of tolerance, withdrawal symptoms or rebound insomnia associated with chronic use of suvorexant. In one abuse liability study in recreational drug users, suvorexant was associated with similar effects as zolpidem on "drug-liking" and other secondary measures of subjective drug effects.

The review concluded that suvorexant HD (30 mg and 40 mg) was not approvable, due to unacceptable risks of potentially serious adverse events such as suicidality, EDS and psychomotor impairment, complex sleep-related behaviours (CSBs) and "cataplexy-like" events.

The "cataplexy-like" and CSB events were of particular concern for their sudden aspect and potential serious consequences. Although in clinical trials they were observed with the HD regimen only, the limited number of patients exposed to the LD was considered limited to assess if the LD was safer.

The sponsor submitted post-marketing data from about 3.5 years of market experience with Belsomra mainly in Japan and the United States. The data did not raise the level of concern. For example, there were no reports showing clear association of suvorexant with unequivocal cataplexy or with muscular weakness severe enough to cause a serious event. The CSB events reported with suvorexant seem similar to those with approved hypnotics, and although risk factors were not identified, it seems reasonable to consider that risk factors for CSBs in general should also apply in this case. It is concluded that risk minimisation via the Product Monograph, based on the evidence available at this time, and continuous monitoring of post-marketing evidence, is an acceptable approach.

A patient counselling information section was recommended as a further step in ensuring prescribers discuss the risks associated with suvorexant with patients, instruct patients to use Belsomra as prescribed, and advise patients to report events such as temporary muscular weakness, sleep paralysis, CSBs, excessive daytime somnolence, and worsening of depression or suicidal thoughts.

The efficacy and safety data support the proposed recommended dosage for Belsomra: the initial dose is 10 mg (5 mg with concomitant moderate CYP3A inhibitor); if the initial dose is well-tolerated but not effective, the dose can be increased to a maximum of 20 mg (or 10 mg with concomitant CYP3A inhibitor), which should not be exceeded.

The benefits of Belsomra as a drug with a novel mechanism of action in the treatment of insomnia in adults is considered to outweigh the risks associated with the treatment, in the conditions of use described in the approved Belsomra Product Monograph.