Abstract & Commentary
Targeting Calcitonin Gene-Related Peptide in Attempts to Prevent Migraine Headaches
By Dara Jamieson, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Jamieson reports no financial relationships relevant to this field of study.
Blockade of the vasoactive peptide calcitonin gene-related peptide, using monoclonal antibodies or small orally absorbed molecules, may decrease the disability of episodic migraine. However, safety concerns with these agents remain an issue.
Dodick DW, et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: A phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014;13:885-892.
Ho TW, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 2014;83:958-966.
Patients with migraine headaches that are frequent, disabling, or refractory to acute treatment should be offered a treatment to decrease the frequency and severity. However, there are few effective preventive medications available. New migraine-specific targets, such as calcitonin gene-related peptide (CGRP), are being investigated to improve preventive efficacy. This study from Dodick et al assessed the efficacy and safety of LY2951742, a fully humanised monoclonal antibody to CGRP, in migraine prevention in men and women, aged 18-65 years, with at least a 1-year history of migraine, according to the International Classification of Headache Disorders (ICHD-II). The migraineurs had between four and 14 migraine headache days per month, which is defined as frequent episodic migraine, but the patients did not have chronic migraine. In a Phase 2 proof-of-concept study performed at 35 centers in the United States, patients who were not on any preventive medication were randomized to LY2951742 (150 mg) or placebo. LY2951742 (n = 108) or placebo (n = 110) was injected subcutaneously by masked trained site personnel once every 2 weeks for 12 weeks. Primary endpoint responders were defined as patients who had a > 50% reduction in the number of migraine headache days in a 28-day period. Safety was assessed over 24 weeks, including the 12-week treatment period and the subsequent 12 weeks after study drug administration. Efficacy analyses were performed by an intention-to-treat, mixed-effects model of repeated measures. Safety measures were analyzed according to the treatment received. The mean change from baseline to week 12 in the number of migraine headache days was -4.2 (SD = 3.1; 62.5% decrease) in the LY2951742 group compared with -3.0 (SD = 3.0; 42.3% decrease) in the placebo group (least-squares mean difference -1.2, 90% CI -1.9 to -0.6; P = 0.0030). Adverse events that occurred more frequently with LY2951742 than with placebo included injection site pain, erythema, or both (21 [20%] of 107 vs 7 [6%] of 110), upper respiratory tract infections (18 [17%] vs 10 [9%]), and abdominal pain (6 [6%] vs 3 [3%]). None of the rare serious adverse events was deemed to be related to the study drug. There were no clinically important changes in laboratory parameters, ECGs, or vital signs between the groups. LY2951742, a well-tolerated parenteral preventive medication, was better than placebo for all secondary efficacy endpoints: monthly migraine attacks, migraine headache days and probable migraine headache days, total headache days, and responder rate. These encouraging results provide preliminary evidence that LY2951742 might be beneficial in migraine prevention and provide support for the role of CGRP in the pathogenesis of migraine.
The study of Ho et al evaluated whether the CGRP receptor-antagonist telcagepant was effective for migraine prevention. In this randomized, double-blind, placebo-controlled, multicenter trial, patients with episodic migraine were randomized to oral telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. There was evidence that telcagepant resulted in a larger reduction from baseline than did placebo for mean-monthly headache days and migraine/probable headache days. However, 13 patients receiving telcagepant, but none on placebo, developed aminotransferase elevations more than threefold above normal; therefore, the trial was prematurely terminated. Of the 13 patients with liver enzyme elevation, 2 were symptomatic and had > 10-fold elevations above normal, with resolution after treatment was discontinued. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points.
Commentary
The mechanisms of action of most migraine-preventive medications are poorly understood and these medications may not directly impact known migraine pathophysiology. This lack of specific targeted therapy is reflected in patients’ lack of satisfaction with the currently available medications used to decrease the frequency and severity of migraine attacks. Specific, targeted preventive therapies are needed. Multiple vasoactive peptides that promote vasodilation and neuroinflammation are involved in the pathogenesis of migraine. Antagonists to specific vasoactive peptides, such as CGRP, have been investigated with variable results. Since CGRP plays an important role in the pathogenesis of migraine, it is an appropriate target for both acute and preventive treatment. Small-molecule CGRP receptor antagonists have shown efficacy in Phase 2 and Phase 3 trials for acute abortive treatment of migraine; however, hepatotoxicity, noted with investigation of CGRP receptor antagonists for preventive treatment, has slowed further research. Telcagepant is no longer under investigation for acute or preventive treatment of migraine. However, new small-molecule CGRP receptor antagonists may hold future promise for the acute treatment of migraine. Because monoclonal antibodies against CGRP and its receptor have long half-lives, they are appropriate for preventive therapy. The large molecules of the monoclonal antibodies are not degraded in the liver, decreasing the potential for drug-drug interactions and hepatotoxicity, as has been found with the small molecules of the CGRP antagonists. In this study of LY2951742, monoclonal antibodies that block the activity of CGRP decreased the disability of episodic
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migraine, without any significant adverse events, other than the minor discomfort of a subcutaneous injection. The encouraging results of this Phase 2 study indicate long-term efficacy and safety of monoclonal antibodies directed against CGRP or its receptor. Further controlled studies are needed to assess the safety and efficacy of monoclonal CGRP antibodies for the prevention of migraine headaches and their related disability.
