TY - JOUR

T1 - Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine

T2 - a randomised, double-blind, placebo-controlled, exploratory phase 2 trial

AU - Dodick, David W

AU - Goadsby, Peter J

AU - Silberstein, Stephen D

AU - Lipton, Richard B

AU - Olesen, Jes

AU - Ashina, Messoud

AU - Wilks, Kerri

AU - Kudrow, David

AU - Kroll, Robin

AU - Kohrman, Bruce

AU - Bargar, Robert

AU - Hirman, Joe

AU - Smith, Jeff

AU - ALD403 study investigators

N1 - Copyright © 2014 Elsevier Ltd. All rights reserved.

PY - 2014/11

Y1 - 2014/11

N2 - BACKGROUND: Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention.METHODS: In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18-55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5-8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, NCT01772524.FINDINGS: Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 [7%] patients vs ALD403 7 [9%] patients), urinary tract infection (4 [5%] vs 1 [1%]), fatigue (3 [4%] vs 3 [4%]), back pain (4 [5%] vs 3 [4%]), arthralgia (4 [5%] vs 1 [1%]), and nausea and vomiting (2 [2%] vs 3 [4%]). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5-8 was -5·6 (SD 3·0) for the ALD403 group compared with -4·6 (3·6) for the placebo group (difference -1·0, 95% CI -2·0 to 0·1; one-sided p=0·0306).INTERPRETATION: No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days.FUNDING: Alder Biopharmaceuticals.

AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention.METHODS: In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18-55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5-8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, NCT01772524.FINDINGS: Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 [7%] patients vs ALD403 7 [9%] patients), urinary tract infection (4 [5%] vs 1 [1%]), fatigue (3 [4%] vs 3 [4%]), back pain (4 [5%] vs 3 [4%]), arthralgia (4 [5%] vs 1 [1%]), and nausea and vomiting (2 [2%] vs 3 [4%]). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5-8 was -5·6 (SD 3·0) for the ALD403 group compared with -4·6 (3·6) for the placebo group (difference -1·0, 95% CI -2·0 to 0·1; one-sided p=0·0306).INTERPRETATION: No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days.FUNDING: Alder Biopharmaceuticals.

KW - Adult

KW - Antibodies, Monoclonal

KW - Calcitonin Gene-Related Peptide

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Female

KW - Humans

KW - Infusions, Intravenous

KW - Male

KW - Middle Aged

KW - Migraine Disorders

KW - Protein Engineering

KW - Respiratory Tract Infections

KW - Time Factors

KW - Treatment Outcome

KW - Urinary Tract Infections

U2 - 10.1016/S1474-4422(14)70209-1

DO - 10.1016/S1474-4422(14)70209-1

M3 - Journal article

C2 - 25297013

VL - 13

SP - 1100

EP - 1107

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 11

ER -