Summary Basis of Decision for Quviviq

As outlined in the What steps led to the approval of Quviviq? section, the clinical review of the New Drug Submission for Quviviq was conducted as per a mix of methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Daridorexant, the medicinal ingredient in Quviviq, is a dual orexin receptor antagonist with equipotent activity on orexin 1 and orexin 2 receptors. Orexin neuropeptides (orexin A and orexin B) act on orexin receptors to promote wakefulness. Daridorexant antagonizes the activation of orexin receptors by orexin neuropeptides and consequently decreases the wake drive, allowing sleep to occur.

The clinical pharmacology package included reports on human pharmacodynamic and pharmacokinetic studies.

Single and multiple-ascending dose studies provided the initial characterization of daridorexant, including its clinical pharmacodynamics and pharmacokinetics, which showed an observable sleep-promoting effect.

In intrinsic factor pharmacokinetic studies, minor differences in the pharmacokinetic profile of daridorexant were found between Caucasian and Asian participants, which were likely attributable to differences in body weight. Based on pharmacokinetic data from patients with mild and moderate hepatic impairment, a dose adjustment is recommended in patients with moderate hepatic impairment. Daridorexant was not studied in patients with severe hepatic impairment; therefore, the use of Quviviq is not recommended in these patients. No dose adjustment of Quviviq was recommended in patients with renal impairment, including those with severe renal impairment.

Daridorexant was not found to exacerbate symptoms in patients with moderate chronic obstructive pulmonary disease or mild to moderate sleep apnea.

In extrinsic factor pharmacokinetic studies, diltiazem, a moderate cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitor, increased the exposure to daridorexant. It is therefore recommended to reduce the Quviviq dose from 50 mg to 25 mg in patients who need to take a medication with a moderate inhibitory effect on CYP3A4. Furthermore, daridorexant is contraindicated in patients taking a concomitant strong CYP3A4 inhibitor. No significant pharmacokinetic drug interactions of daridorexant 25 mg were found with midazolam, a sensitive CYP3A4 substrate and benzodiazepine sometimes used in patients with insomnia, or with rosuvastatin, a breast cancer resistance protein substrate. Similarly, no significant drug interactions were found with famotidine, an inhibitor of gastric secretion, or with efavirenz, a moderate CYP3A4 inducer. Daridorexant had no significant pharmacokinetic and pharmacodynamic drug interactions with citalopram, an antidepressant of the selective serotonin reuptake inhibitor class.

In healthy subjects, daridorexant was found to have an additive effect when co-administered with alcohol. In a driving simulator study in healthy participants, in the morning after first-dose administration, Quviviq impaired simulated driving performance as measured by the Standard Deviation of Lateral Position. The effect was less pronounced with 50 mg than with 100 mg Quviviq. For both doses, no effect on driving performance was detected after 4 consecutive nights of administration. In recreational sedative drug users, daridorexant showed low drug-liking at a therapeutic dose of 50 mg, while this effect was found to be moderate at higher doses (100 mg and 150 mg).

The effect of a high-fat, high-calorie meal on the pharmacokinetics of a single 50 mg dose of daridorexant was assessed in healthy male patients. When compared with the fasted state, the ingestion of a high-fat, high-calorie meal before dose administration delayed the absorption of daridorexant by about 1.5 hours, without significantly altering the rate (measured by the maximum plasma drug concentration) and extent (measured by the area under the concentration-time curve) of drug absorption. Therefore, a statement is included in the Quviviq Product Monograph to indicate that Quviviq may be taken with or without food; however, sleep onset may be delayed if taken with or soon after a high-fat and high-calorie meal.

Overall, the clinical pharmacology data support the use of Quviviq for the recommended indication. Appropriate warnings and precautions are in place in the approved Quviviq Product Monograph to address the identified safety concerns.

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

Clinical Efficacy

The efficacy of Quviviq in patients with insomnia disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM‑5), was supported by two confirmatory efficacy studies (Study 301 and Study 302).

Study 301

Study 301 was a Phase III, multicentre, double-blind, randomized, placebo-controlled, parallel-group, polysomnography study to assess the efficacy and safety of two doses of Quviviq (25 mg and 50 mg) versus (vs.) placebo in adult and elderly patients with insomnia disorder. In addition to meeting the DSM‑5 criteria, the patients had to have a score of 15 or above on the Insomnia Severity Index.

Blood samples were taken for population pharmacokinetic analysis. In total, 3,326 patients were screened, 2,234 patients went through a single-blind run-in, and 930 patients were randomized to receive study treatment. In the intention-to-treat group (number of patients [n] = 930), patients received Quviviq 25 mg (n = 310), Quviviq 50 mg (n = 310), or placebo (n = 310). The study included 306 men (32.9%) and 624 women (67.1%), with an average age (mean ± standard deviation) of 55.40 ± 15.3 years.

The primary endpoints of Study 301 were the change from baseline to Month 1 and Month 3 in wake after sleep onset (WASO) and in latency to persistent sleep (LPS), measured objectively by polysomnography in a sleep laboratory. The key secondary endpoints were patient-reported total sleep time (sTST) and the Insomnia Daytime Symptoms and Impacts Questionnaire - sleepiness domain (IDSIQ-SD). The clinically meaningful effect size to detect (i.e., the pre-specified clinically meaningful improvement), determined based on efficacy exploratory studies and used for sample size calculations, was 15 minutes for WASO and LPS, 20 minutes for sTST, and 5 units for the IDSIQ-SD score. All endpoint results (least squares mean) are baseline- and placebo-subtracted. The primary analyses included 16 hypotheses for all endpoints, dose levels, and time points. For these hypotheses, the pre-specified Bonferroni-based (Bretz et al 2009) gate-keeping procedure was used to control for type 1 errors.

The primary analyses of the impact of Quviviq 25 mg and 50 mg on WASO and LPS showed a statistically significant improvement over placebo at both time points and doses. Quviviq 25 mg and 50 mg reduced WASO by 12.20 minutes and 22.78 minutes, respectively, at Month 1, and by 11.86 minutes and 18.30 minutes, respectively, at Month 3. Quviviq 25 mg and 50 mg reduced LPS by 8.32 minutes and 11.35 minutes, respectively, at Month 1, and by 7.59 minutes and 11.67 minutes, respectively, at Month 3. Only the WASO results for Quviviq 50 mg at both time points met the clinically meaningful effect size to detect duration of 15 minutes or more, while none of the LPS results reached this duration.

The secondary endpoint of sTST resulted in a statistically significant improvement over placebo at both time points and doses. Quviviq 25 mg and 50 mg increased sTST by 12.62 minutes and 22.06 minutes, respectively, at Month 1, and by 9.93 minutes and 19.77 minutes, respectively, at Month 3. The results for sTST were supportive, as they were statistically significant and, at the 50 mg dose, met the clinically meaningful effect size to detect duration of 20 minutes or more at both timepoints. For the secondary endpoint of IDSIQ‑SD, Quviviq resulted in an improvement over placebo. Quviviq 25 mg and 50 mg reduced the IDSIQ‑SD score by 0.75 units and 1.75 units, respectively, at Month 1, and by 0.99 units and 1.90 units, respectively, at Month 3. Of these, only the results for Quviviq 50 mg were statistically significant; however, they did not met the clinically meaningful effect size to detect of 5 units or more.

Study 302

Study 302, identical in design as Study 301, assessed Quviviq at the 10 mg and 25 mg doses. In total, 3,683 patients were screened, 2,201 patients went through a single-blind run-in, and 924 patients were randomized to receive study treatment. In the intention-to-treat number group (n = 924), patients received Quviviq 10 mg (n = 307), Quviviq 25 mg (n = 309), or placebo (n = 308). The study included 286 men (31.0%) and 638 women (69.0%), with an average age (mean ± standard deviation) of 56.70 ± 14.2 years.

For the primary endpoints of WASO and LPS, Quviviq resulted in an improvement over placebo at both time points and doses. Quviviq 10 mg and 25 mg reduced WASO by 2.74 minutes and 11.62 minutes, respectively, at Month 1, and by 1.95 minutes and 10.25 minutes, respectively, at Month 3. Quviviq 10 mg and 25 mg reduced LPS by 2.61 minutes and 6.45 minutes , respectively, at Month 1, and by 3.19 minutes and 9.01 minutes , respectively, at Month 3. Of these, only the WASO results for Quviviq 25 mg at both timepoints were statistically significant; however, they did not meet the clinically meaningful effect size to detect duration of 15 minutes or more.

For the secondary endpoints of sTST and IDSIQ‑SD, Quviviq resulted in an improvement over placebo at both time points and doses. Quviviq 10 mg and 25 mg increased sTST by 13.37 minutes and 16.13 minutes, respectively, at Month 1, and by 13.58 minutes and 19.06 minutes, respectively, at Month 3. Quviviq 10 mg and 25 mg reduced IDSIQ‑SD by 0.43 units and 0.75 units, respectively, at Month 1, and by 0.73 units and 1.25 units, respectively, at Month 3. Of these, only the sTST results for Quviviq 25 mg at both timepoints were statistically significant; however, they did not meet the clinically meaningful effect size to detect duration of 20 minutes or more.

Indication

The New Drug Submission for Quviviq was filed by the sponsor with the following indication:

Quviviq (daridorexant) is indicated for the treatment of adult patients with insomnia, to improve sleep and daytime functioning.

Health Canada revised the proposed indication to adequately reflect the efficacy demonstrated in the patient population studied and to maintain wording consistent with that used for other drugs in the same class. Accordingly, Health Canada approved the following indication:

Quviviq (daridorexant) is indicated for the management of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

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

Clinical Safety

The clinical safety of Quviviq was based on data from Study 301, Study 302 (see Clinical Efficacy section), and Study 303, an open-label, longer-term, nine-month safety extension study to Study 301 and Study 302. Of the 1,847 patients in these studies who received study treatment, 618 patients received Quviviq 25 mg, 308 patients received Quviviq 50 mg, 306 patients received Quviviq 10 mg, and 615 patients received placebo. Approximately 40% of the 1,847 patients were 65 years of age or older. Overall, 490 patients were treated with Quviviq for at least 6 months and 314 patients were treated with Quviviq for at least 12 months.

Four fatalities were reported in patients who received Quviviq at doses ranging from 10 mg to 25 mg. One fatality occurred during Study 301, two occurred during Study 303, and one occurred after discontinuing the drug treatment. While no fatalities were reported in patients who received placebo, the fatalities that were reported may be attributable to random events and, in part, to the relative greater patient exposure to drug treatment.

The adverse events reported during the studies were expected for this class of drug. In Study 301 and Study 302 (pooled data), adverse reactions that occurred in at least 2% of patients who received Quviviq and more frequently (≥1%) than those who received placebo included headache (5.5%), somnolence (2.5%), fatigue (2.5%), dizziness (2%), and nausea (1.5%).

A standard set of terms from the Medical Dictionary for Regulatory Activities (MedDRA) Queries was used to conduct a search of the clinical study dataset. Under the category of general, there was a small uptick in patients who reported a hypersensitivity reaction (0.81% for Quviviq vs. 0.65% for placebo). No cases of anaphylactic or anaphylactoid reactions were reported. Under the category of insomnia-related events, the combined frequency of narcolepsy-like events was 1.06% for Quviviq vs. 0.32% for placebo. The linkage between Quviviq and these adverse reactions is not well understood, as they are associated with patients with sleep abnormalities. An uptick in the frequencies of depression was notable with Quviviq (0.57%) vs. placebo (0.32%). Under the category of reinforcing potential, out of the terms of drug abuse, substance abuse, addiction, dependence, euphoria, mood changes, psychosis, and hallucinations, no safety signals were detected aside from an uptick in the frequency of hallucinations (0.32% for Quviviq vs. 0.0% for placebo). Under the category of laboratory, data for abnormal thyrotropin, thyroid-stimulating hormone, eosinophils, leukocytes, hepatic enzymes, and bilirubin were requested. Results identified a slightly higher frequency in events of reduced thyroxine and increased bilirubin. No events of insomnia rebound or withdrawal symptoms were identified in the clinical trial data.

Quviviq was approved by the United States Food and Drug Administration on January 7, 2022. Given the recent approval, the sponsor was only able to provide a very rough estimate of exposure of approximately 3,000 patients. In this limited post-marketing exposure, the following cases were reported: narcolepsy-like symptoms (n = 14), drug abuse potential (n = 11), depression (n = 5), central nervous system depressant effects (n = 3), anxiety (n = 1), and suicide/self-injury (n = 1).

Appropriate warnings and precautions are in place in the approved Quviviq Product Monograph to address the identified safety concerns.

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

As outlined in the What steps led to the approval of Quviviq? section, the review of the non-clinical component of the New Drug Submission for Quviviq was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non-clinical package included data from primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies.

Pharmacodynamics

The receptor binding and functional activity of daridorexant were investigated in several in vitro and in vivo studies. Theses studies provided evidence that daridorexant is an equipotent dual orexin receptor antagonist that reduces latency to sleep and prolongs sleep time in animals. Unlike traditional sleep medications, such as positive gamma-aminobutyric acid type A receptor modulators, daridorexant does not affect motor functions in rats.

The main metabolites of daridorexant, M1, M3 and M10, do not contribute to the therapeutic effect of the drug. To identify the potential off-target effects of daridorexant, M1, M3, and M10, high-throughput radioligand binding was evaluated using 128 identified targets. Few identified targets showed functional effects (in cells) for daridorexant, M1, and M3. However, the observed half-maximal inhibitory concentrations and half-maximal effective concentrations were in the micromolar range and therefore would not be expected to induce off-target effects during clinical use of the drug. While circulating M3 was the metabolite found in a higher proportion at the maximum plasma drug concentration, it remained in the one micromolar range (1.1 µM for a 50 mg dose).

Safety pharmacology

Multiple cardiovascular studies were performed. No change in QT duration was observed in guinea pigs and dogs. Heart rate reduction observed in the few hours after dosing is thought to be related to the sleep-inducing effect of the drug rather than a direct cardiovascular effect.

In a central nervous system safety pharmacology study and a respiratory safety pharmacology study conducted in rats at doses of 100, 300, and 1,000 mg/kg, daridorexant had no significant effect on the animals. Therefore, the no-observed-adverse-effect level is considered to be 1,000 mg/kg.

Pharmacokinetics

Non-clinical pharmacokinetic studies carried out with daridorexant did not identify any serious safety signals or efficacy issues.

In absorption studies, daridorexant is rapidly absorbed with a time to reach maximal concentration varying between 0.3 and 2 hours, depending on species (rats or dogs) and dose. Additionally, daridorexant exhibited a higher exposure and half-life in female rats compared with males.

In distribution studies, after single oral dose, daridorexant was widely distributed to various tissues throughout the body, including the brain. Daridorexant and its major metabolites (M1, M3, M10) are highly bound to plasma proteins.

In excretion studies, daridorexant and its metabolites were excreted in the milk of lactating rats. The major route of excretion is feces.

In metabolism studies, daridorexant was metabolized via seven primary pathways from which 22 metabolites were identified structurally. Three major metabolites were identified (M1, M3, M10); however, they did not contribute significantly to the overall pharmacological effect of daridorexant. Cytochrome P450 3A4 (CYP3A4) is responsible for 89% of the metabolism of daridorexant.

Toxicology

In repeat-dose toxicity studies, the main clinical signs observed in rats and dogs were decreased activity and sluggish behaviour at lower doses and intermittent head tremors or head shaking at higher doses. These mild effects at the lower doses were expected based on the pharmacology of daridorexant. The clinical signs resolved during the recovery period. In the dogs, there were cataplexy-like clinical signs in the presence of stimulation, which were categorized as fainting. This finding may be due to an exaggerated pharmacological effect of daridorexant. This clinical sign was not observed at the beginning of the recovery period; however, the cataplexy-like clinical sign is considered to be adverse.

In rats, a dose-related increase in hepatocellular hypertrophy was observed; this finding was associated with an increase in liver weights and, in some cases, an increase in liver enzymes. These changes were generally of minimal severity and were reversible during the treatment-free period. Follicular cell hypertrophy in the thyroid gland was observed primarily in rats and was associated with increases in thyroid weight, circulating triiodothyronine, and thyroid-stimulating hormone. These changes were reversible by the end of the treatment-free period. Additionally, findings in the liver and the thyroid appeared to be secondary to the liver enzyme-inducing effect of daridorexant.

Daridorexant was not genotoxic in two in vitro studies and one in vivo study. It was also not oncogenic in carcinogenicity studies in rats and transgenic mice.

Daridorexant had no toxicologically significant effect on male and female fertility, embryo-fetal development, or pre- and postnatal development. No adverse effect was observed on the fertility of the offspring of rats treated with daridorexant.

In operant behaviour studies, daridorexant did not produce a stimulus generalization to zolpidem (a drug with abuse potential) and did not have reinforcing properties. In a physical dependence study, the discontinuation of daridorexant treatment did not produce any changes associated with withdrawal symptoms.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Quviviq Product Monograph. In view of the intended use of Quviviq, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

As outlined in the What steps led to the approval of Quviviq? section, the review of the quality component of the New Drug Submission for Quviviq was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Quviviq has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

A Notice of Non-Compliance (NON) was previously issued by Health Canada on August 15, 2022. It was determined that the sponsor's risk assessment for the potential formation of N‑nitrosamine impurities (N‑Nitrosodiethylamine) during the drug substance manufacturing process did not align with Health Canada's expectations regarding control of nitrosamines. Additionally, the sponsor was requested to define triazole as a starting material. In the Response to the NON, the sponsor provided a revised risk assessment demonstrating a negligible risk for the formation of N‑Nitrosodiethylamine during the commercial process. The proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies). Additionally, triazole was redefined as a regulatory starting material. Therefore, a Notice of Compliance was recommended from a quality perspective.

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

None of the excipients used in the formulation of Quviviq is of human or animal origin.