FDA issues CRL for orally inhaled migraine treatment

FDA has issued a complete response letter (CRL) to dihydroergotamine (Levadex inhalation aerosol, MAP Pharmaceuticals) for the treatment of acute treatment of migraine in adults.

In the CRL, FDA requested that the company address issues relating to chemistry, manufacturing, and controls (CMC) and observations from a recent facility inspection of a third-party manufacturer.

“We believe the issues raised by FDA are very addressable,” Timothy S. Nelson, president and chief executive officer of MAP Pharmaceuticals, said in a conference call Tuesday.

FDA also indicated that it had not been able to complete review of inhaler usability information requested late in the review cycle by FDA. Based on NDA usability study across 1,000 patients and 10,000 headaches, “we believe that there would not be any changes needed for the device itself,” Nelson said.

FDA did not cite any clinical safety or efficacy issues, nor did FDA request that any additional clinical studies be conducted prior to approval. “This is extremely encouraging,” Nelson said.

MAP Pharmaceuticals said that it is pleased with FDA-provided revisions to product labeling and packaging, including correct use of the Levadex trade name.The company plans to request an end-of-review meeting with FDA to discuss the issues raised in the CRL. FDA has 14 days to respond to the company’s request.

Levadex met all 4 primary end points in the efficacy portion of MAP Pharmaceuticals’ phase 3 clinical trial, showing statistically significant improvement in pain relief, freedom from phonophobia (sensitivity to sound), freedom from photophobia (sensitivity to light), and freedom from nausea as reported 2 hours after dosing, the company reported in a press release.

Additional end points showed that Levadex provided rapid and sustained pain relief for up to 48 hours after dosing. Levadex was well tolerated, with the most common adverse event reported being medication aftertaste at 6%, with 2% of patients receiving placebo also reporting medication aftertaste. The next most common adverse event was nausea at 5%, compared with 2% for placebo. There were no mean decreases in lung function, as measured by spirometry, between the Levadex and placebo groups. There were no drug-related serious adverse events reported in the trial.

Migraine is a common, debilitating neurological disorder that affects approximately 30 million people in the United States, according to the National Headache Foundation.

In January 2011, MAP Pharmaceuticals announced a collaboration with Allergan to co-promote Levadex to neurologists and pain specialists in the United States and Canada.

"MAP is committed to making this important new therapy available to people who experience migraine,” Nelson said in the press release.