Risk of Hypertension in Erenumab-treated Patients With Migraine

Analyses of Clinical Trial and Postmarketing Data

David W. Dodick MD; Stewart J. Tepper MD; Jessica Ailani MD; Nicola Pannacciulli MD, PhD; Marco S. Navetta MD; Brett Loop MPH; Feng Zhang MS; Ani C. Khodavirdi PhD; Allison Mann MD; Ahmad Abdrabboh PharmD, MPH; Jawed Kalim MD, MSc

Disclosures

Headache. 2021;61(9):1411-1420. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Hypertension is a common condition characterized by higher-than-normal blood pressure (BP; systolic and diastolic BP ≥140/90 mm Hg) and is associated with increased risk of cardiovascular disease.[1] The estimated prevalence of hypertension in the United States between 2011 and 2014 was 46%, based on the American College of Cardiology/American Heart Association thresholds, and 32%, based on Joint National Committee thresholds, and prevalence increases with age.[2] At least two BP measurements obtained on at least two occasions should be used to confirm a diagnosis of hypertension.[2] Hypertension is more commonly reported in patients with migraine than in migraine-free individuals (33.1% vs. 27.5%, odds ratio 1.4, 95% confidence interval [CI] 1.3–1.6).[3] Because calcitonin gene-related peptide (CGRP) can mediate vasodilation, migraine therapies targeting the CGRP pathway could potentially have cardiovascular effects.[4]

Erenumab (in the United States, erenumab-aooe), an anti-CGRP receptor monoclonal antibody, was approved in the United States in May 2018 for the preventive treatment of migraine in adults.[5] Because of the theoretical risk of cardiovascular effects described above, a number of preclinical and clinical studies were performed to evaluate the cardiovascular safety profile of erenumab. Preclinical data demonstrated that supratherapeutic concentrations of erenumab affected neither the vascular tone of isolated human coronary arteries nor the vasoconstrictive effects of sumatriptan when applied in combination.[6] In telemeterized cynomolgus monkeys, no biologically significant changes in systolic, diastolic, or mean arterial pressures were observed with a single dose of erenumab at 225 mg/kg (yielding a systemic exposure 150 times higher than that in humans at the 140 mg dose level).[6]

Clinical studies of erenumab designed to evaluate the theoretical risk of cardiovascular effects did not demonstrate evidence of an association between erenumab treatment and vascular events.[7] The effect of erenumab in combination with sumatriptan on resting BP was evaluated in a phase 1, randomized, parallel-group, double-blind, placebo-controlled trial performed in healthy participants.[8] No differences were observed in time-weighted averages of mean arterial pressure between intravenous erenumab plus sumatriptan versus sumatriptan plus placebo. Additionally, a post hoc analysis demonstrated that erenumab alone did not affect resting BP. The effect of erenumab on ambulatory BP was evaluated in a phase 1, randomized, double-blind, placebo-controlled, multiple ascending dose study of healthy participants and patients with migraine.[9] Ambulatory BP was evaluated by outpatient, 24-h, continuous BP monitoring 7 days after erenumab or placebo administration, and no statistically significant differences were observed in BP parameters in healthy participants between erenumab (21, 70, 140, or 280/210 mg subcutaneous) and placebo groups.[9] The mean and nocturnal systolic BP were significantly higher with erenumab 21 mg compared with placebo at day 36 (difference from placebo 6.65 and 7.47 mm Hg, respectively; p < 0.05 for both) in patients with migraine; however, these differences may have been an artifact because no statistical differences were observed at the higher dose levels (70, 140, or 280/210 mg) or at other time points.[9] A phase 2, randomized, double-blind, placebo-controlled treadmill study further evaluated the effect of erenumab on potential cardiovascular effects in patients with stable angina.[10] The change from baseline in total exercise time for the erenumab 140 mg intravenous group was noninferior to placebo after 12 weeks of treatment, and there was no difference in peak systolic or diastolic BP between erenumab and placebo groups during an exercise treadmill test. Changes from baseline in systolic and diastolic BP were similar for erenumab and placebo groups at all time points evaluated (4, 8, and 12 weeks), and all were <1.5 mm Hg in magnitude. In phase 2 and 3 placebo-controlled trials, subcutaneous injections of erenumab had no effect on BP or rate of hypertension adverse events (AEs), respectively.[11,12]

AEs of elevated BP or hypertension have been reported following the use of erenumab in the postmarketing setting, and an analysis of postmarketing reports of hypertension AEs following treatment with erenumab was recently published by Saely and colleagues from the US Food and Drug Administration (FDA).[13] In April 2020, the US Prescribing Information for erenumab was updated to include the risk of hypertension based on postmarketing experience.[5,13]

Given the findings described above, it is important to provide a comprehensive review of the risk of hypertension with erenumab. To provide a holistic assessment of the risk of hypertension among patients with migraine receiving erenumab, the present analysis provided a consolidated evaluation of both clinical trial data, by expanding on the work done by Kudrow et al.[7] (focused only on the 12-week, double-blind treatment phase [DBTP] of four published phase 2[12,14] and 3[11,15] studies) and data from the postmarketing setting.

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