Telcagepant Safe, Effective in Migraine Treatment

Susan Jeffrey

November 26, 2008

November 26, 2008 — Results of a randomized trial show that telcagepant, also known as MK-0974, is effective in the treatment of migraine, with efficacy similar to zolmitriptan 5 mg (Zolmig, AstraZeneca) but with fewer adverse effects.

The study, presented earlier this year at the 50th Annual Meeting of the American Headache Society (AHS) and reported by Medscape Neurology & Neurosurgery at that time, was published online November 25 in the Lancet. The trial was funded by Merck Research Laboratories.

"We know migraine patients are always looking for better medications," lead investigator Tony W. Ho, MD, from Merck Research Laboratories in North Wales, Pennsylvania, said in an interview during the AHS meeting. "If this drug is approved, it will certainly offer an additional choice for patients with debilitating migraine pain, without some of the side effects associated with triptans."

Alternative Treatments Needed

Triptans, agonists of the serotonin receptor 5-HT1B/1D, are currently viewed as the best acute-migraine-specific treatments, the authors write, although some patients respond poorly or are unresponsive. Although they are generally well tolerated, adverse effects include dizziness, parasthesia, throat tightness, and chest discomfort that is not thought to be of cardiac origin in most patients, they note.

"Furthermore, because of potential vasoconstrictor effects, triptans are contraindicated in patients with substantial underlying cardiovascular disease, uncontrolled hypertension, and certain migraine subtypes, including hemiplegic and basilar-type migraine," they write.

Calcitonin gene-related peptide (CGRP) is a neuropeptide thought to have a key role in the pathophysiology of migraine, they write. CGRP receptors are found throughout the trigeminal pathways involved in migraine headache pain, and antagonism of these receptors has become an important target for new migraine treatments, they write. Telcagepant is an orally bioavailable antagonist of the CGRP receptor.

The current study was a randomized parallel-treatment placebo-controlled double-blind trial, carried out at 81 sites in Europe and the United States. A total of 1380 adult patients with migraine, diagnosed by International Headache Society criteria, treated moderate to severe migraine attacks with telcagepant in doses of 150 mg or 300 mg, zolmitriptan 5 mg, or placebo.

Zolmitriptan 5 mg, the maximum recommended dose in the United States, was selected as an active comparator "because it is among the most widely used and effective oral triptan treatments," the authors note.

The 5 co–primary end points — pain freedom, pain relief, and the absence of phonophobia, photophobia, or nausea — were all assessed 2 hours after treatment.

When telcagepant 300 mg was compared with placebo, the active drug was significantly more effective on all 5 end points.

Primary End Points: Telcagepant 300 mg vs Placebo

End Point Telcagepant 300 mg Placebo P
Pain freedom (%) 26.9 9.6 < .0001
Pain relief (%) 55.0 27.7 < .0001
Absence of phonophobia (%) 57.8 36.8 < .0001
Absence of photophobia (%) 51.0 28.9 < .0001
Absence of nausea (%) 65.1 55.3 .0061

The efficacy of telcagepant 300 mg and zolmitriptan 5 mg were "much the same," the authors note, and both were more effective than telcagepant 150 mg. "The suggestion in the previous phase 2 study that telcagepant might be more effective than an established triptan treatment in providing sustained duration of relief or pain freedom up to 24 hours was not supported in our study," they write.

Primary End Points: Telcagepant 300 mg vs Zolmitriptan 5 mg

End Point Telcagepant 300 mg Zolmitriptan 5 mg
Pain freedom (%) 26.9 31.3
Pain relief (%) 55.0 56.4
Absence of phonophobia (%) 57.8 55.3
Absence of photophobia (%) 51.0 50.0
Absence of nausea (%) 65.1 71.3

Adverse events were recorded for 31% of patients taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo, the investigators report. This suggests that telcagepant "might offer tolerability advantages over current triptan treatments," they note.

The difference was due in part to fewer adverse events prespecified as "triptan related," such as chest discomfort or asthenia, but was also due to reductions in dry mouth, nausea, myalgia, dizziness, somnolence, and throat tightness, the authors add.

"One potential benefit of the new CGRP-receptor-antagonist class of acute-migraine treatments is the absence of vasoconstriction, a liability of the triptans, which may allow for the safe administration of telcagepant in patients with migraine and cardiovascular disease," the authors speculate.

However, they add, these patients were excluded from this trial, so further trials are required to establish this, as well as the long-term efficacy and safety profile of the drug when used for more than 1 migraine attack.

A "New Era"

In a Commentary accompanying the paper, Lars Edvinsson, MD, from the department of internal medicine at Lund University, in Sweden, points out that Dr. Ho and colleagues' results show equally good efficacy at all time points for both telcagepant and zolmitriptan, but telcagepant was associated with fewer adverse effects.

"This result marks a new era in migraine therapy," Dr. Edvinsson writes. "However, the remaining issue is to understand the site of action of the CGRP-receptor antagonists."

Potential targets are the intracranial blood vessels, parts of the trigeminal nerve, either at the peripheral or central ends or in the central nervous system (CNS) in areas that include the trigeminal nucleus caudalis, periaqueductal gray matter, nucleus solitarius, amygdala, and the colliculi, he writes.

The data from Dr. Ho and colleagues "are intriguing because the clinical dose is high in view of the potency of telcagepant, which suggests a central antimigraine action within the CNS," Dr. Edvinsson concludes. "While this new drug will be of value to clinicians, scientists will battle these questions."

The study was funded by Merck Research Laboratories. Dr. Ho is an employee of Merck. Dr. Edvinsson disclosed no relevant financial relationships.

Lancet. Published online before print November 25, 2008. Abstract Abstract

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