ARTICLE IN BRIEF
Telcagepant 300 mg and telcagepant 150 mg were reportedly more effective than placebo at two hours after dosage on the primary endpoints.
Telcagepant (MK-0974), the first orally bioavailable neuropeptide calcitonin gene-related peptide (CGRP) receptor antagonist, relieved pain and other migraine symptoms within two hours of use and provided sustained pain relief for two to 24 hours, according to a new study published Sept. 22 in Neurology.
The investigators, led by Tony W. Ho, MD, senior director of clinical neurosciences at Merck Research Laboratory, wanted to assess the efficacy of telcagepant as a more universal treatment option for migraine patients. While triptans have been widely used for acute migraine since 1999, the study authors noted that triptans are contraindicated in patients with coronary artery or cerebrovascular disease.
In an e-mail to Neurology Today Dr. Ho explained that “telcagepant is an antagonist of the receptor for CGRP, a potent neuropeptide thought to play a central role in the underlying pathophysiology of migraine.”
During migraine attacks, CGRP binds to and activates CGRP receptors, which help transmit pain impulses. Telcagepant blocks CGRP from binding to its receptors within the CNS, Dr. Ho said, inhibiting the transmission of pain and migraine associated symptoms — photophobia, phonophobia, and nausea.
Because CGRP receptor antagonists are not direct vasoconstrictors, he added, they may be advantageous over triptans for treating acute migraineurs with coronary artery or cerebrovascular disease.
In a randomized, placebo-controlled phase 3 trial, the investigators treated adults with moderate or severe migraine with or without aura: 177 patients were given oral telcagepant 50 mg; 381, 150 mg; 371, 300 mg; and 365 were given placebo.
Telcagepant 300 mg and telcagepant 150 mg were more effective than placebo at two hours after dosage on the primary endpoints: pain freedom, pain relief, as well as absence of photophobia, phonophobia, and nausea. They were also more effective than placebo for two to 24 hour sustained pain relief.
Telcagepant 300 mg was slightly more effective than telcagepant 150 mg on most measures and the results were statistically significant.
Thirty-two percent of trial participants reported adverse events for telcagepant 150 mg; 36.2 percent for telcagepant 300 mg; and 32.2 percent for placebo. The most common side effects were fatigue, dizziness, nausea, upper abdominal pain, somnolence, and vomiting. Most adverse events occurred during the first 48 hours after taking a dose. There were two serious adverse experiences (closed head injury in a patient taking placebo and hypertension in a patient on telcagepant 150 mg), but neither serious adverse experience was attributed to the study drug. No patients died during the study.
Gretchen Tietjen, MD, professor and chair of neurology at the University of Toledo, who was not involved in the study, said the greatest opportunity for telcagepant will occur if it is safe for use in people with cardiovascular disease.
EARLIER TRIAL STOPPED
In April, a phase 2a exploratory study designed to study the safety and efficacy of telcagepant in chronic use for the prevention of migraine was stopped early because 11 people taking the therapy twice daily for up to three months had marked elevations in liver enzymes, more than three times the upper limit of normal, said Dr. Ho.
The study, sponsored by Merck, started in November 2008 and enrolled 660 patients who were randomized to receive either placebo, telcagepant 140 mg twice daily, or telcagepant 280 mg twice daily.
“The twice daily dosing regimen in the prevention study was much higher than the dosing regimen used in phase 3 studies in which telcagepant was intermittently administered in one or two doses to treat individual migraine attacks as they occurred,” said Dr. Ho.
Dr. Ho's phase 3 trial included general lab tests as well as liver enzyme tests, and “laboratory abnormalities during the study were uncommon and no clinically relevant differences were seen between treatment groups,” Dr. Ho said. He added that there were no patients with increases in liver enzymes more than three times higher than normal.
Experts pointed out that the different dosages used in the exploratory study and the phase 3 trial could explain the differences in the findings of elevated liver enzyme levels.
“Some patients in the exploratory study developed liver enzyme abnormalities associated with doses far higher than those used for acute treatment. Telcagepant is intended as an acute treatment for migraine, and in the acute treatment studies liver toxicity was not a problem,” said Richard B. Lipton, MD, professor of neurology, epidemiology, and social medicine at the Albert Einstein College of Medicine in New York. Dr. Lipton, who was not involved in the study.
“Based on the data I have seen, it is likely that there will be a clinically useful acute dosing regimen for telcagepant that is free of the dose dependent hepatotoxicity that emerges at higher doses,” said Dr. Lipton. Occasional use for acute migraine will prove relatively safe, he said. Before submission to the FDA for intermittent use, Dr. Lipton said, “Merck needs to review their data and determine the safe dose and then take steps to ensure that use is exclusively within the safe range.”
Dr. Ho noted that the “company said it no longer expects to file a new drug application with the FDA in 2009, and will provide an updated timeline once additional information is available.”
©2009 American Academy of Neurology
• Connor KM, Shapiro RE, Ho TW. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology
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