Regulatory Decision Summary for Quviviq

This New Drug Submission was filed to seek Canadian market authorisation for Quviviq (daridorexant) for the treatment of adult patients with insomnia to improve sleep and daytime functioning. Upon review, the indication, “Quviviq is indicated for the management of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance”, was approved.

The submission contained two Phase 3 efficacy and safety studies (Studies 301 and 302) and one open-label longer-term safety extension study (Study 303). Study 301 was to assess efficacy and safety of two doses of Quviviq (daridorexant) at 25 milligrams (mg) and 50 mg with placebo control in patients with Insomnia Disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Study 302 was of identical design as Study 301 except the doses studied were 10 mg and 25 mg. The efficacy endpoints were observed at Month 1 and Month 3 time points. Quviviq had convincing efficacy in improving the symptoms of insomnia, in a dose dependent manner at the dose range of 25 mg to 50 mg, in patients diagnosed with Insomnia Disorder for up to 3 months. The main effect of Quviviq was in reducing the awake time while its effect in reducing sleep latency was notable but not clinically significant. Quviviq reduced the objective wake time after sleep onset by 23 minutes at Month 1 and 18 minutes at Month 3 at the 50 mg dose level on average, which are both statistically significant and met the pre-specified clinically meaningful time of less than 15 minutes. It also reduced the objective latency to persistent sleep by 11 minutes at Month 1 and 12 minutes at Month 3 on average. These primary outcomes were supported by the secondary subjective Total Sleep Time endpoint, with a reduction from placebo of 22 minutes at one month and 20 minutes at 3 months. The pre-specified clinically meaningful improvement was 20 minutes for this secondary endpoint.

Daridorexant showed little drug-liking at the therapeutic doses, while this effect was moderate at higher doses. Food high in fat delayed the effect of Quviviq but had little impact in the setting of the management of insomnia. Quviviq’s adverse reactions were consistent with its pharmacological effects as characterized in the clinical development program. Quviviq had no effect on cardiac QT interval safety. The most frequent adverse reactions were headache, somnolence, dizziness, fatigue, and nausea, which were usually mild to moderate and relatively easy to manage in clinical care. Less common adverse reactions were sleep paralysis and hallucinations when falling asleep or waking up. More serious adverse reactions were uncommon. They included narcolepsy-like symptoms of excessive daytime sleep and complex sleep behaviours. The linkage between Quviviq and those adverse reactions are not well understood as they are associated with patients with sleep abnormalities during the course of their clinical management. These uncommon and potentially serious adverse reactions required clear warning. No case of insomnia rebound or withdrawal symptoms were found in the clinical trial data. There were uncertainties with reduced thyroid function and bilirubin increases, which were suitable for risk management through labelling and post-marketing surveillance. Quviviq had a higher exposure in the presence of cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors. It had an additive sedative effect with the concomitant use of alcohol, and it reduced driving performance. These adverse effects were well characterized, and clearly labelled in the Product Monograph.

In addition, pregnant women exposed to Quviviq were encouraged to enrol in a pregnancy registry and prescribers were advised to balance the care of the patient with the unknown effect of milk exposure of daridorexant to the infant.

As worded, the approved indication reflected adequately the efficacy demonstrated in the patient population studied and remained consistent with other drugs in the same class. Based on the available information, the benefit–harm-uncertainty profile for Quviviq was positive when used according to the approved Product Monograph.

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