[13] 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[81] 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%).[82] Similar to other compounds in the same class, tolerability was excellent but development was also discontinued because of concerns related to liver toxicity.[83] 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.[84] 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.[85] 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,[86] and MK-1622 is in Phase 2B, with doses ranging from 1 to 100 mg, for the acute treatment of migraine attacks.[87] 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.[88] 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.