Evaluation of Cardiovascular Outcomes in Adult Patients With Episodic or Chronic Migraine Treated With Galcanezumab: Data From Three Phase 3, Randomized, Double‐Blind, Placebo‐Controlled EVOLVE‐1, EVOLVE‐2, and REGAIN Studies

Abstract

ObjectiveBlood pressure (BP), pulse, electrocardiogram (ECG), and clinical cardiovascular (CV) outcomes in patients with episodic or chronic migraine treated for up to 6 months with galcanezumab compared to placebo were evaluated.BackgroundCalcitonin gene‐related peptide, a potent microvascular vasodilator, has a hypothesized protective role in CV health. Increased CV risks have been reported in patients with migraine.MethodsIn 2 similarly designed episodic migraine 6‐month studies and 1 chronic migraine 3‐month study, data from patients randomized (1:1:2) to subcutaneous injection of galcanezumab 120 mg/month (following initial 240 mg loading dose) or 240 mg/month or placebo were pooled. Treatment comparisons for cardiovascular treatment‐emergent adverse events (CV TEAE) and categorical and mean changes in BP, pulse, and ECG were evaluated using the Cochran‐Mantel‐Haenszel test. Mean changes from baseline in BP, pulse, and ECG were evaluated using the analysis of covariance model.ResultsOverall, among galcanezumab 120 mg (n = 705) and 240 mg (n = 730), and placebo (n = 1451) groups, the percentage of patients reporting ≥1 CV TEAE was low and was similar between the galcanezumab 120 mg (2.6%; odds ratio [OR] = 0.9; 95% confidence interval [CI]: 0.5,1.5) and galcanezumab 240 mg (3.3%; OR = 1.1; 95% CI: 0.7,1.9), and placebo (2.9%) groups. The frequency of any individual CV TEAE, broad or narrow term, was ≤1.4%. The CV‐related serious adverse events that occurred in the galcanezumab 240 mg group (n = 3; acute myocardial infarction, pulmonary embolism, and transient ischemic attack) and placebo group (n = 3; pulmonary embolism, deep vein thrombosis, and myocardial infarction) were not considered treatment related. Four placebo‐ and 1 galcanezumab‐treated patient discontinued due to a CV TEAE. Least squares mean and categorical changes from baseline in BP, pulse, and QT interval corrected using Fridericia’s correction were similar across treatment groups.ConclusionsIn this 6‐month treatment trial, the percentages of galcanezumab‐ and placebo‐treated patients that reported CV TEAEs or serious adverse events were low and similar between groups with few discontinuations. Thus, no clinically meaningful treatment group differences were observed for changes in BP, pulse, or ECG parameters. Additional longer‐term studies in a broader and larger cohort are required to better characterize CV safety.

Relationship of the Calcitonin Gene‐Related Peptide Monoclonal Antibody Galcanezumab Pharmacokinetics and Capsaicin‐Induced Dermal Blood Flow in Healthy Subjects

“…Other studies employing galcanezumab, erenumab, or the small‐molecule CGRP antagonists olcegepant and telcagepant likewise showed no effect on resting blood flow 28,45–47 . Consistent with this, galcanezumab did not produce clinically meaningful changes in blood pressure or pulse rate in phase 3 clinical trials 48 …”

“…28,[45][46][47] Consistent with this, galcanezumab did not produce clinically meaningful changes in blood pressure or pulse rate in phase 3 clinical trials. 48 Based on the use of changes from baseline in vehicle-and capsaicin-induced DBF as measured by LDI as the biomarker representative of PD response, the PK/PD model described here provides evidence for exposure-dependent CGRP binding and neutralization. As shown in Figures S5 and S6, simulations of 150 mg galcanezumab every 2 weeks (75 mg/wk) for 14 weeks are predicted to result in median concentrations well above the estimated IC 50 for more than 30 weeks and a near-maximal response in change from baseline CIDBF.…”

The evolving understanding of risk with calcitonin gene‐related peptide monoclonal antibodies based on real‐world data: A focus on hypertension and Raynaud phenomenon

“…Elevated BP was defined as “initiation of a medication or emergency department visit or hospitalization for emergent de novo or worsening of preexisting hypertension, or BP measurement of ≥140 mm Hg systolic or ≥90 mm Hg diastolic.” 6 Elevated BP was most frequent within a week of the first dose of erenumab (28/61, 46.0%). Pooled analysis of vascular adverse events and BP data from clinical trials for fremanezumab and galcanezumab, like with erenumab, showed low vascular adverse event incidence that was similar across the placebo and treatment groups 7,8 . However, unlike erenumab, postmarketing pharmacovigilance for vascular adverse events associated with these other CGRP mAbs is yet to demonstrate a safety signal, although continued surveillance is required.…”

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

“…The population pharmacokinetic analysis, which included galcanezumab doses from 5 mg to 300 mg, absorption rate, apparent clearance, and apparent volume of distribution, was independent of the dose. No pharmacokinetic drug interactions are expected [98,[100][101][102][103][104]106,107].…”