PHILADELPHIA—MK-3207, a calcitonin gene-related peptide (CGRP) receptor antagonist, met its primary end point of two-hour pain freedom in patients with migraine, according to results of a randomized, double-blind, placebo-controlled study reported at the 14th Congress of the International Headache Society. However, Merck & Co, Inc has discontinued clinical development of the drug, citing delayed, asymptomatic liver abnormalities in some phase I study subjects.
In the phase II trial, 547 patients with migraine were initially given the drug in doses of 2.5, 5, 10, 20, 50, or 100 mg or a placebo. At the end of the first stage, the two lowest doses were stopped due to lack of efficacy, and a 200-mg dose was added.
At baseline, about two-thirds of subjects reported a history of moderate-intensity migraines, while approximately one-third reported severe migraines. Roughly one-fifth of participants had experienced migraines with aura, a significant number had photophobia and phonophobia, and about half experienced nausea. Patients (average age, 42) kept a paper diary and also reported two-hour pain assessments to an interactive voice response system within 24 hours of dosing.
Efficacy on Primary End Point
The results demonstrated a positive dose response across all MK-3207 doses for the primary end point of two-hour pain freedom, compared with a placebo. The 200-mg dose was statistically superior to placebo for pain freedom at two hours, while the 10-mg and 100-mg doses were nominally significant. For the secondary end point of pain relief, all doses were statistically superior to placebo, but for the end points of freedom from photophobia, phonophobia, and nausea (all at two hours), and two- to 24-hour sustained freedom from pain, only the 200-mg dose was statistically superior to placebo.
“The study was powered only to demonstrate efficacy of the primary end point of pain freedom at two hours,” said David Hewitt, MD, Senior Director, Clinical Neuroscience, Merck Research Laboratories in North Wales, Pennsylvania. “To also demonstrate efficacy on all five co-primaries does suggest that the 200-mg dose represents a significant improvement over the lower doses.”
The most common side effects reported in the study include nausea (5.2%), dizziness (4%), fatigue (3.2%), dry mouth (2.7%), and sleepi ness (2.0%), and none of the adverse affects was dose related.
Liver Test Abnormalities Are Observed, Leading to Drug’s Demise
Merck issued a press release regarding halting clinical development of the drug, stating, “While efficacy was demonstrated in a phase II study with MK-3207, some subjects in extended phase I clinical pharmacology studies were found to have experienced delayed, asymptomatic liver test abnormalities, generally following the discontinuation of drug administration. This information led to the decision to discontinue development of MK-3207.”
During his presentation, Dr. Hewitt noted one case of elevated liver enzymes in the phase II trial as well. “In this study we had one patient with an aspartate aminotransferase level (AST) that was elevated to greater than three times the upper limit for the normal range. It was 140 IU/L, with the upper limit being 42 IU/L at this laboratory,” he explained. “Repeat dosing showed the AST going down to 34 IU/L. Of note, this one patient also had an elevated creatine phosphokinase level of 7,511 IU/L and on repeat went down. Also important is that the alanine aminotransferase, alkaline phosphatase, and total bilirubin levels were all normal. “The decision to discontinue development of MK-3207 followed new information that some phase I study participants experienced delayed elevations in liver enzymes that exceeded three times the upper limit of normal for those laboratory measurements,” Dr. Hewitt explained to Neurology Reviews. “The patterns of elevated liver enzymes seen in studies with MK-3207 warranted discontinuation of the clinical pharmacology studies.
—Rebecca K. Abma