New Drug Monograph

By: Madeline McMillan, PharmD Candidate 2022

Generic Name: atogepant

Brand Name: QuliptaTM

Classification: Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist

FDA Approval: September 28, 2021

Indication1: Approved for the prevention of episodic migraine in adults.

Contraindications: None.

Pharmacology1,2: Atogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist. CGRP helps modulate pain transmission in the brainstem. During an acute migraine attack, CGRP levels are usually increased.

Pharmacokinetics1,2

Absorption Atogepant is orally absorbed and reaches peak plasma concentrations within 1-2 hours. The absorption of atogepant is not significantly affected by food; therefore, it may be administered without regard to meals.

Distribution Atogepant is approximately 95% protein bound. The volume of distribution after oral administration was approximately 292 L.

Metabolism Atogepant is primarily metabolized by CYP3A4.

Elimination Atogepant was excreted as 42% unchanged drug in the feces and 5% unchanged drug in the urine. The approximately elimination half-life of atogepant is 11 hours.

Drug Interactions1

CYP3A4 inhibitors Concentrations of atogepant may be increased by CYP3A4 inhibitors. If atogepant must be administered in combination with a strong CYP3A4 inhibitor, the daily dose should be reduced to 10 mg daily. For coadministration of atogepant with moderate or weak CYP3A4 inhibitors, dose reduction may not be necessary.

CYP3A4 inducers Concentrations of atogepant may be reduced by CYP3A4 inducers. If administration of atogepant along with a strong CYP3A4 inhibitor is necessary, the recommended dose of atogepant is either 30 mg or 60 mg daily.

OATP inhibitors Concentrations of atogepant may be increased by OATP inhibitors. The recommended dose of atogepant is 10 mg or 30 mg daily when being used in combination with an OATP inhibitor.

Clinical Efficacy3,4

Goadsby and colleagues conducted a phase 2b/3 trial to assess the safety, tolerability, and efficacy of atogepant for the prevention of episodic migraines. Participants

from 78 different practice sites were included in this randomized, double-blind, placebo-controlled, parallel-group trial. Participants were eligible if they were between the ages of 18 and 75 years old, had a history of migraine with or without aura diagnosed for at least a year prior, and onset before age 50. Participants also needed to average 4 to 14 monthly migraine days in the 3 months before the trial. Participants were excluded if they had more than 15 headache days per monthly, inadequate response to at least 3 other migraine prevention medications, used opioids or barbiturates more than 2 days per month, triptans or ergots more 10 days per month, or other analgesics more than 15 days per month. Patients with significant renal or hepatic dysfunction were also excluded from the trial. All participants were required to use an approved form of contraception, and female patients of childbearing potential were required to have a negative urine pregnancy test prior to starting treatment.

There were 825 patients were randomly assigned 2:1:2:2:1:1 to receive placebo, atogepant 10 mg daily, atogepant 30 mg daily, atogepant 60 mg daily, atogepant 30 mg twice daily, or atogepant 60 mg twice daily. Baseline characteristics were similar between study groups, including monthly migraine days at baseline. The treatment was administered over 12 weeks, during which patients attended 8 clinic visits and used an electronic diary to log information about headache frequency, duration, symptoms, characteristics, and any acute medication use. the change from baseline in mean monthly migraine days across the 12-week treatment period. Secondary outcomes included change from baseline in mean monthly headache days, proportion of patients who saw at least a 50% reduction in monthly migraine days, and change from baseline in acute medication use days per month. After 12 weeks of treatment, patients treated with atogepant had significant fewer monthly migraine days. The average number of monthly migraine days were reduced by 2.9 days in the placebo group, 4.0 days in the atogepant 10 mg daily group, 3.8 days in the 30 mg daily group, 3.6 days in the 60 mg daily group, 4.2 in the 30 mg twice daily group, and 4.1 days in the 60 mg twice daily group (p < 0.05). Patients who were in the atogepant 30 mg twice daily and atogepant 60 mg twice daily groups also saw significant reduction in the number of days requiring acute medication use compared to the placebo group (-1.4 days and -1.2 days, respectively; p < 0.05). The 30 mg twice daily and the 60 mg twice daily groups also saw significantly more patients have at least a 50% reduction in average monthly migraine days compared to placebo (58% and 62% of patients, respectively; p < 0.05). The most common adverse effects observed in this trial were nausea, upper respiratory tract infections, nasopharyngitis, constipation, and fatigue. This study concluded that atogepant was safe and effective for the prevention of episodic migraines.

Ailani and colleagues conducted further research into the efficacy of atogepant for the prevention of migraines in a phase-3, double-blind, randomized, controlled trial between December 2018 and June 2020. There were 910 participants randomized 1:1:1:1 to receive either daily atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks.

Patients were eligible for the trial if they were between 18 and 80 years of age with 4 to 14 migraine days per month in the 3 months prior to the trial. Patients also needed to have at least a 1-year history of migraine with or without aura, diagnosis consistent with the International Classification of Headache Disorders 3rd edition (ICHD-3), and diagnosis prior to age 50. Patients were excluded if they had a diagnosis of chronic migraine, cluster headaches, painful cranial neuropathy, or at least 15 migraine days per month in the 3 months prior to the trial. Patients were also excluded if they did not respond to more than 4 oral medications for the treatment of migraines. Any patients who used opioids or barbiturates more than 2 days per month, triptans or ergots more than 10 days per month, or other analgesic agents (acetaminophen, NSAIDs, aspirin) more than 15 days per month were excluded.

Participants were required to use a medically approved and effective method of contraception and any female participants who were pregnant, lactating, or planning to become pregnant were excluded. All participants in the trial were instructed to take 3 tablets, either 3 placebo tablets or 2 placebo tablets and their assigned dose of atogepant, at the same time each day for 12 weeks. Patients were allowed to take acute migraine treatments such as triptans, ergot derivatives, opioids, analgesics, NSAIDs, and antiemetic agents. Patients were

not allowed to use any other preventative migraine treatments 30 days before the trial or during the trial. Patients used electronic diaries to record headache duration, headache clinical features, non-headache symptoms, and acute treatments used. Other health outcome measures used in this trial include the Activity Impairment in Migraine Diary (AIM-D) and the Migraine-Specific Quality of Life Questionnaire (MSQ). Patients had follow-up visits every 4 weeks for efficacy and adverse effect monitoring.

The primary efficacy endpoint was the change from baseline number of migraine days per month over the 12 weeks of treatment. Secondary efficacy endpoints were the change from baseline in the mean number of headache days per month, change from baseline in the number of days using medication to treat migraine attacks, a reduction of at least 50% from baseline in average monthly migraine days, change from baseline in MSQ score, and change from baseline in the AIM-D score. Baseline characteristics, including baseline average number of migraine days per month, were similar between the study groups.

After 12 weeks, patients taking atogepant had significantly fewer migraine and headache days per month, as well as significantly fewer days that required acute medication use. The number of monthly migraine days was reduced by 2.5±0.2 in the placebo group, 3.7±0.2 in the 10 mg group, 3.9±0.2 in the 30 mg group, and 4.2±0.2 in the 60 mg group (p < 0.001). Similarly, the average number of days that required acute medication use was reduced by 2.4 days in the placebo group, 3.7 days in the 10 mg group, 3.7 days in the 30 mg group, and 3.9 days in the 60 mg group (p < 0.001). There were also significantly more patients who achieved at least 50% fewer monthly migraine days, with 62 (29.0%) patients in the placebo group, 119 (55.6%) in the 10 mg group, 131 (58.7%) in the 30 mg group, and 135 (60.8%) in the 60 mg group (p < 0.001). The most common adverse effects in the study groups were constipation, nausea, fatigue, somnolence, upper respiratory tract infections, and nasopharyngitis. Overall, atogepant was well tolerated and effective at reducing the average number of migraine days per month in patients with episodic migraines.

Adverse Effects1,2: The most common adverse effects of atogepant observed in clinical trials were nausea (7%), constipation (6%), and fatigue (5%), and decreased body weight (4%).

Dosing1: Adult patients may take 10 mg, 30 mg, or 60 mg daily. Do not exceed 60 mg daily. Patients with significant renal impairment (CrCl < 30 mL/min) or on dialysis should receive 10 mg daily. Use is not recommended for patients with severe hepatic impairment (ChildPugh Class C). Atogepant is available in a 10 mg, 30 mg, and 60 mg oral tablet.

Pregnancy and Lactation1: The safety of atogepant in pregnant women has not been assessed in human patients. Animal studies showed that oral administration of atogepant throughout gestation led to lower fetal body weight and decreased skeletal ossification at higher doses (125 and 750 mg/kg). At the no-effect dose (15 mg/kg/ day) for adverse effects on fetal development, plasma exposure (AUC) was about 4 times the AUC reached in humans at the maximum recommended human dose of 60 mg/day.

There are no data regarding the presence of atogepant in human milk or the effects it may have on an infant. Animal studies showed that following oral administration of atogepant, the levels of atogepant in milk was about twice that of the maternal plasma concentration.

Storage1: Store between 20°C and 25°C (68°F and 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).

Cost1,2: Cost information is not yet available.

Summary/Use in Clinical Practice1-6

The American Academy of Neurology (AAN) currently recommends antiepileptic agents (topiramate, divalproex), beta blockers (metoprolol, propranolol), and some antidepressants (venlafaxine, amitriptyline) for the prevention of episodic migraines. The 2012 AAN guidelines have not yet been updated to include recommendations regarding the use of CGRP receptor antagonists. CGRP receptor antagonists have recently emerged as a new option for treatment of migraines, with some agents indicated for prevention and others indicated for acute treatment. Other CGRP receptor antagonists available include galcanezumab (Emgality®), erenumab (Aimovig®), fremanezumab (Ajovy®), eptinezumab (Vyepti®), rimegepant (Nurtec®), and ubrogepant (Ubrelvy®). Galca-

nezumab, erenumab, fremanezumab, and eptinezumab are monoclonal antibodies that are indicated for migraine prophylaxis. They are administered via monthly subcutaneous injection (galcanezumab, erenumab, fremanezumab) or intravenous infusion (eptinezumab). Fremanezumab and eptinezumab also have the option to be administered every 3 months. Rimegepant and ubrogepant are small molecule CGRP antagonists that are administered orally, much like atogepant. Rimegepant is indicated for both the prevention and acute treatment of migraines, while ubrogepant is indicated for the acute treatment of migraines. Atogepant is the latest addition to the CGRP receptor antagonist class, and is safe and effective for the prevention of episodic migraines in adults. Future studies are planned to investigate the effectiveness of atogepant for the treatment of chronic migraines and migraines refractory to other treatments.

At this time, there is insufficient evidence to support the use of atogepant in pregnant or lactating patients. Animal studies indicate that atogepant may cause fetal harm. Atogepant has not been studied for safety or effectiveness in pediatric patients. Atogepant appears to be safe in patients with renal dysfunction, but may require dose adjust in those with severe renal dysfunction (CrCl < 30 mL/min) or on hemodialysis. Use of atogepant is not appropriate in patients with severe hepatic dysfunction (Child-Pugh Class C).

Patients should be counselled to take atogepant at approximately the same time every day, without regard to food. Patients should also inform their health care providers if they are taking other medications or supplements including ketoconazole, cyclosporine, clarithromycin, rifampin, carbamazepine, phenytoin, St. John’s wort, or efavirenz. The most common adverse effects associated with atogepant are nausea, constipation, fatigue, and decreased body weight.

Author: Madeline McMillan is a PharmD Candidate in the Class of 2022 at Campbell University College of Pharmacy and Health Sciences. m_mcmillan0227@email. campbell.edu

References:

1. Atogepant (QuliptaTM). Package insert. AbbVie Inc.; 2021. 2. Lexi-Drugs. Lexicomp [database online]. Hudson, OH: Lexicomp, Inc. http://online.lexi. com. Updated 2021. Accessed October 14, 2021. 3. PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial [published correction appears in Lancet Neurol. 2020 Nov;19(11):e10]. Lancet Neurol. 2020;19(9):727-737. doi:10.1016/S14744422(20)30234-9. 4. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021;385(8):695-706. doi:10.1056/ NEJMoa2035908. 5. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society [published correction appears in Neurology. 2013 Feb 26;80(9):871]. Neurology. 2012;78(17):13371345. doi:10.1212/WNL.0b013e3182535d20. 6. Ashina M, Buse DC, Ashina H, et al. Migraine: integrated approaches to clinical management and emerging treatments. Lancet. 2021;397(10283):1505-1518. doi:10.1016/S01406736(20)32342-4.

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