Regulatory Decision Summary for Zurzuvae

The purpose of this New Drug Submission, filed by Biogen Canada Inc., was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Zurzuvae (zuranolone) 20, 25 and 30 milligram immediate-release capsules. Upon review of the submitted package, Health Canada authorized Zurzuvae for the treatment of moderate or severe postpartum depression in adults following childbirth, while disclosing that the safety and efficacy of Zurzuvae have only been studied as a single 14-day course of treatment with a 31-day follow-up period, and that no data on re-treatment with Zurzuvae in case of a relapse were available.

This New Drug Submission for Zurzuvae (zuranolone) included a comprehensive non-clinical set of studies, Phase 1 clinical pharmacology studies, and two pivotal Phase 3 studies to support the safety and efficacy of Zurzuvae for postpartum depression (PPD), while Phase 2 and 3 studies in other indications (primarily major depressive disorder, or MDD) provided supportive safety data.

Postpartum depression is a severe condition following childbirth that poses significant risks to the mother, including suicide, and impairs infant bonding. Marketed antidepressants are currently first-line in pharmacological treatment of PPD, but require weeks to show therapeutic effect and necessitate chronic administration, creating an unmet medical need for rapid-acting therapies. Zurzuvae administered as a single 14-day oral course offers a novel therapeutic option to address this need, as a novel neuroactive steroid and gamma-aminobutyric acid (GABA_A) receptor-positive allosteric modulator.

The efficacy of Zurzuvae was supported by two pivotal, randomized, double-blind, placebo-controlled, parallel-group clinical trials that evaluated a single 14-day course of zuranolone, administered once a day in the evening, in female patients with severe PPD symptoms. The onset of PPD symptoms must have occurred in the third trimester or within four weeks of delivery. At baseline, patients had experienced depressive symptoms for 4 to 5 months, on average. Study 217-PPD-301 evaluated the 50 milligram (mg) dose of Zurzuvae and Study 217-PPD-201B evaluated a 30 mg dose of a previous zuranolone formulation. Participants received treatment once daily in the evening with fat-containing food for 14 days, with a 31-day follow-up period.

Both studies met their primary endpoint, demonstrating a statistically significant and clinically meaningful superior reduction in depressive symptoms compared to placebo, with a least squares mean treatment difference in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score of 4.0 to 4.2 points at day 15 (end of treatment). This magnitude of effect is within clinically significant treatment differences reported for antidepressants in general for the MDD indication. This therapeutic benefit was observed across different symptom subscales (depressed mood, functional impairment in work/activities, psychic anxiety, agitation, somatic symptoms and the three stages of insomnia). Treatment differences to placebo were statistically significant as early as day 3 (after two doses) with the 50 mg dose, demonstrating a rapid onset of action throughout the 45-day study period (31 days post-treatment), indicating that the therapeutic effect was maintained despite the cessation of dosing.

The safety of Zurzuvae was assessed in the two pivotal PPD studies (N = 176 zuranolone exposed), complemented by a larger safety database from MDD studies (N = 2,476 exposed) and from healthy volunteer studies (N = 658 exposed). Exposure in most Phase 2/3 placebo-controlled studies, including the PPD trials, consisted of a single 14-day treatment course with a follow-up period of around 4 weeks, while longer-term safety data was primarily informed by limited data from open-label MDD studies that evaluated repeated 14-day treatment courses over a follow-up duration of up to 12 months.

The safety profile was consistent with the drug’s mechanism, including dose-dependent central nervous system (CNS) depressant effects. The most frequent treatment emergent adverse events were somnolence (27.6%), dizziness (13.3%), and sedation (11.2%). While most CNS depressant events were generally mild to moderate and diminished after the first few days, dose reduction was required in 16.3% of study participants treated with Zurzuvae at the 50 mg dose who then completed the treatment course. Driving simulation studies showed significant psychomotor impairment 9 hours after a 50 mg dose that persisted after 7 days of treatment, and critically, patients were unable to reliably assess their own impairment. This significant association with psychomotor impairment also raised concerns for the ability for the patient to provide adequate child care. Although direct evidence of impairment of child care was not observed in the clinical trials, a few post-market reports from limited international market experience provided preliminary evidence to add to these concerns, specifically regarding excessive sedation persisting beyond 12 hours. A Serious Warnings and Precautions Box was added to the Product Monograph (PM) recommending restrictions on driving up to 12 hours post-dosing and suggesting arranging for alternative childcare due to impaired alertness and lack of patient insight until they understand how the drug affects them.

In a dedicated clinical study, Zurzuvae demonstrated abuse potential comparable to a benzodiazepine at a dose less than 2-fold the recommended 50 mg dose. Non-clinical and clinical data, especially with higher doses, suggest zuranolone is associated with withdrawal symptoms, including seizures, a known withdrawal effect of GABA modulators, such as benzodiazepines, which are linked to risk of dependence. Seizures were not observed in PPD trials and the likelihood of misuse and serious withdrawal symptoms is mitigated by the short, 14-day course of treatment. Nevertheless, risk mitigation measures mandated the addition of a warning to address these potential risks.

Furthermore, a potential increased risk for suicidal ideation and behavior was identified in the MDD pool (1.4% incidence versus 0.9% placebo), with some limited information from post-market reports. The antidepressant class labelling on suicidality was considered adequate, with added information specific to Zurzuvae.

Regarding reproductive risks, zuranolone was associated with teratogenicity and embryofetal toxicity in non-clinical studies. Additionally, zuranolone is secreted into breast milk, raising concerns for the breastfed infant, especially regarding excessive sedation, as post-market cases have been reported. Due to identified risks to the fetus and infant, Zurzuvae is contraindicated for use during pregnancy and breastfeeding is not recommended while taking the drug. Finally, significant drug interactions were identified: concomitant use with CNS depressants caused additive psychomotor impairment, while strong cytochrome P450 3A4 inducers significantly reduced exposure and inhibitors increased exposure to zuranolone. The safety review did not find adverse effects on respiratory depression or QTc interval prolongation.

The available evidence presented certain limitations. The trials predominantly enrolled patients with severe PPD (based on HAM-D score criterion), however, efficacy in moderate PPD is supported by a subset analysis using a different symptom scale, the Montgomery-Åsberg Depression Rating Scale ), supporting an indication for moderate or severe PPD. Also, although Zurzuvae is proposed as a single 14-day treatment course, and the average duration of a PPD episode is typically months, efficacy and safety were not studied beyond day 45, and no data exists on re-treatment for PPD symptoms relapse. Therefore, re-treatment is not recommended due to lack of demonstrated efficacy and concerns regarding the safety of longer-term treatment (e.g., potential for dependence). However, due to demonstrated potential rapid benefits of this short-treatment course, it was considered that there is a role for Zurzuvae in the treatment of PPD, and the prescriber would have other options for treatment of relapse.

In conclusion, the benefit-harm-uncertainty profile of Zurzuvae was considered favourable for the treatment of moderate or severe postpartum depression in adults following childbirth, contingent upon risk mitigation through strict labelling. The significant benefit of rapid symptom relief within days in a vulnerable population addressed the potential limitations of current chronic therapies and was considered to outweigh the identified harms and uncertainties. The 50 mg dose was justified by its rapid onset and high probability of target engagement, and the associated tolerability burden was generally mitigated by dose reduction. Identified risks were mitigated through risk mitigation measures implemented via the Product Monograph. Dose adjustments are also specified for drug interactions and hepatic and renal impairment.

The recommendation that Zurzuvae is to be taken with fat-containing food is supported by a study demonstrating increased bioavailability of zuranolone, and the administration of Zurzuvae with fat-containing food in the studies evaluating efficacy and safety.

The submitted chemistry and manufacturing information demonstrated that the drug substance and drug product can be consistently manufactured to meet approved specifications.

A Risk Management Plan for Zurzuvae was reviewed by Health Canada and considered acceptable considering the risk mitigation addressed in the Product Monograph and agreed upon post-market surveillance. The final labelling and Product Monograph were also considered acceptable for the described conditions of use and risk minimization strategies.

Overall, the benefit-harm-uncertainty profile was favourable for Zurzuvae for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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