Summary Basis of Decision for Nurtec ODT

As outlined in the What steps led to the approval of Nurtec ODT? section, the clinical review of the New Drug Submission for Nurtec ODT (orally disintegrating tablets) was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Rimegepant, the medicinal ingredient in Nurtec ODT (orally disintegrating tablets), is a calcitonin gene-related peptide (CGRP) receptor antagonist that selectively binds with high affinity to the human CGRP receptor thereby antagonizing CGRP receptor function.

The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. No clinically significant pharmacokinetic differences were observed between elderly and younger subjects.

Population pharmacokinetic (PK) modelling data indicated that clearance was generally insensitive to all levels of renal insufficiency. Subjects with end-stage renal disease and those undergoing dialysis were not studied. The Product Monograph for Nurtec ODT states that no dosage adjustment is recommended in patients with mild, moderate, or severe renal impairment, and that use in patients with end-stage renal disease and those on dialysis should be avoided.

Subjects with severe hepatic impairment had a maximum concentration (C_max) of 89% and an area under the concentration-time curve (AUC) 202% of that in healthy controls. Population PK modelling data was generally consistent with these findings. Therefore, the Product Monograph for Nurtec ODT states that its use in patients with severe hepatic impairment should be avoided.

Limited data are available on the developmental risk associated with the use of rimegepant in pregnant women. Therefore, the effects of rimegepant on maternal, fetal, and neonatal outcomes are uncertain. As a result, the Product Monograph for Nurtec ODT states that it should not be used in pregnant women unless the expected benefit to the mother outweighs the potential risk to the fetus.

Infant exposure to rimegepant through breast milk was found to be relatively low in a dedicated study. Therefore, a statement expressing caution when rimegepant is used in individuals who are breastfeeding was also added to the Product Monograph.

Comparative Bioavailability

The sponsor provided data from four comparative bioavailability studies, which investigated the relative bioavailability of rimegepant from the Nurtec ODT 75 mg and rimegepant tablets 75 mg used in Phase III clinical studies as well as the effects of food and the mode of administration (under versus [vs.] on top of the tongue) on the absorption of rimegepant from Nurtec ODT.

The results of studies BHV3000-110 and -113 for Nurtec ODT administered under or on top of the tongue met the recommended standards for bioequivalence under fasting conditions with the rimegepant 75 mg tablets as the extent of total exposure (AUC_T) and the rate of drug absorption (C_max) were comparable, successfully bridging the two formulations. The bioequivalence standards were also met following administration of Nurtec ODT under or on top of the tongue as the extent and rate of rimegepant absorption were similar for the two modes of administration.

Data was also evaluated from food effect studies on Nurtec ODT (BHV3000-112, -113, and -120). Following administration of Nurtec ODT under fed conditions with a high-fat or low-fat meal, the time to peak drug concentration (T_max) was delayed by approximately 1 to 1.5 hours. Consumption of a high-fat meal 30 minutes before administration of Nurtec ODT under or on top of the tongue decreased rimegepant AUC_T by 32% and 38%, and C_max by 42% and 53%, respectively. Similarly, consumption of a low-fat meal 30 minutes before administration of Nurtec ODT under the tongue decreased rimegepant AUC_T and C_max by approximately 28% and 36%, respectively, compared with administration under fasting conditions.

The potential effect of decreased rimegepant exposure after administration of Nurtec ODT with food is unknown as the proposed product was administered without regard for food in the clinical safety and efficacy studies. Nurtec ODT is proposed to be taken with or without food.

Based on the evidence from Studies BHV3000-110 and -113, the extent and rate of rimegepant absorption between the proposed Nurtec ODT formulation administered under or on top of the tongue and the rimegepant tablet 75 mg used in Phase III clinical studies are comparable.

Pharmacokinetics

Rimegepant is rapidly absorbed following oral administration of Nurtec ODT, with peak plasma concentrations observed being 1.5 to 2 hours post dose. Rimegepant displays greater than dose-proportional pharmacokinetics within the dose range of 10 to 150 mg. Based on population pharmacokinetics analyses, the elimination half-life of rimegepant in normal healthy subjects is approximately 11 hours. Following once-daily dosing, steady state is achieved by Day 2, with no meaningful accumulation. The drug is 96% bound to plasma protein. The mean apparent central volume of distribution of rimegepant (V/F) after single‑dose oral administration is approximately 120 L. Rimegepant is metabolized primarily by cytochrome P450 (CYP) 3A4 and to a lesser degree by CYP2C9. Rimegepant is excreted primarily via the fecal route, while the renal route plays a minor role in elimination. The most prominent circulating component in humans is unchanged rimegepant.

Drug-Drug Interactions

The following clinically relevant drug-drug interaction findings are described in the Nurtec ODT Product Monograph:

• Co-administration with strong CYP3A4 inhibitors should be avoided, and caution should be exercised if rimegepant is co-administered with moderate CYP3A4 inhibitors.

• Co-administration with strong or moderate CYP3A4 inducers is not recommended.

• A second dose of Nurtec ODT should be avoided within 48 hours of concomitant administration with strong inhibitors of P-glycoprotein.

• Concomitant administration of rimegepant and fluconazole increased the area under the concentration-time curve (AUC) of rimegepant by 1.8-fold but did not significantly change C_max.

• Rimegepant did not significantly change metformin pharmacokinetics or glucose utilization.

• Rimegepant did not significantly change pharmacokinetics of oral contraceptives.

• Co-administration of rimegepant and sumatriptan did not significantly alter sumatriptan pharmacokinetics or rimegepant pharmacokinetics.

Overall, the clinical pharmacology data support the use of Nurtec ODT for the recommended indication. For further details, please refer to the Nurtec ODT Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Nurtec ODT (orally disintegrating tablets) for the acute treatment of migraine (with or without aura) was evaluated in three pivotal randomized, double-blind, placebo-controlled, multicentre, single-dose, Phase III migraine attack studies (BHV3000-301, -302, -303, herein referred to as studies 301, 302 and 303). Participants in these studies were adults with a history of migraine (with or without aura), as defined by the International Classification of Headache Disorders (ICHD-3) beta diagnostic criteria, and who experienced 2 to 8 migraine attacks per month with moderate to severe headache pain.

Across the three pivotal studies, approximately 76.0% of participants were White, 19.6% were Black, and 4.4% were other, including Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races. The mean age for Study 301, 302, and 303 was 41.6, 40.6, and 40.2 years, respectively. In Study 301, 302, and 303, 14.5%, 11.3%, and 15.1% of participants were male and 85.5%, 88.7%, and 84.9% were female, respectively.

A total of 3,551 participants were randomized 1:1 to receive placebo, or 75 mg Nurtec ODT or a bioequivalent rimegepant tablet formulation. Participants in Study 303 were treated with 75 mg rimegepant administered using the Nurtec ODT formulation, while those in Study 301 and Study 302 were treated with a bioequivalent 75 mg rimegepant immediate release tablet. The ODT formulation was that proposed for market with the New Drug Submission. A dedicated study established relative bioequivalence of the two formulations used in the clinical studies. No other dose levels were tested. Participants were instructed to treat a migraine of moderate to severe headache pain intensity at the time of onset. Rescue medication (i.e., non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and/or an antiemetic) was allowed 2 hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment.

Across the three pivotal studies, approximately 15.4% of participants were taking preventive medications for migraine at baseline. The most commonly used preventive medications were topiramate, amitriptyline, propranolol, and nortriptyline, and none of the participants in the three studies were on concomitant preventive medication that act on the calcitonin gene-related peptide pathway (CGRP receptor antagonists).

The co-primary endpoints for all three studies were the percentage of patients reporting no pain at 2 hours post-dose and the absence of their most bothersome migraine symptom 2 hours post dose. Patients were instructed to select their most bothersome migraine symptom other than headache pain (i.e., photophobia, phonophobia, or nausea) at the onset of the migraine and before taking study medication. Across the three pivotal studies, of those who selected a most bothersome migraine symptom, photophobia was selected by 55.0%, nausea by 29.9%, and phonophobia by 15.1%.

The recommended dose of 75 mg rimegepant (ODT or tablet) was significantly more effective than placebo for the proportion of patients achieving the co-primary endpoints of pain freedom at 2 hours post dose (19.2%, 19.6%, and 21.2% with 75 mg rimegepant versus [vs.] 14.2%, 12.0%, and 10.9% with placebo in Study 301, 302, and 303, respectively). Similarly, the 75 mg rimegepant treatment was significantly more effective than placebo for the absence of most bothersome symptom (patient-specified choice of photophobia, phonophobia, or nausea) associated with migraine at 2 hours post dose (36.6%, 37.6%, and 35.1% with rimegepant vs. 27.7%, 25.2, and 26.8% with placebo in Study 301, 302, and 303 respectively).

Secondary endpoints were generally supportive, including the key secondary endpoint of pain relief at 2 hours post dose.

Indication

The New Drug Submission for Nurtec ODT was filed by the sponsor with the following proposed indication:

Nurtec ODT (rimegepant orally disintegrating tablets) is indicated for:

• Acute treatment of migraine with or without aura in adults.

• Preventive treatment (prophylaxis) of episodic migraine in adults.

Health Canada revised the proposed indication as issues were identified with the available data for the prophylaxis indication that prevented its approvability as part of the current submission. Accordingly, Health Canada approved the following indication:

Nurtec ODT (rimegepant orally disintegrating tablets) is indicated for:

• Acute treatment of migraine with or without aura in adults.

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

Clinical Safety

The clinical safety of Nurtec ODT was assessed in the three pivotal Phase III studies described above. Across these studies, 3,551 unique patients received single doses of either 75 mg rimegepant (number of patients [n] = 1,771) or placebo (n = 1,782). Of the patients treated with rimegepant, 682 received Nurtec ODT and 1,089 received a 75 mg rimegepant tablet.

The pooled safety data from the three pivotal studies indicated that 10.8% of patients who were treated with rimegepant and 8.6% who were treated with placebo experienced at least one treatment-emergent adverse event (TEAE). No specific TEAE occurred in 2% or more of patients in the rimegepant or placebo group. Nausea was the only on-treatment adverse event (AE) occurring in at least 1% of patients in both the overall rimegepant and placebo groups. In the rimegepant group, 6.4% of patients had at least one on-treatment AE related to the study drug vs. 4.8% in placebo group. On-treatment hepatic-related AEs, AEs related to potential drug abuse, cardiovascular AEs, and suicidality AEs all occurred with low-frequency (less than 1%) and at similar rates in the rimegepant and placebo groups. Across the three studies, there was one serious adverse event (SAE) of back pain in the rimegepant group and two SAEs (chest pain and urinary tract infection) in placebo group.

The long-term safety of rimegepant was assessed in Study BHV3000-201 (201), a multicentre, open-label Phase II/III study with the primary objective to evaluate the safety and tolerability of 75 mg rimegepant when taken up to once daily in patients with migraine. Patients were assigned to one of three treatment groups based on their historical rate of moderate to severe migraines per month (categorized as either 2-8 or 9-14). The dosing regimens and length of time on study varied between groups. The groups were designated as PRN (2‑8); PRN (9-14); and Scheduled EOD + PRN, where PRN indicated that doses were taken as needed, and EOD indicated scheduled dosing where a dose was taken every other day. The numbers in parentheses indicated the self-reported historical rate of migraines per month for the subjects preceding their enrolment in the group.

During the study, 1,800 patients received at least one dose of 75 mg rimegepant in the tablet formulation. Of these patients, 918 (51.0%) had participated in a previous rimegepant study. The average rimegepant exposure (tablets per 4 weeks) was 5.6 tablets in the PRN (2-8) group and 8.5 tablets in PRN (9-14) group. The mean number of weeks in the long-term treatment phase was 42.1 weeks for the PRN (2-8) group and 38.0 weeks for the PRN (9-14) group.

Common on-treatment AEs that occurred in at least 2% of rimegepant-treated patients included upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, bronchitis, nausea, back pain, arthralgia, and dizziness. The most common treatment-related AEs were dizziness, nausea, constipation, and somnolence, and occurred in less than 2% of treated patients. The TEAE profile of rimegepant long-term use (as determined by the long-term extension study) was generally similar to that associated with acute treatment. Rimegepant had no apparent association with medication overuse headache. One SAE that was considered possibly related to the study drug (colitis ischemic) was reported. There were no deaths related to rimegepant.

A supratherapeutic single 300 mg rimegepant dose was evaluated in a dedicated thorough QT study (Study BHV3000-109). In this double-blind, randomized, placebo- and positive-controlled, crossover electrocardiogram assessment study, single 75 mg and 300 mg doses of rimegepant did not show any noteworthy pharmacodynamic effect on the QTc interval, the QRS duration, the PR interval or heart rate in healthy subjects (n = 38).

Overall, rimegepant was generally safe and well-tolerated in both healthy adults and those with migraine. Appropriate warnings and precautions are in place in the approved Nurtec ODT Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box has been included in the Product Monograph for Nurtec ODT to highlight the risk of hypersensitivity reactions, including dyspnea and rash, that have occurred in less than 1% of patients treated with Nurtec ODT in clinical studies. Hypersensitivity reactions, including serious hypersensitivity, can occur days after administration.

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

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Non-clinical pharmacology studies demonstrated that rimegepant is a selective inhibitor of human CGRP receptors. An in vivo study in monkeys demonstrated that rimegepant produced a dose-dependent inhibition of CGRP induced increases in facial blood flow. Rimegepant produced no neurobehavioral, cardiovascular or respiratory effects.

Non-clinical pharmacokinetic studies determined the absorption, tissue distribution, metabolism, and excretion of rimegepant. The tissue distribution study demonstrated that there was little uptake into the brain. Potential drug-drug interactions were determined by studying the interaction of rimegepant with cytochrome P450 and uridine diphosphate (UDP)‑glucuronosyltransferase enzymes and transporters.

Non-clinical toxicology studies demonstrated that the main target organ was the liver. The findings in the liver were considered to be due to a physiological adaptive response to the metabolism of rimegepant rather than due to target organ toxicity. Rimegepant was not mutagenic or carcinogenic and no effects on fertility, embryo-fetal development, postnatal development, or juvenile toxicity, were evident at relevant clinical doses.

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

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

As outlined in the What steps led to the approval of Nurtec ODT? section, the review of the quality component of the New Drug Submission for Nurtec ODT 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 Nurtec ODT 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 48 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.

One of the excipients in the drug product, gelatin, is of animal origin, which originates from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).