麻豆传媒

SAN FRANCISCO -- Two oral calcitonin gene-related peptide (CGRP) inhibitors offer rapid relief from acute headache pain and associated migraine symptoms for about 20% of patients, researchers reported here.

One in five people treated with rimegepant in a phase III study reported freedom from pain at 2 hours after a single dose, and nearly 40% reported relief from their most bothersome symptom, usually photophobia. Similar proportions of patients reported improvement after taking ubrogepant.

The findings were presented at the American Headache Society (AHS) annual meeting.

Vascular dysfunction is thought to play a key role in migraine. CGRP is a potent vasodilator, and blocking the peptide or its receptors can prevent or treat migraine without the cardiovascular side effects often seen with triptans. Monoclonal antibodies are being developed for migraine prophylaxis, while small-molecule oral agents are under study for the treatment of acute attacks.

"This morning we've heard about seven new molecular entities that are effective in acute or preventive treatment of migraine and a couple novel ways of delivering older drugs. This is truly a remarkable time in our field," said Richard Lipton, MD, of Albert Einstein College of Medicine in New York City.

For decades triptans have been the most widely prescribed drugs for the acute treatment of migraine, but many patients cannot use them because of cardiovascular contraindications.

"Perhaps a third of people with migraine don't respond to triptans, 30% to 40% have recurrent attacks, and according to our estimate 3.5 million people have absolute or relative contraindications for triptans among the 40 million people who get migraines," Lipton said. "Clearly there are unmet needs, and the hope is that 'gepants' will address some of those needs."

Study 302 of Rimegepant

Lipton presented findings from Study 302, a double-blind phase III trial comparing rimegepant, an oral CGRP receptor antagonist, versus placebo for the acute treatment of migraine.

The study included 1,072 patients; nearly 90% were women, and median age was 41. Participants had at least a 1-year history of migraine and had two to eight attacks of moderate to severe intensity per month (median 4.6 attacks); those with chronic migraine (more than 15 headache days per month) were excluded. Patients were allowed to be on stable migraine prevention medication. They reported their most bothersome symptom to be photophobia (58%), nausea (16%), and phonophobia (27%).

Participants were randomly assigned to receive 75 mg rimegepant or placebo to treat a single migraine attack. A total of 543 people were treated in each group (some enrolled patients did not experience attacks during the follow-up period). Rescue medication was permitted at 2 hours if needed.

At 2 hours after treatment, 19.6% of patients in the rimegepant group reported pain freedom, compared with 12.0% in the placebo group (P=0.0006). At the same time point, 37.6% and 25.2%, respectively, reported freedom from their most bothersome symptom (P=0.0001).

Looking at secondary endpoints, the researchers found that more people in the rimegepant arm reported being free of photophobia and phonophobia at 2 hours post-treatment. The proportions reporting pain relief at 2 hours were 58.1% in the rimegepant arm and 42.8% in the placebo arm; 32.6% and 23.4%, respectively, were able to function normally. Fewer patients required rescue medication in the rimegepant arm compared with the placebo arm (21.0% versus 37.0%).

The proportion of patients receiving rimegepant reporting freedom from pain after a single dose with no rescue medication rose over time, from 20% at 2 hours to 48% at 8 hours. Significantly more people in the rimegepant arm reported continued pain freedom, pain relief, and ability to function through 48 hours.

Treatment was generally safe and well tolerated, Lipton said. One patient in the rimegepant arm and two in the placebo arm had serious adverse events -- 1.8 and 0.6%, respectively, had treatment-related adverse events. There were no adverse events leading to treatment discontinuation in either group. Elevated liver enzymes are a potential concern with this class of drugs, but no patients had alanine aminotransferase or aspartate transaminase levels that were more than three times the upper limit of normal or bilirubin more than twice the upper limit.

The researchers concluded that rimegepant offers broad and clinically important benefit with a single dose, with an excellent safety profile similar to that of the placebo. Lipton noted that a parallel trial, Study 301, also showed consistent results.

ACHIEVE I Trial of Ubrogepant

David Dodick, MD, of the Mayo Clinic in Phoenix, presented results from ACHIEVE I, a phase III trial evaluating another oral CGRP receptor agonist, ubrogepant.

As previously reported at the American Academy of Neurology annual meeting in April, 19.2% of patients treated with a single 50 mg dose of ubrogepant and 21.2% of those who received 100 mg reported freedom from pain at 2 hours post-treatment, compared with 11.8% of placebo recipients. About 38% in both dose groups were free of their most bothersome symptom at 2 hours, the study found.

Various secondary endpoints also favored ubrogepant over placebo. A third of patients reported satisfaction with ubrogepant at 2 hours, rising to more than 60% at 24 hours. Like rimegepant, ubrogepant was generally safe and well tolerated. Dodick said that "nearly identical" results were seen in the related ACHIEVE II trial.

These pivotal results support the approval of rimegepant and ubrogepant for the acute treatment of migraine, he said. and have indicated that they plan to file New Drug Applications for the agents in 2019.

Commenting on these two drugs and others described at the same session, moderator Andrew Charles, MD, of the David Geffen School of Medicine at UCLA, told 麻豆传媒, "How they sort out in comparison remains to be seen, but it shows that the target [CGRP] is an important one and the medications that are going after this target are all working."