Discovery of the Migraine Prevention Therapeutic Aimovig (Erenumab), the First FDA-Approved Antibody against a G-Protein-Coupled Receptor.
ABSTRACT: In 2018, the United States Food and Drug Administration (FDA) approved Aimovig (erenumab) for the prevention of migraine. Erenumab is the first FDA approved antibody therapeutic against a G-protein-coupled receptor, the canonical receptor of calcitonin gene related peptide (CGRP-R). A novel, epitope-focused antigen was created to reconstruct the extracellular domains of the CGRP-R in a stable conformation. Successful inoculation of XenoMouse animals and careful screening yielded multiple candidate molecules for high potency and exquisite selectivity toward the CGRP-R over related receptors. These efforts led to the discovery of erenumab which has demonstrated the desired efficacy and safety profiles in multiple clinical studies for the prevention of migraine. The innovation developed in the discovery of erenumab furthers the ability to target G-coupled protein receptors using antibody approaches.
Project description:Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAbs) have been the first class of specifically developed preventive treatments for migraine. Clinical trials data suggest superiority of the CGRP mAbs to placebo in terms of prevention of migraine symptoms, migraine-specific quality of life and headache related disability. Treatment-related side effects overall did not differ significantly from placebo and discontinuation rate due to side effects has been low across the clinical trials, perhaps in view of their peripheral mode of action. Along with their route and frequency of administration, these novel class of drugs may constitute an improvement compared with the established arsenal of migraine treatments. Erenumab is a fully human antibody and the only mAb acting on the CGRP pathway by blocking its receptor. It is the first of the CGRP mAb class approved by the US Food and Drug Administration (May 2018) and the European Medicines Agency (July 2018). Erenumab exists in two different doses (70?mg and 140?mg) and it is administered with monthly subcutaneous injections. This review summarises erenumab pharmacological characteristics, clinical trials data, focusing on the potential role of this treatment in clinical practice.
Project description:BACKGROUND:Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP. METHODS:Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark. RESULTS:Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p?=?0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0-90 min (p?=?0.009), and 2-12 h (p?=?0.014). The median peak headache intensity score was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p?=?0.004). CONCLUSIONS:Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy. TRIAL REGISTRATION:Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400 .
Project description:Migraine is a highly disabling neurological condition, and preventative treatment still remains problematic, due to aspecificity of the majority of the currently available prophylactic drugs. Calcitonin-gene-related peptide (CGRP) plays a crucial role in migraine pathophysiology; agents aimed at blocking its activity have, therefore, been developed in recent years, among which are monoclonal antibodies (mAbs) against CGRP, to prevent migraine. Erenumab is the only mAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. This review will report on the most recent data on erenumab characteristics and on the results of clinical trials on its employment in the prevention of episodic migraine (4-14 monthly migraine days): one Phase II and two Phase III trials (completed) and one Phase III trial (ongoing). Monthly subcutaneous administration (70 mg or 140 mg) of erenumab vs placebo for 3-6 months showed significantly higher efficacy in reducing the mean monthly number of migraine days and the use of migraine-specific medication, and in decreasing physical impairment and impact of migraine on everyday activities (P<0.001). A favorable safety profile was demonstrated by the lack of significant differences in the occurrence of adverse events in erenumab-treated vs placebo-treated patients. Global results so far obtained point to erenumab as a new promising candidate for the preventative treatment of episodic migraine. Licence applications for erenumab were recently submitted to the Food and Drug Administration in the USA and European Medicines Agency in Europe (May/June 2017).
Project description:BACKGROUND:Monoclonal antibodies (mAbs) targeting the CGRP pathway are safe and efficacious therapies for the prevention of migraine. In this study we assessed the effects of discontinuation of preventive erenumab and galcanezumab treatment in patients with chronic migraine. METHODS:This retrospective pooled analysis included completers of the open-label extension study phase for the preventive treatment of chronic migraine with galcanezumab (NCT02614261; 9?months) and erenumab (NCT02174861; 12?months) in a single headache center. We compare migraine data until week 12 after open-label treatment completion, when patients did not have any pharmacological preventive medication, to study baseline values of the double-blind trial period, and to the last 4?weeks of the open-label extension. The assessment included changes in monthly migraine days, headache hours, days with severe headache and acute headache medication use. RESULTS:Data from 16 patients after galcanezumab (n =?9) and erenumab (n =?7) open-label treatment completion were analyzed. The mean number of monthly migraine days was 18.38?±?3.74 at baseline, and 12.19?±?4.53 in the last 4?weeks of the open-label extension (p <?0.001). Monthly migraine days remained significantly reduced compared to baseline during the entire 12-week observation period after open-label termination (p =?0.002), with a reduction of 5.38?±?4.92 in weeks 1-4 (p =?0.001), 4.75?±?4.15 in weeks 5-8 (p =?0.001), and 3.93?±?5.45 in weeks 9-12 (p =?0.014). There was no significant difference in monthly migraine days between the 12?weeks after open-label termination and the last 4?weeks of the open-label phase (p =?0.228). All other analyses revealed numerical improvement through week 12 in comparison to baseline. CONCLUSIONS:In this small, self-selected cohort, the results indicate a therapeutic effect of monoclonal antibodies targeting the CRGP pathway in chronic migraine prevention after treatment termination up to 12?weeks.
Project description:OBJECTIVE:To examine the cardiovascular, cerebrovascular, and peripheral vascular safety of erenumab across migraine prevention studies. METHODS:Vascular adverse events (AEs) and blood pressure data were integrated across 4 double-blind, placebo-controlled studies of erenumab and their open-label extensions in patients with chronic or episodic migraine. Subgroup analyses were conducted by acute migraine-specific medication use and number of vascular risk factors at baseline. Standardized search terms were used to identify vascular AEs (cardiovascular, cerebrovascular, or peripheral). An independent committee adjudicated whether targeted events were vascular in origin. RESULTS:In placebo-controlled studies, 2,443 patients received placebo (n = 1,043), erenumab 70 mg (n = 893), or erenumab 140 mg (n = 507) subcutaneously once monthly. Regardless of acute migraine-specific medication use or vascular risk factors at baseline, AE incidence was similar across the placebo and erenumab treatment groups. Hypertension AEs were reported for 0.9% (placebo), 0.8% (erenumab 70 mg), and 0.2% (erenumab 140 mg) of patients. Vascular AEs, which were similar across double-blind and open-label treatment, generally were confounded, with plausible alternative etiologies. In 18 patients with events reviewed by the independent committee, 4 events were positively adjudicated as cardiovascular in origin: 2 deaths and 2 vascular events. All 4 positively adjudicated cardiovascular events occurred during open-label erenumab treatment. CONCLUSION:Selective blockade of the canonical calcitonin gene-related peptide receptor with erenumab for migraine prevention had a vascular safety profile comparable to that of placebo over 12 weeks, with no increased emergence of events over time. Further study of long-term safety of erenumab in patients with migraine is needed. CLINICALTRIALSGOV IDENTIFIERS:NCT02066415, NCT02456740, NCT01952574, NCT02483585, NCT02174861, and NCT01723514. CLASSIFICATION OF EVIDENCE:This analysis provides Class II evidence that for patients with migraine, erenumab does not increase the risk of vascular AEs.
Project description:OBJECTIVE:A phase 2, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab for the prevention of episodic migraine in Japanese patients was conducted. BACKGROUND:Previous global clinical studies have demonstrated the efficacy of erenumab in the prevention of migraine. METHODS:Patients were randomized to placebo or erenumab 28, 70, or 140 mg administered subcutaneously once per month for 6 months. The primary endpoint was change from baseline in mean monthly migraine days over months 4-6 of the double-blind treatment phase. Secondary endpoints included the proportion of patients achieving ?50% reduction from baseline in mean monthly migraine days (?50% response) and change from baseline in mean monthly acute migraine-specific medication treatment days (MSMD) and mean Headache Impact Test (HIT-6™) scores. Efficacy outcomes were also determined at months 1, 2, and 3. RESULTS:Four hundred and seventy five patients were randomized 2:1:2:2 to placebo and erenumab 28, 70, and 140 mg, respectively. Greater reductions in monthly migraine days were observed for erenumab vs placebo with differences of -1.25 (95% CI: -2.10 to -0.41; P = .004), -2.31 (95% CI: -3.00 to -1.62; P < .001), and -1.89 (95% CI: -2.58 to -1.20; P < .001) days for erenumab 28, 70, and 140 mg. The odds of having a ?50% response were 3.2, 5.6, and 4.7 times greater for erenumab 28 mg (95% CI: 1.30-7.88; P = .009), 70 mg (95% CI: 2.60-12.06; P < .001), and 140 mg (95% CI: 2.24-9.99; P < .001) than for placebo. Greater reductions from baseline in mean acute monthly MSMD were observed for erenumab vs placebo with differences of -1.07 (95% CI: -1.80 to -0.35; P = .004), -2.07 (95% CI: -2.66 to -1.49; P < .001), and -2.04 (95% CI: -2.63 to -1.45; P < .001) days for erenumab 28, 70, and 140 mg. Erenumab 70 and 140 mg also resulted in greater improvements in HIT-6™ scores. The safety profile was similar across treatment groups. The most common adverse event was nasopharyngitis, which occurred in 29.4% of patients in the placebo group and 28.9%-33.3% of patients in the erenumab groups. CONCLUSION:Monthly subcutaneous injections of erenumab 70 mg demonstrated statistically significant and numerically maximal efficacy with a favorable safety profile, suggesting that erenumab is a potential new therapy for migraine prevention in Japan.
Project description:BACKGROUND:We performed a post hoc, subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled study of erenumab for prevention of episodic migraine (STRIVE) to determine the efficacy and safety of erenumab in women with self-reported menstrual migraine. METHODS:Patients received placebo, erenumab 70?mg, or erenumab 140?mg subcutaneously once monthly during the 6-month double-blind treatment phase of STRIVE. Women who reported history of menstrual migraine and who were???50?years old were included in the analysis. Endpoints were change from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD; among patients who took acute migraine-specific medications at baseline), proportion of patients achieving ? 50% reduction from baseline in MMD, and incidence of adverse events. RESULTS:Among 814 women enrolled in STRIVE, 232 (28.5%) reported a history of menstrual migraine and were???50?years old. Of the 232 patients, 214 (92%) had a baseline MMD?>?5, suggesting a high proportion of women with attacks outside of the 5-day perimenstrual window (2?days before and 3?days after the start of menstruation). Information on "migraine days" includes (and does not discriminate between) perimenstrual and intermenstrual migraine attacks. Between-group differences from placebo over months 4-6 for erenumab 70?mg and 140?mg were?-?1.8 (P?=?0.001) and?-?2.1 (P?<?0.001) days for MMD and?-?1.6 (P?=?0.002) and?-?2.4 (P?<?0.001) days for acute MSMD, respectively. The odds of having a???50% reduction from baseline in MMD over months 4-6 were 2.2 (P?=?0.024) and 2.8 (P?=?0.002) times greater for erenumab 70?mg and 140?mg, respectively, than for placebo. Erenumab had an overall safety profile comparable to placebo. CONCLUSION:Data from this subgroup analysis of women with menstrual migraine are consistent with data from the overall STRIVE episodic migraine population, supporting the efficacy and safety of erenumab in women who experience menstrual migraine. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02456740. Registered 28 May 2015.
Project description:BACKGROUND:We aimed to assess the efficacy and safety of erenumab, a fully human monoclonal antibody inhibiting the calcitonin gene-related peptide receptor (CGRPr), for the prevention of migraine in a real-life setting. MAIN BODY:We included in our observational study all patients with episodic or chronic migraine treated with erenumab during the year 2019 in the Abruzzo region, central Italy, and with a 6-month follow-up. We included 89 patients; 76 (85.4%) received 6 doses of erenumab, 11 (12.4%) autonomously withdrew the drug due to perceived inefficacy, and 2 (2.2%) due to adverse events. Seventy-eight patients (87.6%) were female, with a mean age of 46.8?±?11.2?years; 84 (94.4%) had chronic migraine, and 64 (71.9%) medication overuse. All patients had ?2 prior preventive treatment failures. Fifty-three patients (69.7%) had a 50% decrease in monthly migraine days (MMDs) within the first three doses; 46 (71.9%) of 64 patients withdrew medication overuse. In the 76 patients who completed a 6-dose treatment, erenumab decreased median MMDs from 19 (interquartile range [IQR] 12-27.5) to 4 (IQR 2-9.5; P?<?0.001), median monthly days of analgesic use from 10 (IQR 4.5-20) to 2 IQR 0-5; P?<?0.001), and median monthly days of triptan use from 5 (IQR 0-15.5) to 1 (IQR 0-4; P?<?0.001). We recorded 27 adverse events in 20 (22.5%) patients, the most common being constipation (13.5%). One adverse event, i.e. allergic reaction, led to treatment discontinuation in one patient. CONCLUSIONS:Our real-life data confirm the efficacy and tolerability of erenumab for the prevention of migraine in a difficult-to-treat population of patients with a high prevalence of chronic migraine and medication overuse.
Project description:OBJECTIVE:To provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine. METHODS:Case reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol. RESULTS:Patients were women 44 and 36 years of age with ?2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events. CONCLUSIONS:Rimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study. CLINICALTRIALSGOV IDENTIFIER:NCT03266588. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.
Project description:BACKGROUND:Erenumab is a human anti-calcitonin gene-related peptide monoclonal antibody developed for migraine prevention. Migraine predominately affects women of childbearing age; thus, it is important to determine potential drug-drug interactions between a common oral contraceptive and drugs used to treat migraine. OBJECTIVES:We sought to evaluate potential drug-drug interactions between erenumab and a common oral contraceptive. METHODS:Healthy women received three cycles of a norgestimate/ethinyl estradiol-containing oral contraceptive with a single 140-mg subcutaneous dose of erenumab during cycle three. Norgestimate metabolites (norgestrel and norelgestromin) and ethinyl estradiol pharmacokinetics were evaluated in the absence and presence of erenumab. Primary endpoint was peak plasma concentration (Cmax) and area under concentration-time curve from time 0 to 24 h (AUCtau). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were evaluated as pharmacodynamic markers. RESULTS:Erenumab did not influence the pharmacokinetics of norelgestromin, norgestrel, or ethinyl estradiol. Least-squares mean estimates (90% confidence interval) for Cmax ratios were 1.05 (0.90-1.23), 1.06 (0.97-1.16), and 1.04 (0.88-1.22) for norelgestromin, norgestrel, and ethinyl estradiol, respectively. Respective AUCtau ratios were 1.02 (0.94-1.12), 1.03 (0.96-1.10), and 1.02 (0.91-1.14). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were similar after exposure to oral contraceptive alone and with erenumab. CONCLUSION:Erenumab did not alter the pharmacokinetics of the active components of an estrogen/progestin combination oral contraceptive. Thus, no change in contraceptive efficacy is expected with erenumab. TRIAL REGISTRATION:ClinicalTrials.gov NCT02792517.