Regulatory Decision Summary for Qulipta

This New Drug Submission – New Active Substance (NDS-NAS) was filed to obtain market authorization for Qulipta (atogepant) for the prevention of episodic migraine (<15 migraine days/month) in adults.

Qulipta (atogepant) is a new active substance and a Calcitonin Gene-Related Peptide (CGRP) receptor antagonist that was proposed for the prevention of episodic migraine (<15 migraine days/month) in adults. Evidence was provided by two pivotal, randomized, placebo-controlled, safety and efficacy studies. Participants were mostly female (88%) and Caucasian (76%). The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. Results of both studies demonstrated modest, somewhat dose-proportional efficacy over the three atogepant doses: both monthly migraine and headache days were lower by approximately 1 to 1.5 days per month and approximately 20% of participants experienced ≥50% reduction in monthly migraine days over the course of the two trials. Most of these endpoints were statistically significant and clinically meaningful. The results of most secondary efficacy endpoints provided further support for efficacy of atogepant.

The most common treatment-emergent adverse events in atogepant treatment arms of the controlled studies were nausea, constipation, and somnolence. Long-term safety of atogepant was established in an open-label study, during which 543 participants took atogepant 60 milligrams (mg) once daily for up to 12 months. Overall, the safety profile of atogepant in the long-term safety study was similar to that of pivotal studies. The most commonly reported adverse events in the long-term study included constipation, hypertension, urinary tract infection, and weight decreased. The most common events that led to the withdrawal of participants from the study were constipation, nausea and fatigue.

Notable uncertainties included a limited number of elderly participants across studies; small, inconclusive imbalances in arrhythmic events and hypertension; events of fatigue, somnolence, and/or dizziness; constipation; and several liver transaminase elevations with a possible association to atogepant (none suggestive of Hy’s Law). Atogepant should therefore be avoided in patients with severe hepatic impairment. Atogepant dose should also be adjusted in patients with severe renal impairment, those with end-stage renal disease, and when atogepant is used in combination with drugs that increase its exposure. Non-clinical studies found atogepant present in the milk of lactating rats. Since there are no human data on atogepant secretion in breast milk, potential benefit to the mother should be considered along with the potential risk to the breastfed infant.

The Sponsor committed to allow Canadian women the option of enrolling in the Pregnancy Registry Program that is to be launched in the United States in Q2 2023.

A Risk Management Plan (RMP) for Qulipta was submitted by the Sponsor to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP was designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. As an additional pharmacovigilance activity, the prospective Pregnancy Exposure Registry and Pregnancy Outcomes Study will be included in the Canadian RMP.

A Notice of Non-Compliance (NON) was issued by Health Canada due to a number of unresolved safety concerns identified during the review. In response to the NON issuance, the sponsor submitted updated clinical data which addressed the safety concerns identified.

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

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

Overall, the benefit-harm-uncertainty profile is favourable for Qulipta tablets for the recommended indication. A Notice of Compliance (NOC) was issued.

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