Inpatient Constipation Among Migraine Patients Prescribed Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies and Standard of Care Antiepileptic Drugs: A Retrospective Cohort Study in a United States Electronic Health Record Database.

INTRODUCTION: Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody (mAb), was approved by the US Food and Drug Administration in May 2018. Constipation with serious complications was added to the Warning and Precautions section in the erenumab Prescribing Information in October 2019 after events were observed during post-marketing surveillance. We aimed to assess and compare the risk of inpatient constipation, and, separately, inpatient constipation with serious complications, among patients with migraine treated with CGRP mAbs and standard of care antiepileptic drugs (AEDs). METHODS: Within Optum's Electronic Health Record Research Database, patients with migraine who initiated erenumab, other CGRP mAbs, and AEDs were identified from May 2018 through March 2020. Erenumab initiators were propensity score-matched separately to initiators of other CGRP mAbs and AEDs. Incident inpatient constipation events, and serious complications, were identified using multiple risk windows for outcome assessment (30-, 60-, 90-day risk windows, and all available follow-up). Odds ratios (ORs) were calculated comparing inpatient constipation risk among matched erenumab initiators relative to comparators. RESULTS: We identified 17,902 erenumab, 13,404 other CGRP mAb, and 49,497 AED initiators who met study criteria. Among matched initiators, the risk of inpatient constipation was 0.46% (95% confidence interval (CI) 0.35-0.60) for erenumab and 0.44% (95% CI 0.33-0.58) for other CGRP mAbs within the 90-day risk window, with a corresponding OR of 1.06 (95% CI 0.72-1.55). Among matched erenumab and AED initiators, inpatient constipation risk was 0.53% (95% CI 0.42-0.66) and 0.76% (95% CI 0.62-0.92), respectively, and the OR was 0.69 (95% CI 0.51-0.94). Few serious complications were observed. CONCLUSION: Patients initiating erenumab had similar risk of inpatient constipation within 90 days of treatment initiation versus patients initiating other CGRP mAbs, and lower risk versus patients initiating AEDs. These findings provide context to events observed during post-marketing surveillance.

Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials.

BACKGROUND: Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations. METHODS: Pooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups < 40 years, 40-49 years, 50-59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation. RESULTS: Overall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively. Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40-49 years, 42.5% vs 49.2%; 50-59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40-49 years, 1.7% vs 1.9%; and 50-59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported. CONCLUSIONS: Erenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifiers: NCT02066415, NCT02456740, NCT02483585, NCT03096834, NCT03333109.

Immunogenicity of erenumab: A pooled analysis of six placebo-controlled trials with long-term extensions.

BACKGROUND: Immunogenicity of erenumab, a human anti-calcitonin gene-related peptide receptor monoclonal antibody developed for migraine prevention, has been evaluated throughout clinical development. METHODS: Integrated post hoc analysis assessing immunogenicity of erenumab across six clinical trials in patients with episodic and chronic migraine (N = 2985). Anti-erenumab antibody incidence and potential impact on pharmacokinetics, efficacy, and safety were evaluated in short-term (double-blind treatment phase 12-24 weeks) and long-term (double-blind treatment phase plus extensions of up to 5 years) analyses. RESULTS: Anti-erenumab binding antibody incidence was low with few patients developing neutralizing antibodies. Antibody responses were mostly transient with low magnitude. Binding antibodies developed as early as 2-4 weeks after the first dose; the majority developed within the first 6 months and very few after the first year. Serum concentrations of erenumab in antibody-positive patients were generally lower than, but within the range of, antibody-negative patients. There was no impact of anti-erenumab antibodies on erenumab efficacy or safety with no differences between antibody-positive and antibody-negative patients in change in monthly migraine days or adverse event rates. CONCLUSIONS: This pooled analysis showed that immunogenicity had no meaningful clinical impact on efficacy or safety of erenumab in patients with migraine.Clinical Trial Registration: ClinicalTrials.gov, NCT01952574; ClinicalTrials.gov, NCT02456740; Clinicaltrials.gov NCT02483585; Clinicaltrials.gov, NCT02174861; Clinicaltrials.gov, NCT02630459; Clinicaltrials.gov, NCT03812224.

Risk of hypertension in erenumab-treated patients with migraine: Analyses of clinical trial and postmarketing data.

OBJECTIVE: To assess the risk of hypertension in patients with migraine who received erenumab in clinical trials and in the postmarketing setting. BACKGROUND: Erenumab is a monoclonal antibody for migraine prevention that targets the calcitonin gene-related peptide (CGRP) receptor. Hypertension is a theoretical risk for inhibitors of the CGRP pathway. Although no evidence of an association between erenumab treatment and hypertension was observed during the clinical development program, adverse events (AEs) of hypertension have been identified in the postmarketing setting. METHODS: Safety data from four phase 2 and phase 3 clinical trials were used to perform a pooled analysis of hypertension AEs in patients with migraine receiving erenumab. Postmarketing AEs of hypertension were identified from the Amgen Global Safety database from May 17, 2018, through January 31, 2020. RESULTS: In the pooled analysis of clinical trials, hypertension AEs (placebo, 9/1043 [0.9%]; erenumab 70 mg, 7/893 [0.8%]; erenumab 140 mg, 1/507 [0.2%]) and percentage of patients initiating medication to treat hypertension (12/1043 [1.2%], 7/893 [0.8%], 1/507 [0.2%], respectively) were similar across treatment groups. A total of 362 AEs of hypertension were identified from the postmarketing setting, 26.2% (95/362) of which were serious, >245,000 patient-years of exposure. The exposure-adjusted incidence of hypertension was 0.144 per 100 patient-years. CONCLUSIONS: Clinical trials did not demonstrate an increased risk of hypertension with erenumab compared with placebo, and AE rates of hypertension reported with erenumab in the postmarketing setting were generally low. Additional data are needed to fully characterize the extent to which hypertension is a risk associated with erenumab.

Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database.

BACKGROUND: We estimated the incidence and prevalence of diagnosed cataracts among patients with cystic fibrosis (CF) versus the general population (GP). METHODS: Using a large US health insurance claims database, we identified a CF cohort and a GP cohort matched with respect to age, gender, and calendar year. The prevalence and incidence of diagnosed cataract (primary outcome) for both cohorts were calculated, as well as the incidence rate ratios (IRRs). RESULTS: The prevalence of diagnosed cataracts among patients with CF alive and enrolled in the health plan on August 31, 2012 was 4.8% versus 2.8% in the GP. The incidence in the CF cohort was higher than in the GP and increased with age in both cohorts. The adjusted IRR comparing the CF and GP cohorts was 1.5 (95% CI: 1.2-1.8). CONCLUSIONS: The study suggests that the risk of developing cataract was higher among patients with CF than among the GP.