Aquipta

Pharmacotherapeutic group: {Analgesics, antimigraine preparations}, ATC code: N02CD07 Mechanism of action Atogepant 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. Pharmacodynamic effects At a dose 5 times the maximum recommended daily dose, AQUIPTA does not prolong the QT interval. Clinical efficacy and safety AQUIPTA was evaluated for the prophylaxis of migraine in two pivotal studies across the migraine spectrum in chronic and episodic migraine. The episodic migraine study (ADVANCE) enrolled patients who met International Classification of Headache Disorders (ICHD) criteria for a diagnosis of migraine with or without aura. The chronic migraine study (PROGRESS) enrolled patients who also met ICHD criteria for chronic migraine. Both studies excluded patients with myocardial infarction, stroke, or transient ischemic attacks within six months prior to screening. Episodic Migraine AQUIPTA was evaluated for the prophylaxis of episodic migraine (4 to 14 migraine days per month) in a randomised, multicentre, double-blind, placebo-controlled study (ADVANCE). A total of 458 patients were randomised 1:1 to receive 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, acetaminophen and opioids) as needed. A total of 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, and 83% were white. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. 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), and change from baseline at week 12 for Headache Impact Test (HIT-6) total score and Migraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR) domain score. The HIT-6 measures the impact of headache on participants' ability to function at work, school, home, and in social situations. 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. AQUIPTA treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo in ADVANCE, as summarized in Table 3. Table 3: Efficacy endpoints in ADVANCE AQUIPTA 60 mg N=226 Placebo N=216 Monthly Migraine Days (MMD) across 12 weeks Baseline 7.8 7.5 Mean change from baseline -4.1 -2.5 Difference from placebo (95% CI) -1.7 (-2.2, -1.1) p -value <0.001 Monthly Headache Days across 12 weeks Baseline 9.0 8.5 Mean change from baseline -4.2 -2.5 Difference from placebo (95% CI) -1.7 (-2.3, -1.0) p -value <0.001 Monthly Acute Medication Use Days across 12 weeks Baseline 6.9 6.5 Mean change from baseline -3.8 -2.3 Difference from placebo (95% CI) -1.4 (-1.9, -0.9) p -value <0.001 ≥ 50% MMD Responders across 12 weeks % Responders 59 29 Difference from placebo (%) 30 p -value <0.001 ≥ 75% MMD Responders across 12 weeks % Responders 38 11 Difference from placebo (%) 27 p -value <0.001 a HIT-6 b at week 12 Baseline 63.8 64.6 Mean change from baseline -9.1 -5.2 Difference from placebo (95% CI) -3.9 (-5.4, -2.5) p -value <0.001 a MSQ v2.1 RFR c at week 12 Baseline 46.6 46.6 Mean change from baseline 31.0 20.0 Difference from placebo (95% CI) 11.0 (6.6, 15.3) p -value <0.001 a Not adjusted for multiple comparisons b Headache Impact Test total score c Migraine Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive domain score Additional pre-specified endpoints included the Activity Impairment in Migraine-Diary (AIM-D) domains and the MSQ v2.1 Role Function-Preventive (RFP) and Emotional Function (EF) domains. 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. 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. The mean change from baseline for the AIM-D PDA domain (placebo: -6.1, 60 mg: -9.1) and AIM-D PI domain (placebo: -4.0, 60 mg: -6.4) demonstrated greater improvements with AQUIPTA 60 mg QD across the 12-week treatment period. The change was significant when adjusted for multiple comparisons. At week 12, the mean change from baseline for the MSQ v2.1 RFP domain (placebo: 16.9, 60 mg: 23.9) and EF domain (placebo: 18.2, 60 mg: 28.8) demonstrated greater improvements with AQUIPTA 60 mg QD (not controlled for multiple comparisons). Figure 1 shows the mean change from baseline in MMD in ADVANCE. Patients treated with AQUIPTA 60 mg QD 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 60 mg QD had greater mean decreases from baseline in weekly migraine days compared to placebo-treated patients. Figure 1: Change from baseline in monthly migraine days in ADVANCE In patients failing one or more prophylactic medications, the treatment difference for the reduction of MMD observed as compared to placebo across the 12-week treatment period was -2.2 (95% CI: -3.0, -1.3) for AQUIPTA 60 mg. The proportions of participants with ≥ 50%, ≥ 75%, and 100% reduction in monthly migraine days was greater in the AQUIPTA 60 mg QD 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. Table 4: Reduction of ≥ 50%, ≥ 75%, and 100% from baseline in MMD by 4-week interval a AQUIPTA 60 mg (%) Placebo (%) ≥ 50% MMD Responders Weeks 1-4 59 27 Weeks 5-8 66 46 Weeks 9-12 71 44 ≥ 75% MMD Responders Weeks 1-4 39 10 Weeks 5-8 40 17 Weeks 9-12 49 22 100% MMD Responders Weeks 1-4 19 4 Weeks 5-8 24 8 Weeks 9-12 27 12 a p < 0.001 for all comparisons between AQUIPTA 60 mg and placebo (not adjusted for multiple comparisons) Long-term efficacy Efficacy was sustained for up to one year in an open-label study in which patients with episodic migraine received AQUIPTA 60 mg once daily. 68.4% of patients completed the treatment period. The reduction in the least-squares mean number of monthly migraine days in the first month (weeks 1-4) was -3.8 days and improved to a least-squares mean reduction of -5.2 days in the last month (weeks 49-52). Approximately 84%, 70%, and 48% of patients reported ≥ 50%, ≥ 75%, and 100% reduction in monthly migraine days at weeks 49-52, 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 randomised 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 statistically significant for primary and secondary efficacy endpoints including several patient-reported outcome measures assessing functioning. Atogepant treatment led to a reduction of 4.2 days in mean MMD compared to 1.9 days in the placebo group (p<0.001). 50.6% (78/154) of patients in the atogepant group achieved at least a 50% reduction from baseline in MMD compared to 18.1% (28/155) in the placebo group (odds ratio [95% CI]: 4.82 [2.85, 8.14], p<0.001). Chronic Migraine AQUIPTA was evaluated for the prophylaxis of chronic migraine (15 or more headache days per month with at least 8 migraine days) in a randomised, multicentre, double-blind, placebo-controlled study (PROGRESS). A total of 521 patients were randomised 1:1 to receive AQUIPTA 60 mg (N = 262) or placebo (N = 259) once daily for 12 weeks. A subset of patients (11%) was allowed to use one concomitant migraine prophylaxis medication (e.g., amitriptyline, propranolol, topiramate). Patients were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, acetaminophen and opioids) as needed. Patients with acute medication overuse and medication overuse headache also were enrolled. A total of 463 (89%) patients completed the 12-week double-blind study. Patients had a mean age of 42 years (range: 18 to 74 years), 87% were female, and 59% were white. The mean migraine frequency at baseline was approximately 19 migraine days per month and was similar across treatment groups. 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), and change from baseline at week 12 for HIT-6 total score and MSQ v2.1 RFR domain score. Key efficacy results of PROGRESS are summarized in Table 5. Table 5: Efficacy endpoints in PROGRESS AQUIPTA 60 mg N=257 Placebo N=249 Monthly Migraine Days (MMD) across 12 weeks Baseline 19.2 19.0 Mean change from baseline -6.8 -5.1 Difference from placebo (95% CI) -1.7 (-2.7, -0.6) p -value 0.002 Monthly Headache Days across 12 weeks Baseline 21.5 21.4 Mean change from baseline -6.9 -5.2 Difference from placebo (95% CI) -1.7 (-2.8, -0.7) p -value 0.002 Monthly Acute Medication Use Days across 12 weeks Baseline 15.5 15.3 Mean change from baseline -6.2 -4.1 Difference from placebo (95% CI) -2.1 (-3.1, -1.1) p -value 0.002 ≥ 50% MMD Responders across 12 weeks % Responders 40 27 Difference from placebo (%) 14 p -value 0.002 ≥ 75% MMD Responders across 12 weeks % Responders 18 6 Difference from placebo (%) 13 p -value <0.001 a HIT-6 b at week 12 Baseline 64.4 63.8 Mean change from baseline -7.8 -5.2 Difference from placebo (95% CI) -2.7 (-4.0, -1.3) p -value <0.001 MSQ v2.1 RFR c at week 12 Baseline 43.3 44.1 Mean change from baseline 23.1 17.3 Difference from placebo (95% CI) 5.8 (2.2, 9.4) p -value 0.002 a Not adjusted for multiple comparisons b Headache Impact Test total score c Migraine Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive domain score 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: 13.6, 60 mg: 19.9) and EF domain (placebo: 15.7, 60 mg: 22.4) demonstrated greater improvements with AQUIPTA 60 mg QD at week 12 (not controlled for multiple comparisons). Figure 2 shows the mean change from baseline in MMD in PROGRESS. Patients treated with AQUIPTA 60 mg QD had a greater mean decrease from baseline in MMD across the 12-week treatment period compared to patients who received placebo. Figure 2: Change from baseline in monthly migraine days in PROGRESS In patients failing one or more prophylactic medications with the same mechanism of action, the treatment difference for the reduction of MMD observed between AQUIPTA 60 mg and placebo across the 12-week treatment period was -1.5 (95% CI: -3.3, 0.4). In patients failing two or more prophylactic medications with different mechanisms of action, the treatment difference was -2.4 (95% CI: -4.2, -0.6). The proportions of participants with ≥ 50%, ≥ 75%, and 100% reduction in monthly migraine days was greater in the AQUIPTA 60 mg QD 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. Table 6: Reduction of ≥ 50%, ≥ 75%, and 100% from baseline in MMD by 4-week interval AQUIPTA 60 mg (%) Placebo (%) ≥ 50% MMD Responders Weeks 1-4 39 a 18 Weeks 5-8 43 a 31 Weeks 9-12 44 38 ≥ 75% MMD Responders Weeks 1-4 17 a 5 Weeks 5-8 24 a 10 Weeks 9-12 28 a 15 100% MMD Responders Weeks 1-4 4 b 0 Weeks 5-8 6 a <1 Weeks 9-12 7 b 3 a p<0.01 for comparison between AQUIPTA 60 mg and placebo (not adjusted for multiple comparisons) b p<0.03 for comparison between AQUIPTA 60 mg and placebo (not adjusted for multiple comparisons)