Summary Basis of Decision for Qulipta

As described above, the clinical review of the New Drug Submission for Qulipta was conducted as per Method 1 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Atogepant, the medicinal ingredient in Qulipta, is a selective calcitonin gene‑related peptide (CGRP) receptor antagonist that blocks the binding of the CGRP to its receptor. Calcitonin gene‑related peptide is a neuropeptide that may play a role in migraine pathophysiology.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Qulipta have been well characterized in patients and healthy volunteers. Atogepant is rapidly absorbed following oral administration. Plasma concentrations greater than 14 nM were observed within 0.5 hours, and the median time to maximum plasma concentration (T_max) ranged from 1.0 to 2.0 hours. Atogepant displayed dose‑proportional pharmacokinetics through 300 mg single dose, with little to no accumulation upon once‑daily dosing. Atogepant is metabolized primarily by cytochrome P450 (CYP) 3A4. The most prevalent circulating components in human plasma were atogepant and a metabolite, M23, which is not expected to be pharmacologically active. The elimination half‑life of atogepant is approximately 11 hours. It is excreted predominantly via the biliary/fecal route (approximately 90%), while the renal route is a minor route of elimination (approximately 10%).

In patients with pre‑existing mild, moderate or severe hepatic impairment (Child Pugh classes A, B, and C, respectively), atogepant exposure increased by 24%, 15%, and 38%, respectively. No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The use of Qulipta in patients with severe hepatic impairment should be avoided.

The effects of renal impairment were evaluated through a population pharmacokinetic analysis based on pooled data from the clinical studies. Atogepant pharmacokinetics was similar between patients with normal renal function (creatinine clearance [CLcr] >90 mL/min) and those with mild (CLcr 60‑89 mL/min) or moderate (CLcr 30‑59 mL/min) renal impairment. Atogepant pharmacokinetics has not been studied in patients with severe renal impairment (CLcr 15‑29 mL/min) or end stage renal disease (ESRD; CLcr <15 mL/min). A physiologically‑based pharmacokinetic model predicted that atogepant exposures increase by approximately 2.3‑fold in patients with severe renal impairment. In patients with ESRD, atogepant exposure is not expected to increase more than 6-fold. Therefore, the maximum recommended daily dose of atogepant in patients with severe renal impairment and ESRD is 10 mg. For patients with ESRD undergoing intermittent dialysis, Qulipta should be taken after dialysis.

Overall, the clinical pharmacology data support the use of Qulipta for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Qulipta was evaluated in two pivotal studies, 3101‑301‑002 and CGP‑MD‑01, conducted in adult patients with an average of 8 migraine days per month (range: 4 to 16 days). Patients in Study CGP-MD-01 (Study 1) had a mean age of 42 years (range: 18 to 73 years), 89% were female, and 11% were male. Patients in Study 3101-301-002 (Study 2) had a mean age of 40 years (range: 18 to 74 years), 86% were female, and 14% were male.

In both studies, patients were randomized to one of four groups to receive either placebo or Qulipta at 10 mg, 30 mg, or 60 mg once daily for 12 weeks. The primary efficacy endpoint in both studies was the change from baseline in the number of monthly migraine days across the 12‑week treatment period. Secondary endpoints in both studies included the change from baseline in monthly headache days across the 12‑week treatment period, the proportion of patients with at least a 50% reduction in monthly migraine days across the 12‑week treatment period (i.e., ≥50% responder rates), and the change from baseline in monthly acute medication use days across the 12‑week treatment period. A total of 316, 415, and 422 participants received at least one dose of atogepant in the 10 mg, 30 mg, and 60 mg treatment groups, respectively, while 408 patients received placebo.

In both studies, monthly migraine days and monthly headache days decreased across the 12-week treatment period by an average of approximately 1 to 1.5 days compared to placebo. These improvements are considered clinically meaningful. Decreases in monthly migraine and headache days were dose-dependent in Study 3101-301-002 but not in Study CGP-MD-01. In study 3101-301-002, secondary efficacy endpoints such as reduction of mean monthly headache days, ≥50% responder rates and reduction in monthly acute medication use days across the 12-week treatment period were all statistically significant across the 12-week treatment period compared to placebo. In study CGP-MD-01, these endpoints were numerically superior to placebo, but only reduction in mean monthly headache days reached statistical significance. Approximately 5% to 8% of patients who received Qulipta and 1% of patients in the placebo group had a 100% reduction in the 3‑month average of monthly migraine days.

Indication

Health Canada approved the following indication:

Qulipta (atogepant) is indicated for the prevention of episodic migraine (<15 migraine days per month) in adults.

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

Clinical Safety

In controlled studies, including the two pivotal studies described in the Clinical Efficacy section, the most common treatment‑emergent adverse events (TEAEs) reported in patients in the Qulipta treatment groups were nausea (7%; 3% in placebo groups), constipation (6%; 1% in placebo groups), and somnolence (3%; 1% in placebo groups). In cases of nausea, the frequency of adverse events was found to be dose‑dependent. Across the two studies, the completion rates were approximately 86% for Qulipta‑treated patients and 90% for patients in the placebo group.

Approximately 3.5% of Qulipta-treated patients and 2.7% of patients in the placebo groups discontinued due to adverse events. The most commonly reported events leading to discontinuation included nausea (6 participants or 0.5%; 0% in placebo groups) and constipation (5 participants or 0.4%; 0% in placebo groups). There were no deaths, life‑threatening adverse events, or safety signals in the pivotal studies.

The long‑term safety of Qulipta was assessed in a 52‑week open‑label study, in which 543 patients were treated with Qulipta 60 mg once daily. The most common TEAEs reported in this study included constipation (39 patients or 7.2%), nausea (34 patients or 6.3%), urinary tract infection (28 patients or 5.2%), and decreased weight (14 patients or 2.6%). This study had a much higher rate of discontinuations compared to the pivotal studies (32% vs 14%). In total, 31 patients (5.7%) discontinued due to adverse events including constipation (1 patient or 0.2%), nausea (3 patients or 0.6%), fatigue and dizziness (2 patients each or 0.4%), and decreased weight (1 patient or 0.2%). Overall, the safety profile of Qulipta in the long‑term safety study was similar to the safety profile observed in the pivotal studies.

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

As described above, the review of the non-clinical component of the New Drug Submission for Qulipta was conducted using various methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The repeated administration of atogepant was well tolerated in general toxicology studies. Oral administration at the highest doses was associated with non‑adverse epithelial vacuolation in the jejunum and duodenum, which was not accompanied by histopathological changes and/or functional impairment of the digestive tract. Reversibility of this finding was observed specifically in the 6‑month study in rats, which included a 1‑month recovery period. The no‑observed-adverse‑effect (NOAEL) in this study was 100 mg/kg/day, which represents an exposure multiple of approximately 33‑fold relative to the maximum recommended human dose (MRHD). In a 9‑month study in monkeys, the NOAEL was 300 mg/kg/day, representing an exposure multiple of 12‑fold relative to the MRHD.

No signs of genotoxicity were detected for atogepant in in vitro (Ames, chromosomal aberration) and in vivo (rat bone marrow micronucleus) assays. No evidence of carcinogenicity was detected in two‑year studies conducted in mice and rats. No signs of phototoxicity were identified in the skin or eyes.

No adverse effects were observed on fertility or reproductive performance following the oral administration of atogepant to male and female rats (mated with drug‑naïve females and males, respectively), at doses corresponding to approximately 20 times the MRHD.

Oral administration of atogepant (0, 5, 15, 125, or 750 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreased fetal body weight. Additionally, an increased incidence of fetal skeletal variations was observed at 125 mg/kg/day and 750 mg/kg/day. Neither of these effects were associated with maternal toxicity. At the NOAEL for embryo‑fetal toxicity in rats (15 mg/kg/day), the exposure of atogepant as measured by the area under the concentration-time curve (AUC) was approximately 5 times higher than the exposure in humans at the MRHD of 60 mg/day.

Slight maternal toxicity was noted at the highest dose of atogepant administered to pregnant rabbits (130 mg/kg/day), with fetal visceral and skeletal variations. The NOAEL was 90 mg/kg/day, which is approximately 3 times the MRHD. In rats, no adverse effects were observed on development at doses up to 125 mg/kg/day (approximately 5 times the exposure in humans at the MRHD as measured by the AUC). Maternal transfer to the pups via lactation was demonstrated by a milk to plasma ratio of 2‑ to 3‑fold.

Breastfeeding mothers should be informed of the potential transfer of the drug via the milk and the risk to their infants, as well as risk during pregnancy. This information should be considered along with the therapeutic benefits of the drug product. As part of their pharmacovigilance activities, the sponsor is expected to establish and maintain a Pregnancy Registry to monitor any post-market use of the drug by pregnant women.

No toxicologically meaningful changes were observed on cardiovascular, respiratory, or nervous system function in safety pharmacology studies. There was no evidence for abuse in self-administration and withdrawal studies in rats.

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

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

A Notice of Non‑compliance (NON) was issued for the New Drug Submission (NDS) for Qulipta due to concerns identified during the quality review, related to the manufacturing process. In response to the NON, the sponsor submitted data that resolved the identified concerns. A Notice of Compliance (NOC) was subsequently issued for the NDS for Qulipta.

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. 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 30 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

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 [ICH] limits and/or qualified from toxicological studies).

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 Qulipta is of human or animal origin.