Summary Basis of Decision for Ubrelvy

 

Clinical Pharmacology

Ubrogepant, the medicinal ingredient in Ubrelvy, is a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist. Calcitonin gene-related peptide is a potent vasodilatory neuropeptide that is believed to play a key role in the pathophysiology of migraine.

The pharmacokinetic profile of ubrogepant following oral administration was determined in several Phase I clinical studies. Ubrogepant exhibits dose-proportional pharmacokinetic properties within the dose range of 1 to 400 mg. It is rapidly absorbed, and the peak plasma concentrations are reached at approximately 1.5 hours post dose.

Food intake affects the absorption of ubrogepant. When ubrogepant was administered with a high-fat meal, the time to maximum plasma concentration was delayed by 2 hours and the maximum plasma concentration was reduced by 20%, with no change in the area under the concentration-time curve. It is unknown if the delayed exposure associated with consumption of a high-fat meal affects the efficacy of Ubrelvy. In the pivotal Phase III studies (described in the Clinical Efficacy section), ubrogepant was administered without regard to food.

In a double-blind, randomized, placebo- and positive-controlled, 4-period crossover electrocardiogram assessment study in 72 healthy subjects, ubrogepant at single doses of 100 mg (a therapeutic dose) and 400 mg (a supratherapeutic dose) was not observed to have any pharmacodynamic effect on the QT interval corrected by Fridericia (QTcF). Ubrogepant was associated with a small, dose-dependent reduction in heart rate. None of the study subjects were observed to have heart rate values lower than 40 beats per minute.

Ubrogepant is eliminated mainly through hepatic metabolism, primarily involving the cytochrome P450 (CYP) enzyme, CYP3A4. The two most prevalent metabolites, M15 and M20, are not pharmacologically active. Ubrogepant has an elimination half-life of 5 to 7 hours, with no appreciable accumulation following repeat daily dosing.

A dedicated hepatic impairment study showed that mild, moderate, and severe hepatic impairment increased ubrogepant exposure by 7%, 50%, and 115%, respectively. As the renal route of elimination accounts for less than 10% of ubrogepant clearance, a dedicated clinical study to evaluate the effect of renal impairment on the pharmacokinetic profile of ubrogepant was not conducted. A population pharmacokinetic evaluation concluded that renal function did not significantly influence the pharmacokinetics of ubrogepant. However, the population pharmacokinetic study did not include participants with severe renal impairment or end-stage renal disease. Based on the aforementioned, the Ubrelvy Product Monograph includes recommendations for dose adjustments in patients with severe hepatic impairment and in those with severe renal impairment. Ubrelvy is not recommended for patients with end-stage renal disease. In addition, dose adjustments are recommended for geriatric patients, given the limited data regarding the pharmacokinetic properties of ubrogepant in this population.

In drug-drug interaction studies, moderate and strong CYP3A4 inhibitors increased ubrogepant exposure by 3.5 and 9.7 times, respectively. There were no data involving mild CYP3A4 inhibitors. Strong CYP3A4 inducers were found to significantly reduce systemic ubrogepant exposure (by 80%). Although ubrogepant is a substrate for breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp), there were no dedicated drug-drug interaction studies involving concomitant use of ubrogepant with inhibitors of these transporters. The sponsor also did not provide any clinical drug-drug interaction studies involving concomitant administration of ubrogepant with other small-molecule calcitonin CGRP receptor antagonists, such as atogepant, which may have additive pharmacodynamic effects yet to be explored. No clinically significant pharmacokinetic interactions were observed when ubrogepant was co-administered with acetaminophen, naproxen, sumatriptan, proton pump inhibitors or the monoclonal antibodies, erenumab (directed against CGRP receptor) or galcanezumab (directed against CGRP). Oral contraceptives did not affect the pharmacokinetics of ubrogepant; however, ubrogepant did reduce peak estradiol levels by 26%. Established or potential drug-drug interactions, along with appropriate precautionary measures, are listed in the approved Ubrelvy Product Monograph. Importantly, concomitant use of Ubrelvy and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is contraindicated.

An integrated exposure-response modelling analysis of two Phase IIb studies of ubrogepant predicted that a dose of 25 mg or higher was likely to achieve significantly better efficacy than placebo and represented the basis for dose selection in the pivotal Phase III studies (described in the Clinical Efficacy section).

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

Clinical Efficacy

The efficacy of Ubrelvy for the acute treatment of migraine with or without aura was supported by data derived from two pivotal Phase III, randomized, double-blind, placebo-controlled, single-attack studies with identical designs (Study 1 [ACHIEVE I] and Study 2 [ACHIEVE II]). The studies enrolled adults 18 to 75 years of age who had a history of migraine with or without aura for at least one year (consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd edition [beta version]), and who had 2 to 8 migraine attacks of moderate to severe headache in each of the 3 months before screening. Patients who had clinically significant hematologic, endocrine, cardiovascular, cerebrovascular, pulmonary, renal, hepatic, gastrointestinal, or neurologic disease were excluded from the study.

In Study 1, patients were randomized to receive Ubrelvy 50 mg or Ubrelvy 100 mg or placebo, whereas in Study 2, patients were randomized to receive Ubrelvy 25 mg or Ubrelvy 50 mg or placebo. Patients were instructed to treat a migraine with moderate to severe headache intensity within the first 4 hours of pain onset. An optional second dose of study medication (Ubrelvy or placebo) or the patient’s usual acute treatment for migraine was allowed 2 to 48 hours after the initial dose if the patient had a non-responding or recurrent migraine. Both studies evaluated the effect of Ubrelvy on a single migraine attack.

In both studies, the co-primary endpoints were freedom from pain at 2 hours after the initial dose, defined as a reduction in the severity of headache from moderate or severe pain before the initial dose to no pain at 2 hours after the dose; and absence of the most bothersome migraine-associated symptom (photophobia, phonophobia, or nausea) at 2 hours after the initial dose.

In Study 1, the groups treated with Ubrelvy (50 mg or 100 mg) had statistically significantly higher proportions of patients who achieved the co-primary endpoints compared to the placebo group. Freedom from pain at 2 hours after the initial dose was experienced by 19.2% of patients treated with Ubrelvy 50 mg and 21.2% of patients treated with Ubrelvy 100 mg versus 11.8% of the placebo-treated patients. Absence of the most bothersome migraine-associated symptom was reported by 38.6% of patients treated with Ubrelvy 50 mg and 37.7% of patients treated with Ubrelvy 100 mg versus 27.8% of patients who received placebo.

Similarly, in Study 2, in the group treated with Ubrelvy 50 mg, there were statistically significantly more patients who experienced freedom from pain at 2 hours after the initial dose (21.8%) compared to the placebo-treated group (14.3%), and more patients who experienced absence of the most bothersome migraine-associated symptom at 2 hours after the dose (38.9%) versus the placebo-treated group (27.4%). The Ubrelvy dose of 25 mg demonstrated superiority over placebo for the co-primary endpoint of freedom from pain at 2 hours after the initial dose, but it failed to achieve statistical significance for the other co-primary endpoint.

The response rates were similar for the 50 mg and 100 mg doses of Ubrelvy. While the data support the efficacy of an optional second dose, issues with study design leave some uncertainty regarding the added benefit of the optional second dose.

Overall, the efficacy of Ubrelvy was modest, as freedom from pain at 2 hours after the initial dose was achieved by 19% to 21% of patients and the treatment differences between Ubrelvy and placebo ranged from 7% to 9% for freedom from pain at 2 hours after the dose, and from 10% to 12% for absence of the most bothersome migraine-associated symptom at 2 hours after the dose. Maximum treatment differences for Ubrelvy versus placebo were observed between 3 and 8 hours after the initial dose. There were no differences in response rates across groups stratified by previous response to triptans (as triptan responders, triptan insufficient responders, and triptan naïve), suggesting that the modest response rate of 19% to 21% applies equally to triptan insufficient responders.

Indication

The New Drug Submission for Ubrelvy was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Ubrelvy (ubrogepant) is indicated for the acute treatment of migraine with or without aura in adults.

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

Clinical Safety

The safety profile of Ubrelvy was evaluated in 3,664 subjects who received at least one dose of Ubrelvy in Phase I, II, and III clinical studies.

In the two pivotal Phase III clinical studies (described in the Clinical Efficacy section), there were 1,439 patients who received at least one dose of Ubrelvy 50 mg (954 patients) or Ubrelvy 100 mg (485 patients). Treatment-emergent adverse events were typically mild or moderate and of low frequency. The most commonly reported (at a frequency of at least 2% and greater than placebo) adverse reactions in the Ubrelvy 50 mg, Ubrelvy 100 mg, and placebo groups were nausea (2%, 4%, and 2% of patients, respectively), somnolence (1%, 2%, and 1%), and dry mouth (<1%, 2% and 1%). There were no serious adverse events or deaths related to study treatment.

In a long-term, open-label extension study, involving treatment of up to 8 migraines per month for up to a year, the safety profile of Ubrelvy was consistent with that observed in the pivotal studies.

Across the pivotal trials and the open-label extension study, very few patients discontinued treatment due to an adverse event. The most commonly reported adverse event that led to treatment discontinuation was nausea.

Given that early studies of first-generation small-molecule CGRP receptor antagonists were halted due to reports of hepatotoxicity, all clinical studies of Ubrelvy included extensive hepatic function assessments. In the pivotal Phase III studies, there were no indications of hepatic injury. Similarly, no evidence of hepatotoxicity was found in a study that evaluated the safety of Ubrelvy administered daily to healthy volunteers at a supratherapeutic dose (150 mg) for 28 consecutive days, and in a dedicated hepatic safety study of Ubrelvy administered intermittently to healthy volunteers at a high frequency (2 days on, 2 days off) for 8 weeks.

Cardiovascular safety was also of special interest, given the role of CGRP as a potent vasodilator and the potential for adverse effects of anti-CGRP treatments. In the controlled clinical studies, there were no clinically significant changes from baseline in mean heart rate, PR interval, QRS, or QT interval corrected for heart rate (QTc), as compared to placebo. The pivotal Phase III studies included a subgroup analysis of patients stratified by the risk (low, moderate, and high) of developing cardiovascular disease within 10 years. There was no evidence of increased incidence of cardiovascular treatment-emergent adverse events with Ubrelvy relative to placebo and no clinically relevant differences in the adverse event profile were observed across the risk categories. However, the studies included low percentages of patients with high risk (3%) and patients with moderate risk (8%) of developing cardiovascular disease in 10 years. Moreover, based on the enrollment criteria, patients with clinically significant cardiovascular and cerebrovascular diseases were excluded from the studies. Therefore, firm conclusions regarding the safety of Ubrelvy in patients with pre-existing cardiovascular conditions cannot be drawn, and relevant pharmacovigilance activities have been recommended.

Additionally, uncertainties remain with respect to the safety of Ubrelvy use in geriatric patients, pregnant or breastfeeding women, patients with severe renal impairment or end-stage renal disease, and obese patients. The safety of concomitant use of Ubrelvy with other gepants also remains unclear.

In addition to the adverse reactions observed during clinical studies, hypersensitivity reactions (e.g., rash, urticaria, facial edema, and dyspnea) were reported during the post-marketing use of Ubrelvy.

The safety issues have been thoroughly addressed through the information provided in the Ubrelvy Product Monograph and relevant pharmacovigilance activities. A pregnancy registry is being established to collect information about the effect of Ubrelvy exposure during pregnancy and the sponsor has committed to providing an update to the Ubrelvy Product Monograph as soon as the registry information becomes available.

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