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Pharmacology: Mechanism of action: Erenumab is a human monoclonal antagonist antibody against the CGRP receptor with no significant pharmacological activity at adrenomedulin, calcitonin, and amylin receptors and lacks agonist activity at the CGRP receptor.
CGRP is a neuropeptide that modulates nociceptive signaling and a vasodilator that has been associated with migraine pathophysiology. In contrast with other neuropeptides, CGRP levels have been shown to increase significantly during migraine and return to normal with headache relief. Intravenous infusion of CGRP induces migraine-like headache in patients suggesting that CGRP may play a causal role in migraine.
The CGRP receptor is located at sites that are relevant to migraine pathophysiology. Erenumab potently and specifically competes with the binding of CGRP and inhibits its function at the CGRP receptor.
Pharmacodynamic effect: In a randomized, double-blind, placebo-controlled study (20140254) to evaluate the effect of Pasurta (140 mg IV, single dose) in patients with stable angina, Pasurta did not decrease exercise duration during a treadmill test compared to placebo and did not aggravate myocardial ischemia in these patients.
Clinical Studies: Pasurta was evaluated for prophylaxis of migraine in two pivotal studies across the spectrum of episodic and chronic migraine. Studies enrolled patients with a history of migraine, with or without aura according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.
Pasurta treatment demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for key efficacy outcomes.
Chronic Migraine: Study 1 (Study 20120295): Pasurta was evaluated for prophylaxis of chronic migraine in a randomized, multi-center, 12 week, placebo-controlled, double-blind study. A total of 667 patients with a history of migraine with or without aura (≥15 headache days per month with ≥8 migraine days per month) were randomized to receive placebo (n = 286), Pasurta 70 mg (n = 191) or Pasurta 140 mg (n = 190) subcutaneous injections monthly for 12 weeks.
Randomization was stratified by region (North America versus other) and the presence of acute medication overuse (present in 41% of overall patients) excluding patients with opioid overuse. The mean migraine frequency at baseline was approximately 18 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study.
Patients had a median age of 43 years (range: 18 to 66 years), 83% were female and 94% were white. Patients could have failed (i.e., no therapeutic response) up to three previous prophylactic treatment categories due to lack of efficacy, while there was no limit to the number of previous failures for poor tolerability. Overall, in this study population, 68% had failed one or more previous prophylactic treatments due to lack of efficacy or poor tolerability, and 49% had failed two or more previous prophylactic treatments due to lack of efficacy or poor tolerability. In addition to excluding patients with opioid overuse, the study excluded patients with concurrent use of migraine prophylactic treatments. A total of 182 (96%) patients in the Pasurta 140 mg arm, 184 (96%) patients in the Pasurta 70 mg arm, and 265 (93%) patients in the placebo arm completed the study (i.e. completed Week 12 assessment). Of the 23 (3.4%) patients who discontinued treatment, 2 patients in the Pasurta 140 mg-treated group, no patients in the Pasurta 70 mg-treated group, and 2 patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline at Month 3 in monthly migraine days. Secondary outcome measures included the achievement of 50 to 100% reduction in monthly migraine days from baseline (≥50% responders), change from baseline in monthly acute migraine specific medication days, and change from baseline in cumulative monthly headache hours. Other than for cumulative monthly headache hours, Pasurta treatment demonstrated statistically significant and clinically meaningful improvements from baseline at Month 3 compared to placebo for efficacy outcomes as summarized in Figure 1 and Table 1.
Reduction in mean monthly migraine days from placebo were observed in a monthly analysis from Month 1 and in a follow up weekly analysis an onset of Pasurta effect was seen from the first week of administration. (See Figure 1 and Table 1.)
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Click on icon to see table/diagram/imageBased on a pre-specified analysis, Pasurta 70 mg and 140 mg were efficacious in patients who had previously been treated with migraine prophylactics. Table 2 provides subgroup results of Study 1 based on prior prophylactic failure(s) due to lack of efficacy or intolerance, in a pre-specified analysis. (See Table 2.)
Click on icon to see table/diagram/imageIn patients with medication overuse (41% of the total population in Study 1), efficacy was observed with 70 mg and 140 mg Pasurta compared to placebo for monthly migraine days [LSM (95% Cl) 70 mg: -3.10 days (-4.83, -1.37)]; 140 mg: -3.10 days (-4.81, -1.39); 50% responders: 34.6% for 140 mg, 36.4% for 70 mg versus 17.7% for placebo), with odds ratio (95% CI) 70 mg: 2.67 (1.36, 5.22); 140 mg: 2.51 (1.28, 4.94)) and in acute migraine-specific medication days (LSM (95% CI) 70 mg: -3.33 (-4.72, -1.94); 140 mg: -2.79 (-4.16, -1.42)).
Improvement in functional ability was assessed by the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires. Mean change from baseline to Month 3 compared to placebo for the patient reported outcome measures are summarized in Table 1. The established between-group Minimally Important Difference (MID) for the reduction in HIT-6 total score is 2.3.
Efficacy was sustained for up to 1 year in the open-label extension of Study 1 in which patients received 70 mg and/or 140 mg Pasurta. 74.1% of patients completed the 52-week extension. Pooled across the two doses, a reduction of -9.3 MMD was observed after 52 weeks relative to core study baseline. 59% of patients completing the study achieved a 50% response in the last month of the study.
Episodic Migraine: Study 2 (Study 20120296, STRIVE): Study 2 was a randomized, multi-center, 24-week, placebo-controlled, double-blind study evaluating Pasurta for prophylaxis of episodic migraine. A total of 955 patients with history of migraine with or without aura for a duration of ≥ 12 months and 4-14 migraine days per month were randomized to receive either Pasurta 70 mg (n = 317), Pasurta 140 mg (n = 319), or placebo (n = 319) by subcutaneous injection monthly for 6 months. Randomization was stratified by use of prophylactic medications (concomitant, prior use or no prior use) and region (North America vs. other). The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study. Patients had a median age of 42 years (range: 18 to 65 years), 85% were female and 89% were white. Patients could have failed to respond up to two previous prophylactic treatments. The study excluded patients with medication overuse. Overall, 865 (90.6%) patients completed the double-blind phase, including 287 (90.5%) in the 70 mg group, 294 (92.2%) in the 140 mg group, and 284 (89.0%) in the placebo group. Of the 87 (9.1%) patients who discontinued treatment, 7 patients in the 70 mg Pasurta group, 6 patients in the 140 mg Pasurta group, and 7 patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline during months 4-6 in monthly migraine days. Secondary outcome measures included the achievement of a 50 to 100% reduction in mean monthly migraine days from baseline (≥50% responders), change from baseline in mean monthly acute migraine specific medication days and change from baseline in the two Migraine Physical Function Impact Diary (MPFID) domain scores: physical impairment (PI) and impact on everyday activities (EA).
The MPFID is a patient reported outcomes instrument that measures the impact of migraine on physical functioning. It contains 13 items evaluating the impact of migraine during the previous 24 hours on two physical functioning concepts of interest - "impact on everyday activities (EA)" (7 items, e.g. difficulty doing activities requiring concentration), "physical impairment (PI)" (5 items, e.g. difficulty doing activities requiring physical effort) and one global item assessing the overall impact on everyday activities. Patients rate the duration of impact or level of difficulty associated with migraine on a daily basis. Monthly MPFID scores are averaged over days with and without migraine; higher scores indicate worse impact on the EA and PI domains.
Pasurta treatment demonstrated statistically significant and clinically meaningful improvements from baseline during Months 4 to 6 compared to placebo for efficacy outcomes as summarized in Figure 2 and Table 3. Differences from placebo were observed as early as Month 1.
Based on a pre-specified analysis, Pasurta 70 mg and 140 mg were efficacious in patients who had previously been treated with migraine prophylactics. Table 4 provides subgroup results of Study 2 based on prior prophylactic failure due to lack of efficacy or intolerance, in a pre-specified analysis. (See Figure 2, Tables 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageEfficacy was sustained up to 1 year in the active re-randomisation part of study 2. Patients were re-randomised in the active treatment phase (atp) to 70 mg or 140 mg Pasurta. 79.8% completed the entire study out to 52 weeks. The reduction in monthly migraine days from baseline to week 52 was 4.22 in the 70 mg atp group and 4.64 days in the 140 mg atp group. At week 52, the proportion of subjects who achieved a ≥50% reduction in mmd from baseline was 61.0% in the 70 mg atp and 64.9% in the 140 mg ATP group.
Study 3 (Study 20120297, ARISE): Study 3 was a randomized, multi-center, 12-week, placebo-controlled, double-blind study evaluating Pasurta for prophylaxis of episodic migraine. A total of 577 patients with history of migraine with or without aura for a duration of ≥ 12 months and 4-14 migraine days per month were randomized to receive either Pasurta 70 mg (n = 286) or placebo (n = 291) by subcutaneous injection monthly. Randomization was stratified by use of prophylactic medications (concomitant, prior use or no prior use) and region (North America vs. other). The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study.
Patients had a median age of 43 years (range: 18 - 65 years), 85% were female and 90% were white. Patients could have failed to respond up to 2 previous prophylactic treatments. The study excluded patients with medication overuse. Overall, 546 (94.6%) patients completed the double-blind phase, including 271 (94.8) receiving Pasurta 70 mg and 275 (94.5) receiving placebo. Of the 31 (5.4%) patients who discontinued treatment, 15 receiving Pasurta 70 mg and 1 patient receiving placebo discontinued due to adverse events.
The primary outcome measure was the change from baseline in monthly migraine days. Secondary outcome measures included the achievement of a 50-100% reduction in mean monthly migraine days from baseline (≥ 50% responders), change from baseline in mean monthly acute migraine-specific medication days and 5-point reduction from baseline in the 2 Migraine Physical Function Impact Diary (MPFID) domains scores: physical impairment (PI) and impact on everyday activities (EA). The Migraine Physical Function Impact Diary (MPFID) is a patient reported outcomes instrument that measures the impact of migraine on physical functioning. It contains 13 items evaluating the impact of migraine during the previous 24 hours on two physical functioning concepts of interest: impact on everyday activities (EA; 7 items: e.g., difficulty doing activities requiring concentration), physical impairment (PI, 5 items: e.g., difficulty doing activities requiring physical effort) and one global item assessing the overall impact on everyday activities. Patients rate the duration of impact or level of difficulty associated with migraine on a daily basis. Monthly MPFID scores are averaged over days with and without migraine; higher scores indicate worse impact on the EA and PI domains.
Pasurta treatment demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for efficacy outcomes as shown in Figure 3 and Table 5. (See Figure 3, Tables 5 and 6.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePharmacokinetics: Erenumab exhibits non-linear kinetics as a result of binding to CGRP receptor. Subcutaneous administration of a 70 mg and 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 6.1 (2.1) mcg/mL and 15.8 (4.8) mcg/mL respectively, and AUClast mean (SD) of 159 (58) day*mcg/mL and 505 (139) day*mcg/mL respectively.
Less than 2 fold accumulation was observed in trough serum concentrations (Cmin [SD] 5.7 [3.1] and 6.2 [2.9] mcg/mL for episodic and chronic migraine subjects, respectively following 70 mg doses; Cmin [SD] 12.8 [6.53] and 14.9 [6.45] mcg/mL for episodic and chronic migraine subjects, respectively following 140 mg doses) administered subcutaneously every 4 weeks and serum trough concentrations approached steady state by 12 weeks of dosing. The effective half-life of Pasurta is 28 days.
Absorption: Following a single subcutaneous dose of 70 mg or 140 mg Pasurta administered to healthy adults, median peak serum concentrations were attained in approximately 6 days, and estimated absolute bioavailability was 82%.
Distribution: Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) L.
Metabolism and excretion: Two elimination phases were observed for Pasurta. At low concentrations, the elimination is predominately through saturable binding to target (CGRP-R), while at higher concentrations the elimination of Pasurta is largely through a non-specific, non-saturable proteolytic pathway.
Specific populations: The pharmacokinetics of erenumab were not affected by age, gender, race, migraine subtype (episodic or chronic migraine), or creatinine clearance, across all approved populations based on population pharmacokinetics (PK) analysis.
Toxicology: Non-Clinical Safety Data: Carcinogenesis, mutagenesis, impairment of fertility: Carcinogenicity studies have not been conducted with Pasurta. Pasurta is not pharmacologically active in rodents and has biologic activity in the cynomolgus monkeys, but this species is not an appropriate model for evaluation of tumorigenic risk. The mutagenic potential of Pasurta has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on surrogate markers of fertility (anatomic pathology or histopathology changes in reproductive organs) in the chronic toxicology study in sexually mature monkeys subcutaneously administered Pasurta at dose levels up to 150 mg/kg twice weekly for 6 months, at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 mg or 140 mg once monthly, respectively based on serum AUC.
Animal toxicology: There were no adverse effects in monkeys dosed up to 150 mg/kg SC twice weekly for up to 6 months at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 or 140 mg once monthly, respectively, based on serum AUC.
