Pauline Anderson

June 07, 2016

COPENHAGEN — An investigational agent that blocks a key headache-related receptor significantly reduces the number of mean monthly migraine days, new phase 2 data show.

Findings showed that after 52 weeks, 18.5% of patients with migraine were free of these attacks, Uwe Reuter, PD Dr, MBA, Department of Neurology, and headache clinic director, Charité Universitätsmedizin, Berlin, Germany, reported.

Dr Reuter presented results of a 12-week, phase 2, randomized, placebo-controlled trial of the agent, called AMG344, as well as data at week 52 of an open-label extension phase, here at the Congress of the European Academy of Neurology (EAN) 2016.

AMG334 is a human IgG2 monoclonal antibody that binds selectively to the calcitonin gene-related peptide (CGRP) receptor and blocks it.

"CGRP is a neuropeptide, the most potent vasodilator in the body, and it's believed to be the crucial neuropeptide in the development and generation of a migraine attack," said Dr Reuter.

He reported that preclinical trials that tested AMG344 in doses up to 200 mg via subcutaneous injection and 140 mg by intravenous infusion showed an adverse event profile similar to that of placebo, without effects on blood pressure over 24 hours. In one surrogate model, a 70-mg dose of AMG344 was shown to "inhibit a CGRP response completely," he said.

The current study enrolled patients with 4 to 14 migraine days per month and fewer than 15 headache days per month. A migraine day was defined as one with a migraine headache lasting 30 or more minutes with two or more pain features (unilateral, throbbing, moderate to severe, exacerbated with exercise/physical activity) and/or nausea or vomiting, photophobia, and phonophobia.

Among the study patients, up to two previous prophylactic therapies had failed. Rescue medications were allowed during the study, but medication overuse was not. Patients could have depression or anxiety.

Study patients were randomly assigned to one of four arms: AMG344 at 70 mg (n = 107), 21 mg (n = 108), or 7 mg (n = 108) or placebo (n = 160) given once a month subcutaneously.

Demographic characteristics were similar in all groups: Patients were roughly 40 years old, and most (about 80% overall) were female. Patients had 8.6 to 8.9 migraine days per month and 5.3 to 5.5 monthly migraine attacks, depending on the group.

There were 4.2 to 4.5 days of migraine-specific medication (eg, triptans) use per month.

Migraine Days

The primary endpoint was change in monthly migraine days at week 12. The researchers found that all groups had a decrease in monthly migraine days but that the 70-mg group was "clearly significantly superior to placebo and the other groups of AMG334," said Dr Reuter.

The total reduction of migraine days with the 70-mg group was about 3. The difference between placebo and the 70-mg AMG334 dose was 1.2 days.

A graph depicting the change in monthly migraines in all groups over time showed a steady and steep decline in the 70-mg group to week 4. The decline continued but was less steep to week 8 and then leveled off to week 12.

A post hoc analysis showed that a significant treatment effect was evident as early as week 2, said Dr Reuter.

The secondary endpoint was a 50% or greater responder rate at 12 weeks. The study found no significant difference between the placebo and the lower-dose group but a significant difference (P < .05) between the placebo group (30%) and the 70-mg group (47%) in this outcome. The significant difference could already be seen at week 4, said Dr Reuter.

At the end of the randomized part of the study, patients were all entered into an open-label extension phase, during which they took only 70 mg of AMG344. This extension phase is to continue for 5 years.

Dr Reuter presented results in 151 patients at week 52 of this extension phase. During the first few weeks, those who were originally receiving the 70-mg dose continued to have fewer migraine days, so that at about week 16, their reduction in monthly migraine days had increased from 3 to 4. At about this time, those who had switched to this dose caught up to the 70-mg dose group in terms of this reduction.

Those taking the 70-mg dose continued to have fewer headaches throughout the rest of the study.

"So there's an additional benefit over the course of 1 year," commented Dr Reuter.

The response rate during this extension phase was also high. At 52 weeks, 18.5% of patients had a 100% reduction in migraine days, 38.4% had a 75% or greater reduction, and 62.3% a 50% or greater reduction.

"At the end of the double-blind phase, we had a 47% responder rate, so this rate (of 62.3%) increased over the year."

The researchers also looked at an "exploratory" endpoint of change in monthly use of migraine-specific medications. The study showed there was a decrease of about 1.7 days per month of migraine medication use.

As for adverse events (AEs), during the double-blind phase of the trial, about 50% of patients in all groups had an AE. These included nasopharyngitis, fatigue, headache, influenza, back pain, and arthralgia, and most were mild. A few patients had injection-site reactions, which is "normal," said Dr Reuter.

These safety data "also held true" during the extension phase, he said. "There was not much of a difference in the adverse event profile at week 52."

Asked by a delegate to further speculate on the possible mechanism of the drug, Dr Reuter said that other than it blocks a key receptor, "I don't have a good answer" and that he could only "purely speculate."

When asked about the long-term safety of a drug that blocks CGRP, which could be important for regulation of vascular tone, Dr Reuter noted that all the serious adverse events reported at 52 weeks have been "nonspecific," with no evidence that the drug is harmful to the heart or to vessels.

"There is nothing specific that can be attributed to a clear-cut vascular ischemic mechanism."

However, he stressed the importance of following patients for 5 years. "So the study will definitely show whether there are any long-term adverse events."

This study was supported by Amgen Inc.

Congress of the European Academy of Neurology (EAN) 2016. Abstract O2211. Presented May 29, 2016.

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