Efficacy of BMS-927711 and other gepants vs triptans: There seem to be other players besides CGRP

Dear Editor,

We read with great interest the paper by Marcus et al. (1), and the accompanying editorial (2), in the February issue of Cephalalgia on the results of BMS-927711, the fifth calcitonin gene-related peptide (CGRP) receptor antagonist (“gepant”), for the acute treatment of migraine. While the tolerability of this compound was placebo-like, its efficacy was not impressive. Correctly, pain freedom at two hours (PF2h), the recommended efficacy measure in migraine, was the primary efficacy endpoint in this clinical trial. Efficacy in terms of therapeutic gain (TG) was superior for three doses of BMS-92771, 75 mg (16.1%), 150 mg (17.6%) and 300 mg (14.4%) vs placebo. However, efficacy for 600 mg, the highest dose, did not significantly differ from that of placebo (TG 10%) and, while still far from its 29% TG in the triptan meta-analysis, the arm of 100 mg sumatriptan showed the numerically highest TG (19.7%) in this clinical trial. As already pointed out (3,4), the mean TG for PF2h for the four randomized trials of telcagepant 300 mg, the gepant for which more studies are available, was lower (15%) than that expected for sumatriptan 100 mg from the meta-analysis (5). Direct comparative randomized clinical trials are generally held to be the golden standard for comparing drugs. Telcagepant 300 mg efficacy was shown to be similar to that of 5 mg zolmitriptan in one comparative trial (6), and numerically higher than that of 10 mg rizatriptan 10 mg in another randomized comparative trial (30.9% vs 19.1%) (7). These results must be interpreted with great caution. First, TGs for the 400 mg (10%) and 600 mg (17.8%) doses of telcagepant were dramatically lower than that of 300 mg in the last trial and below that of rizatriptan 10 mg. Second, as already pointed out for sumatriptan 100 mg, both for zolmitriptan 5 mg and mainly for rizatriptan, TGs for PF2h were clearly below those expected from the meta-analysis (for instance, 30.4% for rizatriptan) (5). In a phase II trial of BI 44370, other oral gepant, the highest TG for PF2h was 18.8% for the 400 mg dose vs 26.2% for 40 mg eletriptan (8). In addition to the low numbers of patients in each arm, in these comparative clinical trials around two-thirds of the patients had the usual use of triptans, and patients not satisfied with triptans are more likely to enter into a trial with a new drug than those patients satisfied with the response to triptans. Therefore, a definite statement concerning the efficacy of oral gepants could be issued only after large comparative trials in triptan-naïve patients, but in general from the available data in terms of PF2h the efficacy of oral gepants seems to be somewhat inferior to that of the most efficacious triptans. This could also be concluded from the results of the only intravenous trial with olcegepant (9). The TGs for PFs at one hour and two hours of the highest doses of olcegepant were 14% and 42% for 2.5 mg, 10% and 23% for the 5 mg dose and 15% and 23% for the 10 mg dose, which are in general below those obtained for the 6 mg (37% at one hour and 42% at two hours) and 8 mg doses (45% at one hour and 55%) subcutaneous sumatriptan in its pivotal trial (10). In summary, taken together, these results could be interpreted as showing that there is an inherent limit of efficacy, a step below that of the best triptans, for this class of drugs. Even though there is no doubt a crucial role of the CGRP released by the afferent arm of the trigemino-vascular system in the pathophysiology of migraine pain (11), it is also true that other pain-producing molecules, such as vasoactive intestinal peptide (VIP) or pituitary adenylate cyclase-activating polypeptide (PACAP) released by the parasympathetic efferent arm of this system, could also contribute to the development of pain in migraine attacks. Because of their pre- and postsynaptic action on 5-HT1B and 5-HT1D (and also on 5-HT1F) receptors, triptans have been shown to be able to revert the release not only of CGRP but also of other peptides during migraine attacks (12). It is therefore possible that just antagonizing CGRP would not be enough to achieve an optimal efficacy for the abortive treatment of migraine attacks. To end with a soccer comparison, to defeat Real Madrid (migraine) it would be important but not enough to stop Cristiano Ronaldo (CGRP), the current Fédération Internationale de Football Association (FIFA) world player.