The pain field has seen its share of disappointment on the drug development front, to the point where the so-called “failure of translation” has become an unavoidable cliché. But over the past several months, the migraine field’s own search for new medications has turned out quite differently, with several innovative medications receiving regulatory approval. Those who treat migraine and people who suffer from it can now celebrate another triumph.
Based on the results of two recent clinical trials, the US Food and Drug Administration (FDA) has approved ubrogepant, an oral small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, for the acute treatment of migraine. The first trial, led by Richard Lipton, Montefiore Headache Center, Albert Einstein College of Medicine, New York, US, found that ubrogepant increased the proportion of patients who reported pain freedom two hours after taking the medication, compared to placebo. This Phase 3, multicenter, randomized, double-blind trial of 1,686 adults also found that the drug increased rates of freedom from the most bothersome migraine-associated symptom, when used at the higher of the two doses tested in the study.
“Migraine is more than just a pain disorder,” said Michael Oshinsky, National Institute of Neurological Disorders and Stroke, Bethesda, US. “It is a neurological disorder where pain is normally the symptom that brings the patient to discuss their migraine headaches with their primary care physician or their neurologist. But during that discussion, what comes up as being disruptive in their life is much more than the pain, and that includes some of the symptoms of migraine ─ photophobia, phonophobia, and nausea. This trial is very useful, as it looks at the effect of ubrogepant on these associated symptoms that the patients report as being a significant disruption to their daily life,” according to Oshinsky, a migraine and pain researcher who was not involved in the new research.
The trial was published November 19, 2019, in JAMA.
The second trial, published shortly thereafter in the New England Journal of Medicine on December 5, 2019, also found that ubrogepant increased the proportion of patients who had freedom from pain, and freedom from the most bothersome migraine-associated symptom, two hours after taking the drug. This Phase 3 trial included 1,672 participants.
Staying the course
Estimates suggest that migraine affects approximately one billion people around the globe, including some 40 million in the United States alone. There is a range of medications for the acute treatment of migraine, including triptans, nonsteroidal anti-inflammatory drugs, and combination analgesics. However, many patients have contraindications to these medications and are unable to use them. Furthermore, a proportion of patients who can take these drugs report dissatisfaction because of unwanted side effects or insufficient pain relief.
In the search for new drug targets, migraine researchers turned their attention to CGRP. In the 1980s, Lars Edvinsson and Peter Goadsby demonstrated that this peptide played a critical role in the pathophysiology of the condition, with years of work ultimately showing increased levels of CGRP in the blood of migraineurs (see RELIEF related news story). Consequently, blocking the actions of CGRP became a prominent strategy to treat migraine.
Several pharmaceutical companies began developing drugs that interfered with CGRP’s ability to bind to its receptor. While initial results were very promising, many molecules fell out of development because of findings showing increased liver toxicity in clinical trial participants.
But the CGRP story wasn’t over yet.
A number of companies set out to find a safer way to block CGRP, this time by using antibodies to CGRP itself or to its receptor. In 2018, three antibodies targeting the CGRP system were approved in the US, with a fourth now under consideration for approval by the FDA. Along with the antibodies, a new class of small-molecule CGRP receptor antagonists called gepants are in development and have been shown to be effective in the acute treatment of migraine, without causing damage to the liver (Voss et al., 2016Lipton et al., 2019Croop et al., 2019Goadsby et al., 2019a). Ubrogepant, an oral gepant, is one of them, and the first gepant to successfully cross the drug approval finish line.
Putting ubrogepant to the test
In the JAMA study, Lipton and colleagues recruited 1,686 patients with a history of migraine, with or without aura, for at least one year from 99 primary care and research clinics across the United States. Of the 1,465 participants who would receive a treatment (drug or placebo), the mean age was 41.5 years, and 90 percent were women. To be included in the trial, patients had to report experiencing between two and eight migraine attacks in each of the three months prior to screening.
Trial participants were randomized to receive 25 mg of ubrogepant, 50 mg of ubrogepant, or placebo. They were instructed to take one tablet of study medication as quickly as they could within four hours of the onset of a qualifying migraine attack. To qualify as a migraine attack, the migraine had to be of moderate to severe pain intensity and be accompanied by at least one bothersome migraine-associated symptom, whether nausea, photophobia (sensitivity to light), or phonophobia (sensitivity to sound). The study had two co-primary outcomes that were assessed two hours after the initial dose, including freedom from pain and freedom from the most bothersome migraine-associated symptom.
Both the 25 mg and 50 mg dose of ubrogepant performed better than placebo on the pain freedom outcome: About 20 percent of patients in both drug groups (90 out of 435 in the 25 mg group and 101 of 464 in the 50 mg group) reported pain freedom at two hours, compared to 14 percent of the placebo group (65 of 456).
With respect to the second co-primary outcome, the percentage of participants reporting the absence of the most bothersome migraine-associated symptom at two hours was greater in the 50 mg group (180 of 463, or 39 percent) compared to placebo (125 of 456, or 27 percent). There was no difference between the 25 mg group and the placebo group in this outcome. Finally, the incidence of adverse events was similar between drug and placebo groups, the most common being nausea and dizziness.
“The results were very much in line with expectation,” Lipton said. “However, I would have expected that the 25 mg dose would separate from the placebo on both pain freedom and the most bothersome symptom.”
“This was a well-designed study, but I will give one caveat,” Oshinsky noted. “The authors only identified the presence or absence of photophobia, phonophobia, or nausea. It would be helpful if the field could take this research to another level and produce instruments or clinical tests that will quantify the amount of photo- or phonophobia reported by the patient. It might not be appropriate to do this work in a Phase 3 clinical trial, but it gives us a hint that this is an area of research that has a lot of potential.”
In the meantime, Lipton is looking forward to having another therapeutic option for migraineurs. “I’ve been waiting for a very long time and working on drugs that did not make it to FDA approval. It’s exciting to have a new class of acute treatments for migraine and to be able to use them in the clinic.”
The second trial, published in NEJM and also a Phase 3 randomized, double-blind, placebo-controlled study, reported similar findings. Here, patients were randomized to receive 50 mg of ubrogepant, 100 mg of ubrogepant, or placebo. Approximately 21 percent of those in the 100 mg group and 19 percent of those in the 50 mg group reported freedom from pain at two hours, compared to 12 percent in the placebo group. Further, the percentage of participants with freedom from the most bothersome migraine-associated symptom at two hours was approximately 38 percent in the 100 mg group, 39 percent in the 50 mg group, and 28 percent in the placebo group. Yet again, a trial of ubrogepant met both co-primary outcomes, and here, too, the drug appeared safe.
Based on these results, the FDA announced approval of ubrogepant (which goes by the trade name Ubrelvy and will be sold by Allergan) on December 23, 2019, for the acute treatment of migraine with or without aura in adults. It is the first gepant to hit this milestone.
Finally, in January 2020, results of a Phase 3 extension trial were published in Headache (Ailani et al., 2020). This study, which included patients who had completed one of the two Phase 3 studies described above, compared 50 mg of ubrogepant and 100 mg of ubrogepant to usual care, reporting that the drug was safe and well tolerated over the yearlong extension.
From famine to feast
Ubrogepant is just one of several new treatment options for migraine (Goadsby et al., 2019aGoadsby et al., 2019bLipton et al., 2019Kielbasa and Helton, 2019Garland et al., 2019Dodick et al., 2014). Along with the gepants and other CGRP-targeted therapies, the field also saw the October 2019 FDA approval of lasmiditan for acute migraine. This drug, known as a ditan, is a serotonin receptor agonist specific for the 5HT1F receptor subtype.
This recent success story is a far cry from the lack of new drugs since triptans were introduced about 30 years ago.
“From the early 1990s until three months ago, we did not have a new acute pharmacologic treatment mechanism for migraine,” Lipton said. “The therapeutic arsenal is much broader now than what it was when I entered the field. This is really good news for patients, their families, and clinicians to have novel treatment options that work.”
Lipton further said that having a range of options is important since not all migraineurs will respond to the same drug.
“One of the fascinating things about migraine is that there simply isn’t a treatment for everybody,” he explained. “That might be because there are biological differences from one person to the next. So one person might have a triptan-responsive migraine, another person might have a gepant-responsive migraine, and another person might have a ditan-responsive migraine. Ultimately, our task is going to be identifying the biological differences that distinguish among these groups.”
Lipton also said that it’s important for the migraine field to remain appreciative of its recent victories.
“When I was presenting the results of the ubrogepant study at the 2019 American Academy of Neurology Annual Meeting, I was the third person in a row to present the results of a positive study for migraine treatments, and the audience was sort of bored with it. I actually said to them, ‘Listen, we need to contrast the experience in this room with what’s going on in the room with our Alzheimer’s colleagues. They have no positive studies, and we have the excitement of many positive studies. Let’s be grateful for where we are at.’”
Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on Twitter @lincolntracy.
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