Pharmacology: Pharmacodynamics: Mechanism of action: Atogepant (ATC code: N02CD07) is an orally administered, small molecule, selective calcitonin gene-related peptide (CGRP) receptor antagonist that blocks the binding of the CGRP to the receptor and antagonizes CGRP receptor function. CGRP is a neuropeptide that has been associated with migraine pathophysiology. In the trigeminovascular system, CGRP modulates nociceptive signaling and inflammation, and also functions as a vasodilator.
Cardiac Electrophysiology: At a dose 5 times the maximum recommended daily dose, AQUIPTA does not prolong the QT interval to any clinically relevant extent.
Clinical Studies: Episodic Migraine: The efficacy of AQUIPTA for the preventive treatment of episodic migraine (4 to 14 migraine days per month) in adults was demonstrated in one randomized, multicenter, double-blind, placebo-controlled study (Study 1 [ADVANCE]). The study enrolled patients with at least a 1-year history of migraine with or without aura, according to the International Classification of Headache Disorders (ICHD-3) diagnostic criteria.
In Study 1 (NCT03777059), 910 patients were randomized 1:1:1:1 to receive AQUIPTA 10 mg (N = 222), AQUIPTA 30 mg (N = 230), AQUIPTA 60 mg (N = 235) or placebo (N = 223) once daily for 12 weeks. Patients were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, paracetamol, and opioids) as needed. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine. The study excluded patients with myocardial infarction, stroke, or transient ischemic attacks within six months prior to screening.
The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) across the 12-week treatment period. Additional endpoints included the change from baseline in mean monthly headache days; the change from baseline in mean monthly acute medication use days; the proportion of patients achieving at least a 50% and 75% reduction from baseline in mean MMD (3-month average); the change from baseline at week 12 for Headache Impact Test (HIT-6) total score; Migraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR) domain score; and the change from baseline across the 12-week treatment period in mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) domain scores and mean monthly AIM-D Physical Impairment (PI) domain scores.
The HIT-6 measures the impact of headache on patients' ability to function at work, school, home, and in social situations. The AIM-D evaluates difficulty with performance of daily activities (PDA domain) and physical impairment (PI domain) due to migraine. A reduction in scores from baseline indicates improvement. The MSQ v2.1 RFR domain score assesses how often migraine impacts function related to daily social and work-related activities. An increase in scores from baseline indicates improvement.
A total of 805 (88%) patients completed the 12-week double-blind study period. Patients had a mean age of 42 years (range: 18 to 73 years), 89% were female, 83% were White, 14% were Black and 9% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups.
AQUIPTA treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo in Study 1, as summarized in Table 1. (See Table 1.)
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Additional pre-specified endpoints included the MSQ v2.1 Role Function-Preventive (RFP) and Emotional Function (EF) domains. MSQ v2.1 assesses how migraine prevents daily social and work-related activities (RFP domain) and the emotions associated with migraine (EF domain). An increase in scores from baseline indicates improvement. At week 12, the mean change from baseline for the MSQ v2.1 RFP domain (placebo: 17.0, 10 mg: 22.8, 30 mg: 23.9, 60 mg: 24.1) and EF domain (placebo: 18.4, 10 mg: 26.7, 30 mg: 28.1, 60 mg: 29.0) demonstrated greater improvements with AQUIPTA (not controlled for multiple comparisons).
Figure 1 shows the mean change from baseline in MMD in Study 1. Patients treated with AQUIPTA had greater mean decreases from baseline in MMD across the 12-week treatment period compared to patients who received placebo. During the first month of treatment (starting the first day after the initial dose), AQUIPTA had greater mean decreases from baseline in weekly migraine days compared to placebo-treated patients. (See Figure 1.)
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In patients failing one or more prophylactic medications, the treatment difference for the change from baseline in MMD observed as compared to placebo across the 12-week treatment period was -1.5 (95% CI: -2.4, -0.6), -1.5 (95% CI: -2.3, -0.7), and -2.2 (95% CI: -3.1, -1.4) for AQUIPTA 10 mg, 30 mg and 60 mg, respectively.
In Study 1, the proportions of patients with ≥50%, ≥75%, and 100% reduction in monthly migraine days was greater for atogepant compared with placebo in each of the 4-week intervals assessed (Weeks 1-4, 5-8, and 9-12), and the percentage of responders at each threshold generally increased over time. (See Table 2.)
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Results of Long-Term Study: Results from a multicenter, randomized, open-label, 52-week clinical study evaluating atogepant 60 mg safety and tolerability in 546 randomized patients with episodic migraine, demonstrated that efficacy was sustained over the 1-year treatment period. 68.4% of patients completed the treatment period. Atogepant treatment was associated with reduction in the least squares (LS) mean number of monthly migraine days in the first month (Weeks 1-4) of -3.84 days and continued to improve during the remainder of the 52-week treatment period to an LS mean reduction of -5.19 days in the last month (Weeks 49-52).
The proportion of patients who responded with ≥50%, ≥75%, and 100% reduction in monthly migraine days at Weeks 1-4 was 60.4%, 37.2%, and 20.7%, respectively and the proportion of patients at Weeks 49-52 was 84.2%, 69.9%, and 48.4%, respectively.
Patients With Previous Failure to 2 to 4 Classes of Oral Prophylactic Treatments: In the ELEVATE study, 315 adult patients with episodic migraine who previously failed 2 to 4 classes of oral prophylactic treatments (e.g., topiramate, tricyclic antidepressants, beta-blockers) based on efficacy and/or tolerability were randomized 1:1 to receive either atogepant 60 mg (N = 157) or placebo (N = 158) for 12 weeks. Results in this study were consistent with the main findings of previous episodic migraine efficacy studies and were statistically significant for primary and secondary efficacy endpoints including several patient-reported outcome measures assessing functioning. Atogepant treatment led to a reduction of 4.3 days in mean MMD compared to 1.9 days in the placebo group (p<0.001).
51.0% (77/151) of patients in the atogepant group achieved at least a 50% reduction from baseline in MMD compared to 17.5% (27/154) in the placebo group (odds ratio [95% CI]: 5.15 [3.02, 8.79], p<0.001). 27.8% (42/151) of patients in the atogepant group achieved at least a 75% reduction from baseline in MMD compared to 1.9% (3/154) in the placebo group (not adjusted for multiple comparisons).
A reduction of 4.2 days in mean monthly headache days compared to 1.9 days in the placebo group (p<0.001) and a reduction of 3.8 days in mean monthly acute medication use days compared to 1.1 days in the placebo group (p<0.001) were also observed.
Greater improvement from baseline in MSQ v2.1 RFR domain score at Week 12 were demonstrated for atogepant 60 mg QD compared with placebo (placebo: 15.4, 60 mg: 33.1, p<0.001). Additionally, greater improvements from baseline in mean monthly AIM-D PDA domain score (placebo: -5.0, 60 mg: -9.7, p<0.001) and in mean monthly AIM-D PI domain score (placebo: -3.0, 60 mg: -7.4, p<0.001) across the 12-week treatment period were demonstrated for atogepant 60 mg QD compared with placebo.
There was also a greater improvement from baseline in HIT-6 total score at Week 12 demonstrated for atogepant 60 mg QD compared with placebo (placebo: -4.2, 60 mg: -10.6) (p<0.001, not adjusted for multiple comparisons).
Chronic Migraine: The efficacy of AQUIPTA for the preventive treatment of chronic migraine (15 or more headache days per month with at least 8 migraine days) in adults was demonstrated in one randomized, multicenter, double-blind, placebo-controlled study (Study 2 [PROGRESS]). The study enrolled patients with at least a 1-year history of chronic migraine, according to the ICHD-3 diagnostic criteria.
In Study 2 (NCT03855137), 778 patients were randomized 1:1:1 to receive AQUIPTA 30 mg twice daily (N = 257), AQUIPTA 60 mg once daily (N = 262), or placebo (N = 259) for 12 weeks. Patients were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, paracetamol, and opioids) as needed. Patients with acute medication overuse and medication overuse headache also were enrolled. A subset of patients (11%) was allowed to use one concomitant migraine preventive medication (e.g., amitriptyline, propranolol, topiramate). The use of a concomitant medicinal product that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine. The study excluded patients with myocardial infarction, stroke, or transient ischemic attacks within six months prior to screening.
The primary efficacy endpoint was the change from baseline in mean MMD across the 12-week treatment period. Additional endpoints included the change from baseline in mean monthly headache days; the change from baseline in mean monthly acute medication use days; the proportion of patients achieving at least a 50% and 75% reduction from baseline in mean MMD (3-month average); the change from baseline at week 12 for Headache Impact Test (HIT-6) total score and MSQ v2.1 RFR domain score; and the change from baseline across the 12-week treatment period in mean monthly AIM-D PDA domain scores and mean monthly AIM-D PI domain scores.
Patients had a mean age of 42 years (range 18 to 74 years), 88% were female, 59% were White, 3% were Black, 36% were Asian, and 4% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 19 migraine days per month and was similar across treatment groups. A total of 694 (89%) patients completed the 12-week double-blind study period.
Key efficacy results of Study 2 are summarized in Table 3. (See Table 3.)
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Additional pre-specified endpoints included the MSQ v2.1 RFP and EF domains. The mean change from baseline for the MSQ v2.1 RFP domain (placebo: 13.4, 30 mg BID: 21.4, 60 mg QD: 20.2) and EF domain (placebo: 15.6, 30 mg BID: 22.0, 60 mg QD: 22.4) demonstrated greater improvements with AQUIPTA at week 12 (not controlled for multiple comparisons).
Figure 2 shows the mean change from baseline in MMD in Study 2. Patients treated with AQUIPTA had greater mean decreases from baseline in MMD across the 12-week treatment period compared to patients who received placebo. (See Figure 2.)
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In patients failing one prophylactic pharmacotherapy, the treatment difference for the change from baseline in MMD observed between AQUIPTA and placebo across the 12-week treatment period was -2.0 (95% CI: -3.9, -0.2) for 30 mg BID and -1.8 (95% CI: -3.6, 0.1) for 60 mg QD. In patients failing two or more prophylactic pharmacotherapies, the treatment difference was -2.9 (95% CI: -4.7, -1.1) for 30 mg BID and -2.5 (95% CI: -4.2, -0.7) for 60 mg QD.
The proportions of patients with ≥50%, ≥75%, and 100% reduction in monthly migraine days was greater in the atogepant treatment group than in the placebo treatment group for each of the 4-week intervals assessed (Weeks 1 to 4, 5 to 8, and 9 to 12), and the percentage of responders at each threshold increased over time. (See Table 4.)
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Pharmacokinetics: Absorption: Following oral administration of AQUIPTA, atogepant is rapidly absorbed with plasma concentrations >14 nM (EC
90 based on capsaicin induced dermal vasodilation model [CIDV]) within 0.5 hours and median T
max values ranging from 1 to 2 hours. Atogepant displays dose-proportional pharmacokinetics through 300 mg single dose and 170 mg multiple once-daily doses with no accumulation upon once daily dosing.
When AQUIPTA was administered with a high-fat meal, the food effect was not clinically significant (AUC and C
max were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration). AQUIPTA was administered without regard to food in clinical efficacy studies.
Distribution: Plasma protein binding of atogepant was not concentration-dependent in the range of 0.1 to 10 μM; the unbound fraction of atogepant was approximately 4.7% in human plasma. The mean apparent volume of distribution of atogepant (Vz/F) after oral administration is approximately 292 L.
Metabolism: Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulating components in human plasma.
Excretion: The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL/F) of atogepant is approximately 19 L/hr. Following single oral dose of 50 mg
14C-atogepant to healthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in feces and urine, respectively.
Pharmacokinetics in special populations: Based on a population pharmacokinetic analysis, age, sex, race, and body weight did not have a significant effect on the pharmacokinetics (C
max and AUC) of atogepant. Therefore, no dose adjustments are warranted based on these factors.
Pediatric: Data not available.
Geriatric: Population pharmacokinetic modeling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects.
Renal impairment: The renal route of elimination plays a minor role in the clearance of atogepant. Based on physiologically based pharmacokinetic (PBPK) and population pharmacokinetic analysis, there is no significant difference in the pharmacokinetics of atogepant in patients with mild or moderate renal impairment (CLcr 30-89 mL/min) relative to those with normal renal function (CLcr ≥90 mL/min). As patients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease (ESRD; CLcr <15 mL/min) have not been studied, use of the lowest effective dose of atogepant (10 mg) is recommended in those patients. No dose adjustment is recommended for patients with mild or moderate renal impairment.
Hepatic impairment: In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe hepatic impairment (Child-Pugh Class C), total atogepant exposure was increased by 24%, 15% and 38%, respectively. However, unbound atogepant exposure was approximately 3-fold higher in patients with severe hepatic impairment. Avoid use of AQUIPTA in patients with severe hepatic impairment. No dose adjustment is recommended for patients with mild or moderate hepatic impairment.
Drug interactions:
In Vitro Studies: Enzymes:
In vitro, atogepant is not an inhibitor for CYPs 3A4, 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations. Atogepant does not inhibit MAO-A or UGT1A1 at clinically relevant concentrations. Atogepant is not anticipated to be a clinically significant perpetrator of drug-drug interactions through CYP450s, MAO-A, or UGT1A1 inhibition.
Atogepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
Transporters: Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment for concomitant use of AQUIPTA with inhibitors of OATP is recommended based on a clinical interaction study with an OATP inhibitor (see Dosage & Administration).
Coadministration of atogepant with BCRP and/or P-gp inhibitors is not expected to increase the exposure of atogepant. Atogepant is not a substrate of OAT3, OCT2, or MATE1.
Atogepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, NTCP, BSEP, MRP3, or MRP4 at clinically relevant concentrations. Atogepant is a weak inhibitor of OATP1B1, OATP1B3, OCT1, and MATE1. No clinical drug interactions are expected for atogepant as a perpetrator with these transporters.
In Vivo Studies: CYP3A4 Inhibitors: Co-administration of AQUIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a clinically significant increase (C
max by 2.15-fold and AUC by 5.5-fold) in the exposure of atogepant in healthy subjects (see Interactions).
PBPK modeling suggested co-administration of AQUIPTA with moderate (e.g., cyclosporine [ciclosporin], ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak (e.g., cimetidine, esomeprazole) CYP3A4 inhibitors increase atogepant AUC by 1.7- and 1.1-fold, respectively. The changes in atogepant exposure when coadministered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant.
CYP3A4 Inducers: Co-administration of AQUIPTA with rifampicin [rifampin], a strong CYP3A4 inducer, decreased atogepant AUC by 60% and C
max by 30% in healthy subjects (see Interactions). No dedicated drug interaction studies were conducted to assess concomitant use with moderate CYP3A4 inducers. Moderate inducers of CYP3A4 can decrease atogepant exposure (see Interactions). Clinically significant interaction was not observed with concomitant administration of topiramate, a weak inducer of CYP3A4 and AQUIPTA.
BCRP/OATP/P-gp Inhibitors: Co-administration of AQUIPTA with single dose rifampicin [rifampin], an OATP inhibitor, increased atogepant AUC by 2.85-fold and C
max by 2.23-fold in healthy subjects (see Interactions).
Co-administration of AQUIPTA with quinidine, a P-gp inhibitor, increased atogepant AUC by 26% and C
max by 4% in healthy subjects. The changes in atogepant exposure when co-administered with P-gp inhibitors are not expected to be clinically significant.
PBPK modeling suggests that co-administration of AQUIPTA with BCRP inhibitors increases atogepant exposure by 1.2-fold. This increase is not expected to be clinically significant.
Other Drug Interaction Evaluations: Co-administration of AQUIPTA with oral contraceptive components ethinyl estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, sumatriptan, or ubrogepant did not result in significant pharmacokinetic interactions for either atogepant or co-administered drugs.
Toxicology: Pre-Clinical Safety Data: Carcinogenicity: Atogepant was administered orally to mice (0, 5, 20, or 75 mg/kg/day in males; 0, 5, 30, 160 mg/kg/day in females) and rats (0, 10, 20, or 100 mg/kg in males; 0, 25, 65, or 200 mg/kg in females) for up to 2 years. There was no evidence of drug-related tumors in either species. Plasma exposures at the highest doses tested in mice and rats were approximately 8 and 20-35 times, respectively, that in humans at the maximum recommended human dose (MRHD) of 60 mg/day.
Mutagenicity: Atogepant was negative in
in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and
in vivo (rat bone marrow micronucleus) assays.
Impairment of fertility: Oral administration of atogepant (0, 5, 20, or 125 mg/kg/day) to male and female rats prior to and during mating and continuing in females to Gestation Day 7 resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested are approximately 15 times that in humans at the MRHD.
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