Another day, another anti-CGRP readout in migraine. But this one is different. Allergan’s oral project ubrogepant, which posted a win in its first phase III trial today, will not compete with the better-known injectable CGRP inhibitors – the former is being trialled as an acute treatment, while the latter are awaiting approval as preventative therapies.
Instead ubrogepant could go up against another oral anti-CGRP, Biohaven’s rimegepant, which is due to report pivotal results soon, and Lilly’s oral serotonin agonist lasmiditan, which on the data available so far looks more effective (see table below). The battle in the acute migraine space is beginning to look as fierce as that for the prophylactic market.
Lasmiditan has already succeeded in phase III and is set to be filed in the second half of the year. Results from the Samurai and Spartan trials appear to give Lilly’s project a slight edge over ubrogepant based on the latest Achieve 1 study – although the usual caveats about cross-trial comparisons apply.
|Cross-trial comparison of ubrogepant and lasmiditan phase III studies|
|% of patients pain free at 2h, 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.|
Still, ubrogepant should be able to compete, Evercore ISI analyst Umer Raffat believes, pointing to an unmet need in acute migraine. He also highlighted the two projects’ different mechanisms and mooted the possibility that they could be combined.
First, though, Allergan will also have to put any concerns about liver toxicity to bed – this has been an issue with other small molecule CGRP antagonists such as Merck’s telcagepant, development of which was halted in 2011.
In Achieve 1, six patients had aminotransferase (ALT) elevations greater than three times the upper limit of normal across all arms, only one of which was in the placebo arm. This represents a much lower rate of ALT>3x than that seen with telcagepant, Mr Raffat noted, suggesting that liver toxicity will not be a problem with Allergan’s project.
Results from the Achieve 2 trial, which is due to complete in March, will still be needed to assuage any lingering doubts on safety.
Another unanswered question is how ubrogepant performed in triptan non-responders – as generic versions of triptans are now available, patients will be given these first. The triptan refractory market is large, with around 30-40% of patients thought to be non-responders.
Lasmiditan, which Lilly reacquired from Colucid Pharmaceuticals last year, could also have an advantage here: its benign cardiovascular safety profile means it could be used in migraine patients with cardiovascular problems who therefore cannot take triptans.
At least Allergan can claim a win in Achieve 1, and ubrogepant has also set the bar for Biohaven’s rimegepant, which is due to yield data from two phase III trials this quarter (Upcoming events – Biohaven’s turn in migraine and Madrigal’s latest lipid test, January 19, 2018).
However, for these novel oral agents to become commercially successful, they still need to show that they can treat patients who do not repond to triptans, which will remain a first-line treatment option for cost-conscious payers.
|Lasmiditan||Lilly||Filing H2 2018||Samurai (NCT03235479); Spartan (NCT02605174)||Reported|
|Ubrogepant||Allergan||Phase III||Achieve 1 (NCT02828020); Achieve 2 (NCT02867709)||Reported;
|Rimegepant||Biohaven||Phase III||BHV-3000-301 (NCT03235479);