An Oral CGRP-Targeted Treatment Option for Migraine Prevention
Migraine, which is characterized by an incapacitating headache and changes to sensory perception, is the second leading cause of disability across the world in the context of years lived with disability.1,2 The disorder is defined by the International Headache Society as a headache with a 4- to 72-hour duration that involves at least 2 of the following features: location on one side of the head, a pulsing feeling, moderate to severe pain, and worsening with movement. It also includes nausea and/or vomiting or photophobia and phonophobia.2 The disability associated with migraine can lead to considerable impacts on patient quality of life.3,4
Although some patients have chronic migraine (headache persisting for at least 15 days per month), most patients experience episodic migraine, in which, by definition, headache occurs fewer than 15 days per month.2,5,6 A cure for migraine does not exist; however, preventive treatment can offer a beneficial management strategy.4,6 The goals of migraine prevention, as outlined in the 2021 American Headache Society (AHS) Consensus Statement, include lowering migraine occurrence, severity, length, and disability; lowering dependence on acute therapies; empowering patients to manage their condition; enhancing patient health-related quality of life; and reducing overall costs of treatment.4 Preventive treatment should be considered for all patients with 4 or more headache days per month. Additional criteria for identifying patients who could benefit from preventive treatment include migraine that considerably impairs activities of daily living despite use of acute therapies; inability to use acute treatments due to contraindication, acute therapy failure, overuse, or acute therapy adverse events (AEs); or patient preference.4 The AHS recommends a stratified-care approach for preventive treatment that is modifiable per the need of each individual patient.4
Approximately 40% of patients with migraine experience either at least 4 headache days or at least 2 headache days with impairment per month. These patients could benefit from preventive treatment, but the rate of preventive therapy use in clinical practice is low, ranging from 3% to 30%.3,4,7 Providers may have low awareness of and low confidence in available clinical guidelines for migraine preventive therapy.6
Targeting the calcitonin gene-related peptide pathway for migraine prevention
The calcitonin gene-related peptide (CGRP), which has been found to be elevated in serum during a migraine, acts as a potent vasodilator in intracranial arteries and exerts neurogenic effects in both the peripheral and central nervous systems; these effects result in sensitization and amplified nociception.5,8 Over the past 20 years, CGRP has been established as a primary driver of migraine pathogenesis, and with results from a phase 2 proof-of-concept trial in 2004, the peptide was confirmed as an effective therapeutic target for migraine treatment.5 This discovery led to the subsequent development of several monoclonal antibodies and CGRP receptor antagonists that inhibit the CGRP pathway for migraine treatment.5
Currently, 4 monoclonal antibodies that target CGRP are approved by the United States Food and Drug Administration (FDA) and European Medicines Agency for migraine preventive treatment.3 In 2021, the FDA approved QULIPTA™ (atogepant), the only once-daily oral preventive CGRP receptor antagonist indicated for the preventive treatment of episodic migraine in adults. It is available in 60 mg, 30 mg, and 10 mg dosing options, and its most common adverse reactions are nausea, constipation, and fatigue.9
QULIPTA™ (atogepant) Efficacy and Safety Data
The efficacy and safety profiles of QULIPTA for migraine preventive treatment were investigated in both a pivotal randomized, double-blind, phase 3 trial (N = 910) and a randomized, double-blind, phase 2b/3 dose-finding study (N = 834).3,8 Participants in both trials were adults with a migraine diagnosis for at least a year who had experienced 4 to 14 migraine days per month in the 3 months prior to the first study visit and 4 to 14 migraine days in the 28-day baseline period. Individuals with chronic migraine were excluded.3,8 Patients with myocardial infarction, stroke, or transient ischemic attacks within 6 months prior to screening were also excluded.9 In both trials, 31% of participants had a history of gastrointestinal disorders and 43% had a history of psychiatric disorders.10 Treatment was given over 12 weeks in both trials. In the dose-finding study, patients were randomly assigned 2:1:2:2 to receive placebo; QULIPTA 10 mg, 30 mg, or 60 mg once daily. In the pivotal trial, patients were randomly assigned 1:1:1:1 to receive placebo or QULIPTA 10 mg, 30 mg, or 60 mg once daily. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine.3,8,9
Migraine day reduction
In results from the pivotal trial, QULIPTA 60 mg once daily (n = 222) demonstrated a 54% migraine day reduction across 12 weeks, which was 4.2 fewer monthly migraine days from a 7.8-day baseline; dissimilarly, placebo (n = 214) was associated with a 33% reduction (2.5 fewer monthly migraine days from 7.5-day baseline); this was the primary efficacy endpoint.8 QULIPTA 30 mg once daily (n = 223) and 10 mg once daily (n = 214) also achieved improvements in fewer monthly migraine days across 12 weeks (30 mg: -3.9 days from a 7.9 baseline; 10 mg: -3.7 days from a 7.5 baseline).8
Figure 1. Reductions in Migraine Days per Month From Baseline With QULIPTAa-d,8
aThe baseline for migraine days per month was 7.7 on average.
bThe analyses of additional endpoints were not tested in hierarchical order or adjusted for multiplicity. Results could represent chance findings. Data should be interpreted with these factors in mind.
cResults from the modified intention-to-treat population.
dQULIPTA 10 mg: -4.24 migraine days at Weeks 9-12 (n = 188).
QD, every day; SE, standard error.
Additional endpoints
The majority of impact with QULIPTA 60 mg occurred within weeks 1 through 4; however, the migraine reductions continued across 12 weeks (Figure 1).8 Reductions with QULIPTA 60 mg were experienced as early as day 1 after the first dose, at which point 88% of QULIPTA 60 mg patients did not have a migraine (185/211) versus 75% of placebo patients (151/202).11* By week 1, patients receiving QULIPTA 60 mg (n = 216) experienced a 53% migraine day reduction, whereas those receiving placebo (n = 211) experienced a 15% reduction. This was calculated from week 1 data; QULIPTA 60 mg: Baseline MMD was 1.93; change from baseline: -1.03. Week 1 placebo: Baseline MMD was 1.88; change from baseline: -0.29.12 The analyses of additional endpoints were not tested in hierarchical order or adjusted for multiplicity. Results could represent chance findings. Data should be interpreted with these factors in mind.
In the 60-mg group, 61% of patients achieved a 50% to 100% reduction of monthly migraine days across 12 weeks (secondary efficacy endpoint).9 During the last 4 weeks of the treatment period (weeks 9 through 12), 71% achieved a 50% to 100% reduction (Figure 2).12,13
Figure 2. Patients Who Achieved a 50% to 100% Reduction in Monthly Migraine Days With QULIPTA 60 mg8,9,13
QD, every day; MMD, monthly migraine days.
Similar results with QULIPTA 60 mg once daily were demonstrated in the Phase 2b/3 dose-finding study, in which the 60 mg once-daily dose was associated with 3.6 fewer monthly migraine days across 12 weeks from the baseline of 7.7 monthly migraine days (n = 177) (primary endpoint).3 QULIPTA 30 mg once daily and 10 mg once daily also achieved improvements in fewer monthly migraine days across 12 weeks -3.8 days, 30 mg; -4.0 days, 10 mg; primary endpoints.3
Well tolerated across patients and safety established in all doses
Across both the pivotal trial and dose-finding study, AEs of 2% or more for QULIPTA 60 mg once daily and greater than placebo were nausea, constipation, fatigue/somnolence and decreased appetite. Similar AE rates were experienced with 10 mg and 30 mg doses (Table 1).9,11 A decrease in weight was also observed. The proportion of patients with a weight decrease of at least 7% at any point was 2.8% for placebo, 3.8% for 10 mg, 3.2% for 30 mg, and 4.9% for 60 mg.9,11 In both studies, the discontinuation rates due to adverse events for QULIPTA and placebo were similar. In the pivotal trial, the discontinuation rates were 4% for 10 mg, 2% for 30 mg, 3% for 60 mg and 3%for placebo. In the dose-finding study, the discontinuation rates for once-daily doses were 4% for 10 mg, 6% for 30 mg, 3% for 60 mg and 3% for placebo.3,8 Long-term tolerability was assessed in a multicenter, randomized, open-label, 52-week long-term safety study that evaluated the safety and tolerability of QULIPTA 60 mg in participants who experienced episodic migraine (n = 543).11 AEs of 5% or more for QULIPTA 60 mg were upper respiratory tract infection, constipation, nausea, and urinary tract infection (Table 2).9,11 The discontinuation rate due to adverse events was 5.7%.11
Table 1. Adverse Events With an Incidence of at Least 2% and Greater Than Placebo in the Pivotal Trial and Dose-Finding Study9,11
AEs, adverse events.
Table 2. Adverse Events With an Incidence of at Least 5% for QULIPTA 60 mg (n = 543) in the 52-week long-term safety trial9,11
Conclusions
The CGRP receptor antagonist QULIPTA is an oral preventive therapy for episodic migraine in adults and is associated with considerable reductions in migraine days and has been well tolerated. Its efficacy and safety, coupled with the capability to adjust doses, positions QULIPTA as an option for migraine prevention.3,8,9
* This was calculated from day 1 data; 12.3% (26/211) of QULIPTA 60 mg patients had a migraine day versus 25.2% (51/202) of placebo patients.11
INDICATION
QULIPTA™ (atogepant) is indicated for the preventive treatment of episodic migraine in adults.
IMPORTANT SAFETY INFORMATION
ADVERSE REACTIONS
The most common adverse reactions (at least 4% and greater than placebo) are nausea, constipation, and fatigue.
DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: 10 mg once daily.
Strong and Moderate CYP3A4 Inducers: 30 mg or 60 mg once daily.
OATP Inhibitors: 10 mg or 30 mg once daily.
USE IN SPECIFIC POPULATIONS
Severe Renal Impairment or End-Stage Renal Disease: 10 mg once daily.
Avoid use in patients with severe hepatic impairment.
Please see full Prescribing Information.
References
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2. Headache Classification Committee of the International Headache Society (IHS) the International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. doi:10.1177/0333102417738202.
3. Goadsby PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of orally administered Qulipta for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol. 2020;19(9):727-737. doi:10.1016/S1474-4422(20)30234-9.
4. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: update on integrating new m.igraine treatments into clinical practice. Headache. 2021;61(7):1021-1039. doi:10.1111/head.14153.
5. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552. doi:10.1146/annurev-pharmtox-010814-124701.
6. Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012;52(6):930-945. doi:10.1111/j.1526-4610.2012.02185.x.
7. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-9. doi:10.1212/01.wnl.0000252808.97649.21.
8. Ailani J, Lipton RB, Goadsby PJ, et al; ADVANCE Study Group. Qulipta for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695-706. doi:10.1056/NEJMoa2035908.
9. QULIPTA [Prescribing Information]. Allergan USA; 2021. Accessed September 16, 2022. https://www.rxabbvie.com/pdf/QULIPTA_pi.pdf.
10. Data on file: TBL 200922 history. Allergan USA; 2020.
11. Data on file: Clinical Slides. Atogepant for migraine prevention: Phase III pivotal (episodic migraine) and long-term safety: topline results. AbbVie; 2020.
12. Data on file: 3101-301-002 Clinical Study Report. Allergan USA; 2021.
13. Data on file: Responder Data table: 25% and 50%. Allergan USA.
