Article In Brief
A new oral agent, ubrogepant, was approved by the US Food and Drug Administration for treatment of acute migraine. The approval was based in part on the phase 3 trial data described in this article.
A randomized trial found a greater percentage of participants taking ubrogepant had freedom from pain and absence of a most disturbing migraine-related symptom in comparison to the placebo group.
The trial of ubrogepant—an oral, small-molecule calcitonin gene-related peptide receptor (CGRP) antagonist for acute migraine treatment—evaluated its efficacy, safety, and side-effect profile in a study published December 5, 2019, in The New England Journal of Medicine. The US Food and Drug Administration approved the drug for acute migraine on December 23, 2019.
About 20 percent of individuals in the ubrogepant groups—administered either 50 mg or 100 mg for a single migraine attack—experienced freedom from pain within two hours after a dose, compared with 12 percent of participants randomized to receive placebo.
In addition, 27.8 percent of patients in the placebo group had freedom from the most bothersome symptom—photophobia, phonophobia, or nausea—at two hours compared with 38.6 percent in the 50 mg ubrogepant group (p= 0.002), and 37.7 percent in the 100 mg ubrogepant group (p=0.002).
In 38 percent of participants receiving ubrogepant, the most bothersome symptom associated with migraine was absent at two hours, compared with 28 percent in the placebo group.
Ubrogepant belongs to the “gepants” class of drugs. Unlike the CGRP targeted monoclonal antibodies—erenumab, galcanezumab, and fremanezumab—injectables for the prevention of migraine—gepants are oral agents that are being studied for acute treatment.
“Gepants offer a mechanistic alternative to triptans,” Richard B. Lipton, MD, FAAN, a co-author of the study and director of the Montefiore Headache Center at Albert Einstein College of Medicine, told Neurology Today.
“Triptans activate serotonin receptors and constrict blood vessels,” explained Dr. Lipton, who is also professor and vice chair of neurology.
“Gepants block CGRP receptors and do not constrict blood vessels. They will be most useful in people who do not respond to triptans, have side effects limiting triptan use (triptan sensations such as chest pressure, diaphoresis, flushing), or who have cardiovascular contraindications or precautions restricting the use of triptans. These include cardiovascular events such as myocardial infarction and stroke, cardiovascular conditions such as angina, claudication or ischemic colitis, or multiple cardiovascular risk factors.”
In the study, the authors indicated that “although the sites of action of ubrogepant are not known, CGRP receptors are expressed peripherally on cranial blood vessels and on neurons and glial cells in the trigeminal ganglion, as well as centrally on terminals of trigeminal afferents and at multiple sites in the brain stem, cerebellum, and cerebral hemispheres. All these are potential signaling sites for CGRP and, correspondingly, potential sites of action of the gepant group of drugs.”
Nausea, somnolence, and dry mouth were the most commonly reported adverse events in the trial. The investigators recommended additional studies to gauge the durability and safety of ubrogepant for acute migraine treatment and to evaluate how the drug stacks up against other medications.
Meanwhile, “the side-effect profile of gepants looks very favorable,” Dr. Lipton said, citing studies in 2019 in the New England Journal of Medicine and Journal of the American Medical Association, which demonstrated consistent efficacy and tolerability. However, he acknowledged that these were studies of single migraine attacks. There is also data on long-term safety, which has been published in abstract form and presented at scientific meetings.
The study was funded by Allergan, manufacturer of ubrogepant.
Study Design, Findings
The randomized, double-blind, placebo-controlled, parallel-group trial enrolled a total of 1,672 participants at 89 centers in the United States between July 22, 2016 and December 14, 2017. An automated web-response system randomly assigned participants in a 1:1:1 ratio, to receive placebo, ubrogepant at a 50 mg dose, or ubrogepant at a 100 mg dose.
Of the total participants, 559 were randomized to the placebo group, while 556 received 50 mg of ubrogepant, and 557 were given 100 mg of ubrogepant.
To maintain masking of trial groups, the tablets looked identical and were enclosed in identical blister cards. In the event of unabating or recurring moderate or severe headache, participants had the option of taking a second dose or their own rescue medication two to 48 hours after the initial dose.
Participants had four clinic visits, with screening at the first appointment and randomization at the second. The third visit occurred two to seven days after an initial dose for a qualifying migraine. Telephone follow-ups were conducted 14 days after the initial dose. The fourth visit, which occurred four weeks after the initial dose, assessed safety.
Exclusions included current pregnancy, a history of 15 or more headache days per month (on average) during the six months that preceded screening, or a current chronic migraine diagnosis. The trial also excluded participants who had been treated for an acute migraine on 10 or more days in any of the three months before screening or anyone who had taken part in a trial with an injectable monoclonal antibody against CGRP or the CGRP receptor.
A total of 11.8 percent of the placebo group were free from pain at two hours, compared with 19.2 percent in the 50-mg ubrogepant group (p=0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2 percent in the 100-mg ubrogepant group (p<0.001).
Before taking the initial dose for a qualifying migraine attack, participants immediately selected the most bothersome migraine-associated symptom (photophobia, phonophobia, or nausea). Then they recorded the presence or absence of that symptom at two hours after the dose.
Adverse events within 48 hours after the initial or optional second dose were documented in 12.8 percent of participants in the placebo group, in 9.4 percent of the 50-mg ubrogepant group, and in 16.3 percent of the 100-mg ubrogepant group. Nausea, somnolence, and dry mouth (reported in 0.4 to 4.1 percent) were the most frequent adverse events, occurring more commonly in the 100-mg ubrogepant group (reported in 2.1 to 4.1 percent).
In both ubrogepant groups, serious adverse events reported within 30 days included appendicitis, spontaneous abortion, pericardial effusion, and seizure. However, none transpired within 48 hours after medication intake.
Commenting on the study, Kathleen B. Digre, MD, FAHS, professor of neurology and ophthalmology and chief of the division of headache and neuro-ophthalmology at the University of Utah School of Medicine, said the expected upcoming addition of ubrogepant to the neurologist's armamentarium “opens up new targets for us to be treating patients,” and hailed the therapy as “another designer drug for migraines.”
“Altogether, the variety of new drugs for migraine treatment means I've got more tools in my box than I ever had,” said Dr. Digre, who is president of the American Headache Society but commented independently.
As a CGRP antagonist, “ubrogepant represents a new class of acute treatment for headaches in patients with migraine,” said Andrew D. Hershey, MD, PhD, FAAN, FAHS, endowed chair and director of the Headache Center and division of neurology at Cincinnati Children's Hospital Medical Center.
“Although CGRP antagonists have demonstrated efficacy compared to placebo, it is not known what role they will play, compared with triptans and over-the-counter remedies, largely nonsteroidal anti-inflammatory drugs,” Dr. Hershey said.
These existing classes have a history of being effective and tolerable, he said, so it is likely that gepants would be used when these medications fail to alleviate symptoms. Gepants also could be more appropriate for patients with potential cardiovascular disease who cannot tolerate triptans and patients with bleeding or gastrointestinal disorders who cannot take anti-inflammatories, he added.
The well-designed study was very large, and the separation was sustained between the ubrogepant groups and placebo for freedom of pain at two hours after the dose. While there were no serious side effects, somnolence could be of concern, Dr. Hershey said, adding that nausea may have been due to the headaches, not the medication.
In general, the tolerability of ubrogepant and other medications in its class is “the real selling point,” said Stewart J. Tepper, MD, FAHS, professor of neurology at the Geisel School of Medicine at Dartmouth and director of the Dartmouth Headache Center. “The advantage of this drug and of its cousin (rimegepant) is the side effects are really minimal,” he added.
As a result, “those of us in headache medicine are comfortable and are ready for FDA approval,” Dr. Tepper said. In his practice, he said hardly any patients would have contraindications to the gepants class of drugs. In fact, he suspected ubrogepant could work even better in real life than in the trial because patients may take it early in a migraine attack.
However, with migraine being a chronic disorder characterized by recurrent headaches, the study based on a single attack could not adequately validate the drug's safety with frequent use over an extensive period, said Yulia Orlova, MD, PhD, DMedSc, a headache specialist and assistant professor of neurology at the University of Florida College of Medicine in Gainesville.
Earlier generations of drugs used to treat an acute migraine attack posed the challenge of medication overuse headache (also known as rebound headache) when taken too frequently, Dr. Orlova pointed out.
“It will take some time before we can answer the question if ubrogepant also carries the risk of medication overuse,” Dr. Orlova said. “In the meantime, we will still need to be very vigilant if patients will be taking this medication very often and for a longer period of time.”
Dr. Lipton disclosed relationships with Acorda Therapeutics, Inc., Alder, Allergan, Amgen, Avanir Pharmaceuticals, Inc., Biohaven, CVS Health, Dr. Reddy's, Eli Lilly and Company, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Sun Pharmaceutical Industries, Inc., Supernus Pharmaceutical, Inc., and Teva. Dr. Tepper disclosed receiving grants for research (no personal compensation) from Alder, Allergan, Amgen, Dr. Reddy's, ElectroCore, Eli Lilly, eNeura, Neurolief, Novartis, Scion Neurostim, Teva, Zosano. He has received consulting fees for serving as a consultant and/or on advisory boards (honoraria) from Acorda, Alder, Alexsa, Align Strategies, Allergan, Alphasights, Amgen, Aperture Venture Partners, Aralez Pharmaceuticals Canada, Axsome Therapeutics, BioDelivery Sciences International, Biohaven, Charleston Labs, Currax, Decision Resources, DeepBench, Dr. Reddy's, ElectroCore, Eli Lilly, eNeura, Equinox, ExpertConnect, GLG, GSK, Guidepoint Global, Impel, M3 Global Research, Magellan Rx Management, Marcia Berenson Connected Research and Consulting, Medicxi, Navigant Consulting, Neurolief, Nordic BioTech, Novartis, Pfizer, Reckner Healthcare, Relevale, Revance, Satsuma, Scion Neurostim, Slingshot Insights, Sorrento, Spherix Global Insights, Sudler and Hennessey, Teva, Theranica, Thought Leader Select, Trinity Partners, XOC, Zosano. Drs. Digre and Orlova disclosed no competing interests.