Allergan is planning a 2019 NDA submission to the FDA for its agent, ubrogepant, based on a pair of new trials.
Richard Lipton, MD
Recently, Allergan announced the completion of a pair of positive safety and tolerability studies of ubrogepant for the acute treatment of migraine.1
The first, UBR-MD-04, assessed long-term safety and tolerability of ubrogepant at 2 doses, 50 mg and 100 mg, compared to usual care 1 year. The second, 3110-105-002, evaluated the hepatic safety and tolerability of the 100-mg dose compared to placebo in healthy study participants over an 8-week period. The company also announced it would be submitting a New Drug Application (NDA) to the FDA by the first quarter of 2019 as a result of these trials.
In order to gain further insight into the clinical knowledge of ubrogepant, as well as the future implications of its potential approval, NeurologyLive spoke with Richard B. Lipton, MD, the Edwin S. Lowe Chair in Neurology at the Albert Einstein College of Medicine, and director of the Montefiore Headache Center, about the therapy.
Richard B. Lipton, MD: There were 2 pivotal phase 3 studies on ubrogepant—ACHIEVE-1 and ACHIEVE-2. Each of the studies differed in doses a little bit, one study 50 mg and 100 mg the other study 25 mg and 50 mg. Both studies had as their primary end point, pain freedom of 2 hours and freedom from the most bothersome symptoms. To assess that, people were migraine were asked before they were treated, which of nausea, photophobia, and phonophobia they found most bothersome and what they designated as their most bothersome symptoms became the per-protocol primary end point for 2 hours.
The bottom line is that in both studies, 50-mg dose separated from the placebo on both primaries, the 100-mg dose separated from placebo on the primaries, and the 25-mg dose did not fully separate from placebo on the primaries. In both studies, there were a number of important secondary end points that were also statistically significant.
For most of this period of development of triptans, the primary pain end point in migraine trials was something called “2-hour headache response” or “2-hour headache relief.” The proportion of people they monitored with severe pain at the time they were treated developed mild pain or no pain at 2 hours, and, obviously, headache-response rates are higher than pain-free rates. The headache-response rates for ubrogepant were in a similar range to the triptans, so pain-free rates were around 20%.
The phase 3 trials were single-attack studies—people were allowed to re-dose within the attack. But people had at most 2 exposures to ubrogepant, and of course, migraine is a chronic disorder with episodic attacks, meaning that if I give someone an acute treatment for migraine, they’re likely to take it over and over again over a long period of time for multiple attacks if they find it effective. Although the safety data looked really good in these single-attack studies, they didn’t really speak to what we might expect to see with longer-term use. The first of the 2 studies was a long-term safety study in people with migraine, where people were rolled over from the 2 pivotal studies and were allowed to treat with ubrogepant 50 mg or ubrogepant 100 mg for up to a 1-year period. They were allowed to re-dose for individual attacks, and the goal was really to see if any safety problems emerged. The data in that study looked really clean, with up to a year of use in that treatment, so that’s really reassuring.
The other study was a phase 1 study, meaning that the people who were treated didn’t have migraines. In that study, patients were treated with ubrogepant independent of headache because they weren’t really headache people. They took a tablet 2 days in a row, and then took 2 days off, then took a tablet 2 days in a row again. So, in any 4-week period, the volunteers in this study would be on medication for 2 years. In this study—again, very few people would take that much ubrogepant in a real treatment setting, so the idea was to see what happens when people dose very regularly over 3 months, and again the safety signals from that study were also very clean.
The gepants class, this class of drugs CGRP receptor, small-molecule blockers, has carried baggage regarding hepatotoxicity that was observed with another agent, telcagepant. My long-standing belief has been telcagepant liver toxicity was specific to that molecule, and not related to binding CGRP receptors. There are many reasons to believe that, including that there are no CGRP receptors in the liver, and that the Amgen monoclonal antibody—that’s now FDA approved as a migraine preventive—binds to the CGRP receptor and doesn’t have the hepatotoxicity. So, these were very much the results I expected, and I have to say it’s nice to see them even though it’s not a surprise.
Allergan Announces Completion of Two Positive Safety Studies for Ubrogepant — an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine [press release]. Dublin, Ireland: Allergan plc; Published October 17, 2018. prnewswire.com/news-releases/allergan-announces-completion-of-two-positive-safety-studies-for-ubrogepant--an-oral-cgrp-receptor-antagonist-for-the-acute-treatment-of-migraine-300732518.html. Accessed October 24, 2018.