Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial

Abstract

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.

Migraine Care in the Era of COVID‐19: Clinical Pearls and Plea to Insurers

“…Thus, we urge providers to first consult the American Academy of Neurology/American Headache Society Guidelines (last published in 2012 45 ; new ones are currently being produced) and to re‐evaluate patients' responses to the medications listed in those guidelines. In addition, therapies which have been demonstrated to be beneficial since the development of that guideline include: CGRP and CGRP receptor antagonist monoclonal antibodies (mAbs) : In the past 2 years, mAbs against CGRP or the CGRP receptor have been FDA approved for preventive treatment of both episodic and chronic migraine – erenumab‐aooe, 46‐48 galcanezumab‐gnlm, 49‐51 fremanezumab‐vfrm, 52,53 and eptinezumab‐jjmr 54,55 . The first 3 are intended for self‐injection at home, with detailed instructions available for each product on its website. Angiotensin‐converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) : Candesartan 56,57 now has evidence of efficacy and good tolerability in migraine prevention, 58,59 and lisinopril 56,60 was considered “possibly effective” in the 2015 guideline.…”

Population pharmacokinetic and exposure‐response analysis of eptinezumab in the treatment of episodic and chronic migraine

“…Renal function was normal in 55.3% of patients/subjects, with mild or moderate decreases in estimated glomerular filtration rate (eGFR) in 41.9% and 2.7% of patients/subjects, respectively. The average MMD during the screening period of studies CLIN‐005, CLIN‐006, and CLIN‐011 was approximately 14 days (CLIN‐005, 16.5 MMD; CLIN‐006, 8.7 MMD; CLIN‐011, 16.1 MMD).…”

“…PK parameters from the final population PK model were used to derive exposure metrics: area under the curve from time 0 to 12 weeks (AUC 0‐12wk ), maximum concentration ( C max ), average concentration ( C avg ), and trough concentration ( C trough ). The exposure‐response relationship of plasma eptinezumab was evaluated using these single‐dose exposure parameters and the change in frequency of MMD (weeks 1‐12) from studies CLIN‐005, CLIN‐006, and CLIN‐011 . A saturable inhibitory maximum‐effect ( E max ) model was used to assess relationships between the exposure metrics of eptinezumab and the reduction in MMD.…”

“…Eptinezumab (ALD403) is a humanized anti‐CGRP antibody with an IgG1 backbone that binds to both the α and β forms of CGRP and is currently under development for migraine prevention. In controlled clinical studies, it has demonstrated efficacy compared to placebo in the prevention of migraine in patients with episodic migraine (EM) and chronic migraine (CM) . This report describes a population PK modeling analysis conducted for the IV administration of eptinezumab at single doses of 10‐1000 mg in healthy subjects and in patients with EM and CM from eight studies in the eptinezumab clinical program .…”

“…In controlled clinical studies, it has demonstrated efficacy compared to placebo in the prevention of migraine in patients with episodic migraine (EM) and chronic migraine (CM) . This report describes a population PK modeling analysis conducted for the IV administration of eptinezumab at single doses of 10‐1000 mg in healthy subjects and in patients with EM and CM from eight studies in the eptinezumab clinical program . A further goal was to assess the dose‐ and exposure‐response relationships of selected endpoints in patients with EM and CM who received eptinezumab.…”