Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Read More →

Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide whose involvement in migraine pathophysiology is well established. Originally migraine was believed to be a disease of the vasculature, but research has highlighted this to be a disease of the brain with CGRP playing an important role. While targeting CGRP using small molecule antagonists against the receptor has been effective, long-term use of these agents has not been possible due to safety concerns and/or formulation challenges.Read More →

In The Lancet Neurology, David Dodick and colleagues1 report an important study of treatment in migraine prophylaxis: parenteral administration of LY2951742, a monoclonal antibody to calcitonin gene-related peptide (CGRP). Mean decrease from baseline in migraine days in 4 weeks was higher in patients given LY2951742 (4·2) than in those given placebo (3·0; p=0·003).1 Results of other trials that use antibodies against CGRP will probably be published soon.Read More →

Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. Read More →

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.Read More →

In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3–14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥1 associated symptom). The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥1 dose of study medication, and 14 had completed the trial. Read More →

In The Lancet Neurology, David Dodick and colleagues1 introduce monoclonal antibodies into the specialty of primary headache therapy. They report findings from a randomised, placebo-controlled, double-blind, phase 2 clinical trial of LY2951742, a neutralising humanised monoclonal antibody against calcitonin gene-related peptide (CGRP), for migraine prevention. The subcutaneous administration of LY2951742 once every 2 weeks reduced the mean number of migraine headache days per 28-day period between baseline and weeks 9–12 (primary endpoint; least-squares mean difference −1·2, 90% CI −1·9 to −0·6; p=0·0030) in a population with a high frequency of migraine; the antibody was also superior to placebo in several secondary endpoints after 12 weeks of treatment.Read More →