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Merck’s Investigational Migraine Treatment MK-0974 Significantly Improved Migraine Pain on Several Efficacy Measures in a Phase II Study


CHICAGO,- Clinical results from a Phase II study presented for the first time at the American Headache Society (AHS) annual meeting showed that MK-0974, an investigational oral calcitonin gene-related peptide (CGRP) receptor antagonist, significantly improved migraine pain relief two hours after dosing compared to placebo, and the relief was sustained through 24 hours. MK-0974 was generally well tolerated in the study. Responses specific to other measures, such as migraine-associated symptoms, functional disability and use of additional rescue medications also were reported. MK-0974 is Merck’s investigational medicine in Phase III clinical development for the acute treatment of migraine in adults and, if approved, may be the first in a new class of migraine treatments since the approval of the first triptan drug in 1991.

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

About MK-0974
MK-0974 is an antagonist of the receptor for CGRP, a primary neuropeptide involved in the pathophysiology of migraine. CGRP and its receptors are found in areas of the central and peripheral nervous system that are important for the transmission of migraine pain. During migraine attacks, CGRP activates these receptors and facilitates the transmission of pain impulses. MK-0974 blocks the binding of CGRP to receptors within these areas and thereby is believed to inhibit the transmission of pain signals that lead to migraine headaches.

Study design
The findings being presented are from a randomized, double-blind, placebo- and active-controlled dose-ranging clinical trial in patients with migraine. An innovative, two-stage, adaptive dose-ranging design formulated through computer simulation was used to facilitate optimal dose selection.

A total of 420 adult patients who experienced migraine attacks, as defined by the International Headache Society criteria, were randomized (330 took drug) to treat a moderate or severe migraine attack with MK-0974 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 enrolled were primarily female (89 percent) with an average age of 41 years. Most treated headaches were moderate in baseline severity and did not have aura.

The first stage of the study evaluated all doses of MK-0974 with rizatriptan and placebo. When a preset number of migraine attacks were treated, an interim efficacy analysis was conducted resulting in dropping the four lowest doses of MK-0974 based on a pre-specified algorithm. The second stage of the study continued with randomization of patients to MK-0974 300 mg, 400 mg or 600 mg or to rizatriptan 10 mg or placebo.

Overall treatment effect was analyzed by comparing the average response of the MK-0974 treatment groups (300 mg, 400 mg and 600 mg) to the response observed in the placebo group. The study was not powered to detect differences between the individual doses of MK-0974 or between MK-0974 doses and rizatriptan.

Study results
For the primary endpoint, the overall treatment effect of MK-0974 in relieving migraine pain (reduction from severe or moderate to mild or none) two hours after dosing was significant compared to placebo (p=0.015). The proportion of patients reporting pain relief at two hours for those treated with MK-0974 was 68.1 percent (300 mg; n=38), 48.2 percent (400 mg; n=45) and 67.5 percent (600 mg, n=40); and 69.5 percent for rizatriptan (n=34) compared to 46.3 percent for placebo (n=115).

A similar pattern was observed for secondary measures in which the overall treatment effect of MK-0974 for each measure was significant compared to placebo (p0.001), and included:

* two-hour pain freedom (reduction to no pain): 45.2 percent for 300 mg, 24.3 percent for 400 mg and 32.1 percent for 600 mg of MK-0974 respectively; 33.4 percent for rizatriptan and 14.3 percent for placebo;
* 24-hour sustained pain-relief (defined as those with pain relief at two hours with no recurrence of headache and no use of optional second dose or rescue medication during the 2-24 hour period): 52.6 percent for 300 mg, 37.8 percent for 400 mg, 52.5 percent for 600 mg of MK-0974 respectively; 35.3 percent for rizatriptan and 23.5 percent for placebo; and
* 24-hour sustained pain-freedom (defined as those with no pain at two hours who remain free of pain during the 2-24 hour period with no use of optional second dose or rescue medication): 39.6 percent for 300 mg, 22.0 percent for 400 mg, 32.0 percent for 600 mg of MK-0974 respectively; 18.4 percent for rizatriptan and 11.0 percent for placebo.

In addition to the measure of migraine pain, MK-0974 provided relief of migraine-associated symptoms, including nausea and sensitivity to light and sound, and improved functional disability two hours post dose, as well as reduced patients’ need for rescue medication. However, the study was not powered to evaluate a statistical response to these measures.

In the study, treatment with MK-0974 was generally well tolerated with no reports of serious adverse events. The most common adverse experiences occurring in patients treated with MK-0974 were nausea, dizziness and somnolence. There also were no increases in adverse events associated with increasing doses studied.

“These results provide additional evidence of the potential benefit of CGRP receptor antagonists as a new and promising class of migraine therapies,” said Alan Rapoport, M.D., clinical professor of Neurology at the David Geffen School of Medicine at UCLA in Los Angeles, California; founder and director-emeritus of The New England Center for Headache; and clinical investigator for the Phase II study.

Merck continues to anticipate filing a New Drug Application (NDA) for MK-0974 with the U.S. Food and Drug Administration in 2009.

About migraines
Migraine headaches impact approximately 28 million Americans, primarily women. Unlike a bad headache, migraines are characterized by attacks of intense, usually one-sided, throbbing head pain that can last from four to 72 hours. The pain associated with migraine is frequently accompanied by other associated symptoms, including nausea, vomiting and increased sensitivity to light and/or sound.


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