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Calcitonin Gene-Related Peptide Receptor Antagonist Found Safe and Effective for Migraine
Possible Alternative to Triptans

ARTICLE IN BRIEF

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In a randomized, double-blind, placebo- and active-controlled dose ranging trial, an oral calcitonin gene-related peptide receptor antagonist, called MK-0974, significantly relieved migraine pain within two hours when compared to placebo, and continued to do so for 24 hours with few side effects.

The first new treatment for migraine since triptan medications were approved in the early 1990s has cleared a phase 2 study, and its manufacturer says it will file a new drug application with the FDA next year.

Investigators at Merck & Co reported in the April 29 Neurology that a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, called MK-0974, significantly relieved migraine pain within two hours when compared to placebo, and continued to do so for 24 hours with few side effects.

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DR. TONY HO: “The findings of this early-stage trial demonstrate the therapeutic potential of MK-0974. Larger clinical trials, such as those now under way, will provide more insight into the efficacy and safety profile of MK-0974.”

The randomized, double-blind, placebo- and active-controlled dose-ranging clinical trial included 420 adult migraine patients; MK-0974 was given orally at doses of 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 600 mg, or rizatriptan 10 mg, or placebo. Patients were primarily women (89 percent), and most had moderate migraine without aura.

Within two hours, MK-0974 relieved migraine (from severe or moderate to mild or none) within two hours, compared to placebo (p=0.015), in 68 percent of patients at the 300 mg dose; 48.2 percent at the 400 mg dose; and 67.5 percent (600 mg). Response was 69.5 percent for rizatriptan compared to 46.3 percent for placebo patients. The number of patients who experienced 24-hour relief was 52.6 percent for 300 mg, 37.8 percent for 400 mg, and 52.5 percent for 600 mg.

“The findings of this early-stage trial demonstrate the therapeutic potential of MK-0974,” said Tony Ho, MD, senior director of Clinical Neuroscience at Merck Research Laboratories. “Larger clinical trials, such as those now under way, will provide more insight into the efficacy and safety profile of MK-0974.”

In addition to pain relief, MK-0974 eased other migraine-associated symptoms, including nausea and sensitivity to light and sound. It also improved functional disability two hours post dose, as well as reduced patients' need for rescue medication.

‘PROOF OF CONCEPT’

Stephen D. Silberstein, MD, professor of neurology at Jefferson Medical College and director of the Jefferson Headache Clinic in Philadelphia, told Neurology Today that the findings are important for several reasons.

“This is potentially a new delivery mechanism for CGRPs — an oral dose. What we have now is proof of concept that this works. Until now, CGRPs could be delivered only by intravenous injection. That the oral version appears to work so well, and without cardiovascular side effects, is good news.”

Another potential benefit is that it appears to be long-acting in most patients, he told Neurology Today in a telephone interview.

“With triptan drugs, headaches often come back. And there have always been concerns about cardiovascular side effects. It does not appear that this is an issue with MK-0974, according to the trial results. In addition, many patients experienced sustained 24-hour relief without the need for rescue medication. These are major benefits over triptan therapy.”

REFERENCE

• Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70:1594–1600.