Summary Basis of Decision for Belsomra

Clinical Pharmacology

Suvorexant, the medicinal ingredient in Belsomra, is an orexin receptor antagonist. The orexin neuropeptide signalling system plays a critical role in promoting wakefulness. Orexin is secreted by neuronal cell bodies located in the hypothalamus, which project to neurons in the brain. The binding of orexin to the orexin receptors on these neurons promotes wakefulness. Suvorexant binds reversibly to orexin receptors, preventing orexin from binding and thereby promoting sleep.

Due to the mechanism of action of suvorexant, many of the potential adverse events are also symptoms associated with narcolepsy. Narcolepsy has been linked to a decrease in orexinergic neurotransmission in animals and in humans. Symptoms include excessive daytime sleepiness (EDS), hypnagogic or hypnopompic hallucinations, sleep paralysis, and cataplexy.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of suvorexant have been characterized in patients and healthy volunteers. Similar pharmacokinetic profiles were observed in healthy subjects and in patients with insomnia. The increase in exposure is less than dose-proportional, as absorption of suvorexant decreased at higher doses over a range of 10 mg to 80 mg. Suvorexant is metabolized primarily by cytochrome P450 (CYP) 3A, and to a lesser extent by CYP 2C19. The main routes of elimination are the feces and urine, in which 66% and 23% of the administered dose were recovered, respectively. The mean half-life (t_½) of suvorexant is approximately 12 hours.

Although the pivotal trials were designed with lower doses for elderly patients than for non-elderly adult patients, the pharmacokinetic and safety data indicate that dose adjustment is not required based solely on the age of a patient. The recommended initial dose is 10 mg for both elderly and non-elderly adult patients (or 5 mg for patients using moderate CYP 3A inhibitors concurrently), and may be increased gradually if the previous dose is tolerated but not effective.

The pharmacodynamic profile of suvorexant was also characterized through several studies. The next-morning effects on driving performance were examined in healthy elderly and non-elderly adults, nine hours after the administration of suvorexant. Clinically meaningful impairment was observed after receiving the 20 mg and 40 mg doses for one night, and after receiving the 40 mg dose for eight nights. Statistically significant differences were not observed in the driving performance of elderly subjects after receiving the 15 mg or 30 mg doses for one and eight nights. Patients are advised not to drive, operate machinery, or engage in other activities requiring full mental alertness until they understand how suvorexant affects them the next day. A decrease in delayed word recall was observed at 11 hours post dose in healthy subjects the morning after receiving a 40 mg dose of suvorexant, and effects on balance were observed the morning after receiving a 20 mg or 40 mg dose of suvorexant. No respiratory depressant effects were observed in healthy adults after one night of treatment with a 40 mg or 150 mg dose. Prescribers should consider the effects of suvorexant on respiratory function if prescribing to patients with compromised respiratory function. Suvorexant does not prolong the QT interval to any clinically relevant extent.

For further details, please refer to the Belsomra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Belsomra was demonstrated mainly through two Phase III pivotal studies: Study 1 (PN028) and Study 2 (PN029). Both studies were randomized, double-blind, and placebo-controlled, in patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Both studies were three months long. Study 1 had an optional three-month extension phase for patients who completed the initial three-month treatment phase. Sleep latency and sleep maintenance were assessed objectively through polysomnography (PSG) and subjectively through electronic patient diaries.

The main objective in both pivotal studies was to demonstrate the efficacy of a high dose of Belsomra, defined as 30 mg for elderly patients and 40 mg for non-elderly adult patients. A low dose, defined as 15 mg for elderly patients and 20 mg for non-elderly adult patients, was also evaluated in both studies. Elderly and non-elderly patients were randomized separately to one of three treatment arms: the high dose group, the low dose group, or the placebo group. The blinded treatment (suvorexant or placebo) was administered once daily, five to ten minutes before going to bed, or approximately 30 minutes before going to bed on nights when PSG measurements were taken.

Efficacy was assessed by measuring the changes in sleep latency and sleep maintenance from baseline at pre-determined time points during each study. Polysomnography data was analysed at Night 1, Month 1, and Month 3. Data from patient diaries was analysed at Week 1, Month 1, and Month 3.

In Studies 1 and 2, statistically significant improvements in both sleep latency and sleep maintenance were observed for the high dose relative to the placebo. In Study 1, statistically significant improvements were observed for the low dose compared to placebo in the objective and subjective sleep maintenance parameters for all time points, and for the objective sleep onset parameter at Month 1, as per the multiplicity testing procedure. Similar results favouring the low dose over placebo were seen in Study 2, however, statistical inferences were not allowed as the low dose was not included in the multiplicity testing strategy.

Although both studies were designed with an emphasis on the 30 mg and 40 mg doses, the overall data from these two studies are considered adequate to demonstrate the efficacy of the 15 mg and 20 mg doses. The 30 mg and 40 mg doses were not approvable due to safety concerns. The 15 mg and 20 mg doses were approved, but not for use as initial doses. The 10 mg dose showed significant results for an objective sleep maintenance outcome in a small Phase II study, which supported the recommendation of 10 mg as an initial dose.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Belsomra (suvorexant) is indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated. Belsomra (suvorexant) is indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. The clinical trials performed in support of efficacy were up to three months in duration in adults and elderly patients.

The 30 mg and 40 mg doses were originally proposed by the sponsor as the recommended starting doses, with options to reduce to 15 mg or 20 mg if the higher doses were not well-tolerated. However, the 30 mg and 40 mg doses were not approvable due to unacceptable safety profiles. The 15 mg and 20 mg doses were approved, but not for use as initial doses. Health Canada recommends a 10 mg initial dose for Belsomra, with options to increase the dose to 15 mg or 20 mg if the previous dose was tolerated but ineffective. Generally, patients are advised to use the lowest effective dose, and not to exceed the maximum recommended dose of 20 mg. For patients using moderate CYP 3A inhibitors concurrently, the recommended initial dose is 5 mg and the maximum dose is 10 mg.

For more information, refer to the Belsomra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The evaluation of safety in clinical trials included 922 subjects in Phase I trials and 2,027 primary insomnia patients in Phase II/III trials. In the Phase III trials combined, a total of 1,784 patients received Belsomra daily, with 1,218 patients treated for at least three months (290 patients treated with the low dose), 507 patients for six months or longer (42 patients treated with the low dose), and 160 patients for 12 months or longer (all treated with the high dose).

The two Phase III pivotal trials described in the Clinical Efficacy section (Study 1 and Study 2) evaluated the safety and efficacy of a high dose (defined as 30 mg for elderly patients and 40 mg for non-elderly adult patients) and a low dose (defined as 15 mg for elderly patients and 20 mg for non-elderly adult patients), with higher numbers of patients and longer duration of treatment in the high dose groups. The clinical review of Belsomra also included a review of results from the supportive studies Study 3 (PN006) and Study P009. Study 3 was a randomized, double-blind, placebo-controlled Phase IIb crossover study consisting of two four-week periods. The safety, tolerability, and efficacy of four dosage strengths (10 mg, 20 mg, 40 mg, and 80 mg) were evaluated in non-elderly adult patients. Study P009 was a Phase III long-term safety study to evaluate the safety and tolerability of the 30 mg and 40 mg doses of Belsomra over 12 months of treatment.

Two Notices of Deficiency (NOD) were issued for this product prior to the issuance of the Notice of Compliance (NOC). Both NODs were issued for safety-related concerns. The sponsor has submitted additional data to address these concerns, and the risks identified for Belsomra are now considered manageable through product labelling and ongoing post-market surveillance.

Suvorexant targets the orexinergic system by blocking the wake-promoting effects of orexins. Decrease in orexinergic neurotransmission is associated with narcolepsy in animals and in humans. Therefore, symptoms associated with narcolepsy were potential adverse effects of suvorexant. Narcolepsy is a neurological disorder characterized by EDS and recurrent intrusions of elements of rapid eye movement (REM) sleep into the transition period between sleep and wake (e.g., sleep-related hallucinations and sleep paralysis). Narcolepsy is also commonly associated with cataplexy. Cataplexy is thought to occur only after substantial loss of orexinergic neurons in patients with narcolepsy, possibly involving an autoimmune mechanism.

Events of Clinical Interest (ECIs) were selected for the clinical program based on labelled safety concerns with other marketed hypnotic medications, and on theoretical safety considerations for suvorexant. For Phase III trials, ECIs included: suicidal ideation and/or behaviour, complex sleep-related behaviours (CSBs), hypnagogic and hypnopompic hallucinations, EDS, sleep paralysis, cataplexy, falls, and adverse events associated with traffic or motor vehicle accidents. Adverse events suggestive of cataplexy and all falls were submitted to an external committee of experts for review and adjudication as potential cataplexy.

Somnolence was the most common adverse event observed in the Phase III trials, for which the incidence was higher in the treatment groups than in the placebo group (11% in the high dose group, 7% in the low dose group, and 3% in the placebo group). Events of suicidal ideation were also observed, at frequencies of 0.4% in the high dose group, 0.2% in the low dose group, and 0.1% in the placebo group. Two CSB events were reported in patients in the high dose group. Sleep paralysis and hypnagogic/hypnopompic hallucinations occurred infrequently in the treatment groups, and were not observed in the placebo group. One case of muscular weakness temporarily associated with laughter occurred in the high dose group. The external expert committee concluded this was not cataplexy. Other events of muscular weakness were reported, but because of characteristics inconsistent with cataplexy (i.e., event duration and lack of associated potential trigger), they were not submitted for adjudication.

The clinical development program for Belsomra was designed with the primary objective of supporting 30 mg and 40 mg as the recommended doses. However, significant safety concerns were identified for these doses during the initial clinical review, and the 30 mg and 40 mg doses were not approvable due to unacceptable risks of serious adverse reactions such as suicidality, EDS and psychomotor impairment, CSBs, and "cataplexy-like" events.

The "cataplexy-like" events and CSBs were particularly concerning due to their sudden onset and potentially serious negative consequences. These events were only observed in patients who received the 30 mg and 40 mg doses. However, due to the limited data available for the low doses, it was not possible to determine whether they were safer than the high doses, and a NOD was issued. The submission was later withdrawn by the sponsor.

The NDS was resubmitted with post-marketing adverse event reports from other jurisdictions, gathered over a period of 2.5 years. Based on the data submitted, it was not possible to identify risk factors or vulnerable populations, which were needed for the development of risk mitigation strategies for "cataplexy-like" events and CSBs. A second NOD was issued for Belsomra.

The sponsor filed a response to the NOD to address the non-clinical findings originally interpreted as suvorexant-associated cataplexy in dogs, and to further explore the available data from approximately 3.5 years of post-market experience with Belsomra, mainly in Japan and the United States, as well as in Australia. The review concluded that the overall available evidence supported the approval of Belsomra with appropriate labelling of risks and continuous monitoring of post-market evidence.

A contraindication in patients with narcolepsy, a warning on "cataplexy-like" and other REM sleep-related events, and an expanded warning on CSBs to include risk factors generally associated with parasomnias, were included in the Product Monograph.

Important risk minimization strategies for Belsomra include taking a lower initial dose, using the lowest effective dose for the patient, and limiting the maximum dose to 20 mg.

A patient counselling information section was recommended as a further step in ensuring that 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, EDS, and worsening of depression or suicidal thoughts.

Based on the information available at the time of review, Health Canada determined that the risks identified for Belsomra can be mitigated through product labelling and through continuous post-market surveillance of adverse events.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Belsomra, and to promote its safe and effective use. Overall, the benefit-harm-uncertainty profile of Belsomra is favourable for the approved indication. For more information, refer to the Belsomra Product Monograph, approved by Health Canada and available through the Drug Product Database.