Biohaven’s lead project, the acute migraine candidate rimegepant, is looking like an also-ran based on phase III data reported today.
The two pivotal trials met their co-primary endpoints, so should be enough for approval – but a cross-trial comparison against another oral CGRP inhibitor, Allergan’s ubrogepant, makes Biohaven’s asset look disappointing, raising questions of how it will fare in the market (see table below).
Biohaven executives talked up rimegepant’s apparently more benign safety profile on a conference call today, but the results still sent the company’s stock down 32% this morning.
The group plans to take aim at the four million or so migraine patients in the US who either have not responded to or cannot take triptans, an older drug class that is contraindicated in patients with cardiovascular disease.
Biohaven’s chief executive, Vlad Coric, declined to say whether the company would market rimegepant alone or whether it would seek a partner. Going solo against a competitor like Allergan would be a hard task even with emphatic efficacy data.
And rimegepant might have another rival in the acute migraine space in the form of Lilly’s oral serotonin agonist lasmiditan, which looked even more promising than Allergan’s candidate in phase III, albeit in yet another trial.
|Comparison of rimegepant, ubrogepant and lasmiditan's phase III data|
|Trial name||% of patients pain-free at 2hr, placebo-adjusted|
|Ubrogepant 50mg||Ubrogepant 100mg|
|Achieve 1||7.4 (p=0.0023)||9.3 (p=0.0003)|
|Lasmiditan 50mg||Lasmiditan 100mg||Lasmiditan 200mg|
|Samurai||–||12.9 (p<0.001)||16.9 (p<0.001)|
|Spartan||7.3 (p=0.003)||10.1 (p<0.001)||17.5 (p<0.001)|
|Source: Company press releases.|
In spite of the apparently lacklustre efficacy data, Biohaven is convinced that rimegepant can compete. Mr Coric highlighted the fact that Study 301 and 302 evaluated a single dose of the compound without rescue medications, saying trials of rival agents looked at multiple doses and permitted rescue meds.
For example, Allergan’s trial allowed a second dose of ubrogepant two hours after the initial treatment – however, this would not have affected the two-hour pain relief endpoint.
Mr Coric told an analyst call today that other agents, including lasmiditan, showed a less favourable side-effect profile than rimegepant: “With a lot of these other agents you’re looking at a 20-40% incidence of adverse events – here we’re seeing an incidence of individual adverse events at around 2%, and I believe that will be a very important discriminator.”
Even within the CGRP inhibitor class rimegepant could have an edge on safety, Biohaven believes. Liver toxicity has been a particular concern with small-molecule CGRP antagonists, and forced Merck & Co to discontinue development of telcagepant in 2011.
In the two trials of rimegepant this did not appear to be an issue, with only two cases of liver enzyme elevations greater than three times the upper limit of normal, one in the rimegepant and one in the placebo group. There were no cases of liver enzyme elevations greater than five times the upper limit of normal.
This appears to compare favourably against Allergan’s Achieve 1 trial, which reported six cases of liver enzyme elevations greater than three times the upper limit of normal, five with ubrogepant and one with placebo. Two of these cases were over five times the upper limit of normal and one was more than 10 times over.
Of course, it could be argued that this discrepancy might be due to an insufficient rimegepant dose. When asked on the call if Biohaven had found the optimum dose Mr Coric replied that he was pleased with the project’s performance and confident that there was no need to dose higher.
Rimegepant’s efficacy appeared to improve past the two-hour point, which Evercore ISI analyst Umer Raffat said could be down to a delay in its maximum serum concentration (Tmax).
Biohaven recently started a phase III trial with an orally disintegrating tablet formulation of rimegepant, which could bring the Tmax forward by 30 minutes and perhaps have an impact on the two-hour pain endpoint.
Results with the new formulation should be available before the end of the year. Biohaven will not need these data to file rimegepant with the FDA, which it expects to do in 2019 – but Mr Coric would not give a more specific timeline.
Allergan is awaiting readout from a second pivotal trial, Achieve 2, testing a lower 25mg dose of ubrogepant. A win here, particularly with cleaner liver toxicity data, could make Biohaven’s future look even bleaker.
|Rimegepant orally disintegrating tablet||BHV3000-303||NCT03461757|