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BOSTON -- The CGRP receptor modulator erenumab bested placebo at reducing migraine days in two phase III episodic migraine prevention trials presented here.

In the 6-month STRIVE trial, patients on either of two once-monthly doses of the drug had a significantly greater reduction in migraine days per month than those on placebo (-3.7 days for 140 mg and -3.2 days for 70 mg versus -1.8 days for placebo), Peter Goadsby, MD, of the University of California San Francisco, reported during the clinical trials plenary session at the American Academy of Neurology meeting.

Results of the 3-month, single-dose ARISE study tracked similarly, with a greater reduction in monthly migraine days for those on 70 mg of the drug compared with placebo (-2.9 days versus -1.8 days, P<0.001), David Dodick, MD, of the Mayo Clinic in Phoenix, reported during a late-breaker session.

The trials "establish that blockade of the CGRP pathway is going to be the first mechanism-specific, migraine-targeted preventive approach, ever," Goadsby said during his talk. "We are standing on the edge of a development to treat the biggest neurologic cause of disability on the planet -- an entirely new way forward."

The treatment appears well tolerated in the short term, but during the plenary where STRIVE was presented, moderators raised a question about vascular issues, given the known role that CGRP plays in vascular tissue.

"The receptor is prevalent throughout the cerebrovascular and cardiovascular system," said Natalia Rost, MD, of Massachusetts General Hospital, who wasn't involved in the study, during a press briefing on the results. "When you target one receptor that may be vital for vascular health, and when you start treating someone at an early age and expose them to that medication for a lifetime potentially, there may be some unexpected long-term effects."

"So while we're excited to have a disease-specific treatment ... we have to be mindful about the potential long-term complications," she said.

Calcitonin gene-related peptide (CGRP) levels are elevated during migraine, and acute blockade of the protein has anti-migraine effects. Erenumab, a fully humanized monoclonal antibody, targets the CGRP receptor complex. Several other monoclonal antibodies aimed at the CGRP system are in development, including Lilly's galcanezumab, Alder's eptinezumab, and Teva's fremanezumab.

For the STRIVE study, Goadsby and colleagues enrolled 955 patients with episodic migraine (4 to 14 migraine days per month), whose mean age was around 40 and the majority were female. Patients were randomized to a monthly injection of enerumab at 70 mg or 140 mg, or to placebo injection.

In addition to a significant reduction in migraine days, they also found that a larger proportion of patients in both drug groups achieved at least a 50% reduction in migraine days (50% for 140 mg and 43.3% for 70 mg versus 26.6% for placebo).

They also saw better results for the drug on the secondary endpoints of reduction in monthly acute migraine medication treatment days (-1.6 days and -1.1 days versus -0.2 days), and in improvement in migraine physical function diary scores for both everyday activities and physical impairment.

Goadsby said the drug was very well tolerated, with none of the serious adverse events being related to treatment; the most common adverse effect was injection-site reaction.

Only 5.6% of patients developed anti-erenumab antibodies, with 8% in the 70-mg group (one patient in this group developed neutralizing antibodies) and 3.2% in the 140-mg group.

Enrollment characteristics were similar in the ARISE trial (4 to 14 migraine days per month, mostly women, age 40), which randomized patients to 12 weeks of placebo of a 70-mg dose of the drug.

Dodick and colleagues found a significantly greater reduction in monthly migraine days (-2.9 versus -1.8, P<0.001), as well as a significantly higher 50% responder rate (40% versus 30%, P=0.01), and a greater reduction in acute monthly migraine medication days (-1.2 versus -0.6).

Adverse events were similar, with 54% of those on placebo and 48% of those on erenumab having any event, the most common being upper respiratory tract infection, injection site pain, nasopharyngitis, influenza, fatigue, nausea, migraine and sinusitis.

There were 8 serious adverse events, 5 in the placebo group and 3 in the drug group. These included intervertebral disc protrusion, urinary tract infection, acute cholecystitis, flank pain, hypersensitivity, hyponatremia, and uterine leiomyoma.

"The ARISE study confirms the results of the STRIVE study in episodic migraine, demonstrating efficacy for the preventive treatment of enerumab in episodic migraine," Dodick said.

Goadsby sold an enthusiastic vision for the implications for migraine treatment during the clinical trials plenary.

"Imagine a world where I can give a patient a migraine preventive and I don't have to explain to them that I don't think they're depressed. I don't have to explain to them that you don't have epilepsy. I don't have to explain that you don't have blood pressure problems," he said. "We're going to have a specific treatment for the disorder. It's very exciting in that context."

In addition to concerns about vascular risk, Rost noted that there are no head-to-head trials comparing this new class of drug with other standard migraine treatments, particularly the triptans.

"I think we may not have those trials," she said. "These medications are already on the market and they probably won't be willing to enter head-to-head comparisons."

Also, the between-group differences in reduction in monthly migraine days weren't that dramatic, with the largest gap being a reduction of 2 migraine days per month.

"Migraine patients may be happy with any reduction in migraine days per month, and the details are on the favorable side, although this doesn't stand out as a huge absolute difference," she said.