In spite of the promising clinical efficacy data, telcagepant development was discontinued because of concerns regarding liver toxicity. Elevations of hepatic enzymes were seen in some participants in a Phase IIa study where telcagepant was given twice daily for the prevention of migraine. Similar elevations were seen in a short-term study http://www.selleckchem.com/products/ensartinib-x-396.html of menstrual migraine.[13, 80] A third CGRP-RA, MK-3207, was 40- to 65-fold more potent than telcagepant and was tested in an adaptive design exploring doses from 2.5 to 200 mg. The
100 and 200 mg doses yielded pain-free rates of 23.7% and 36.2% (placebo = 9.8%), and pain relief rates of 52.5% and 69% (placebo = 36.1%). Similar to other compounds in the same class, tolerability was excellent but development was also discontinued because of concerns related to liver toxicity. Finally, a Phase 2 trial
tested BI44370A in 341 patients. Doses ranged from 50 to 400 mg, and were compared with placebo and 40 mg eletriptan. The primary endpoint, 2-hour pain freedom, was achieved buy Panobinostat significantly more often by patients receiving the 400 mg dose (27.4%) and eletriptan (34.8%) than placebo (8.6%). Other doses were not significantly different from placebo for the primary endpoint. Tolerability was excellent. In addition to demonstrating proof of efficacy, the CGRP-RA clinical trials also demonstrated the extraordinary tolerability of this class. The issue was best explored in the development of telcagepant, where in addition to the large pivotal studies, a distinct clinical trial was conducted specifically to evaluate its long-term tolerability for acute treatment of migraine attacks. The trial consisted of PIK-5 1068 patients. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Both regimens were well
tolerated but fewer drug-related adverse events (difference: –15.6%; 95% CI −22.2, −9.0) were reported for telcagepant vs rizatriptan. Other CGRP-RAs are being developed and, at the time of this writing, clinicaltrial.gov lists 2 of them: BMS-927711 is listed in Phase 1, and MK-1622 is in Phase 2B, with doses ranging from 1 to 100 mg, for the acute treatment of migraine attacks. mAbs, or antibodies produced by a single clone of cells, were first shown to have therapeutic activity in 1982, when a patient with lymphoma experienced a complete response when given antibodies against his tumor cells produced in mice. In the past 20 years, their clinical utility has expanded dramatically with more than 20 mAbs that are Food and Drug Administration (FDA)-approved for human use.