Merck & Co., Inc. updated the status of the clinical development programmes for telcagepant (MK-0974) and MK-3207, the company's investigational oral calcitonin gene-related peptide (CGRP) receptor antagonists for the intermittent treatment of acute migraine. The company provided this update in conjunction with poster presentations of new data from two phase III clinical studies of telcagepant at the 14th International Headache Congress.
Merck is currently reviewing available clinical data for telcagepant, which is currently in phase III of clinical development, in preparation for discussions that the company plans to have with regulatory agencies later this year.
Separately, Merck is discontinuing the clinical development programme for MK-3207, the company's other investigational CGRP receptor antagonist, and will not start confirmatory phase IIb/III studies. 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 discontinuation of drug administration. This information led to the decision to discontinue development of MK-3207.
"Merck believes that the blocking of CGRP receptors remains an exciting pathway to address the underlying pathophysiology of migraine," said David Michelson, M.D., vice president of clinical neurosciences, Merck Research Laboratories. "We are continuing our efforts to offer patients a new treatment approach."
In a long-term, randomized, double-blind clinical trial, the safety and tolerability of telcagepant for the acute treatment of migraine with and without aura was assessed in patients who took either 280 mg telcagepant tablets, bioequivalent 300 mg oral soft elastic telcagepant capsule, or rizatriptan 10 mg. The primary endpoint of the study was the proportion of patients with at least one pre-specified adverse event (chest pain, chest tightness, asthenia, paraesthesia, dysaesthesia or hyperaesthesia). Patients intermittently treated up to eight acute migraine attacks per month for a period of up to 18 months. An average of 31 and 35 attacks were treated with telcagepant and rizatriptan, respectively.
Significantly fewer patients treated with telcagepant reported at least one pre-specified adverse event compared with those treated with rizatriptan (5.0 per cent vs. 11.2 per cent; p<0.001). The most common clinical adverse events (reported with a frequency of greater than 3 per cent in either treatment group) included dry mouth, somnolence, nausea, dizziness, fatigue, nasopharyngitis, vomiting, upper abdominal pain, diarrhoea, upper respiratory tract infection, asthenia and paraesthesia. Of these events, nausea (9.0 per cent vs. 6.4 per cent), nasopharyngitis (3.4 per cent vs. 3.2 per cent), vomiting (3.3 per cent vs. 3.2 per cent) and upper abdominal pain (3.1 per cent vs. 2.2 per cent) were slightly higher in the telcagepant group compared with the rizatriptan group, respectively. The other events (dry mouth, somnolence, dizziness, fatigue, diarrhoea, upper respiratory tract infection, asthenia and paraesthesia) were slightly higher in the rizatriptan group compared to the telcagepant group.
In the study, three patients treated with telcagepant experienced greater than three-fold elevations in liver enzymes (without accompanying elevations in total bilirubin). All events were clinically asymptomatic, transient and deemed by the investigator to be not drug-related (one patient had a co-occurring musculoskeletal injury, one event occurred two months after the last dosing, and one event occurred in a patient who continued to treat with telcagepant without further enzyme elevations).
Telcagepant is a novel oral CGRP receptor antagonist in development for the intermittent treatment of acute migraine, which does not constrict blood vessels and works via a mechanism that does not affect serotonin. The compound is an antagonist of the receptor for CGRP, a potent neuropeptide thought to play a prominent role in the underlying pathophysiology of migraine. CGRP and its receptors are found in many areas of the brain that are important for the transmission of migraine pain. During migraine attacks, CGRP binds to and activates CGRP receptors, helping to transmit pain impulses. Telcagepant blocks CGRP from binding to its receptors within the nervous system and is believed thereby to inhibit the transmission of the pain signals that lead to migraine headaches.
Merck announced in April 2009 that the company would not file a New Drug Application for telcagepant with the US Food and Drug Administration in 2009 based on findings from a phase IIa exploratory study in which a small number of patients taking telcagepant twice daily for three months for the prevention of migraine were found to have marked elevations in liver transaminases. The daily dosing regimen in the prevention study was different than the dosing regimen used in Phase III studies in which telcagepant was intermittently administered in one or two doses to treat individual migraine attacks as they occurred.
Migraine is a disabling disorder of the brain that affects 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 symptoms, including nausea, vomiting and increased sensitivity to light and sound.
Maxalt (rizatriptan benzoate) is a selective 5HT1B/1D receptor agonist indicated for the acute treatment of migraine attacks with or without aura in adults. Maxalt is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. Safety and effectiveness of Maxalt have not been established for cluster headache, which is present in an older, predominantly male population. Maxalt should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease. Because Maxalt may increase blood pressure, it should not be given to patients with uncontrolled hypertension.