Pozen MT 100 Indication For Migraine Without Nausea To Be Considered By Committee

FDA's Peripheral & Central Nervous System Drugs Advisory Committee will weigh whether Pozen should go forward with additional study in non-nauseated migraine patients.

A limited indication for Pozen's MT 100 for treatment of migraine without nausea will be discussed by FDA's Peripheral & Central Nervous System Drugs Advisory Committee at its Aug. 4 meeting.

"Does an indication limited to the subpopulation of migraine patients with no nausea at baseline represent a clinically meaningful and acceptable indication?" FDA will ask the committee.

The committee will consider whether the benefits from the combination naproxen/metoclopramide therapy outweigh the risks of tardive dyskinesia, potential carcinogenicity, and vascular risks.

[Editor's Note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

"The goal of the [advisory committee] meeting is to determine - before Pozen conducts an additional efficacy study - if the risk of TD with the expected use of metoclopramide in the migraine population is low enough to consider approval of MT 100 for use in the subpopulation of non-nauseated migraine patients," Division of Neuropharmacological Drug Products Team Leader Eric Bastings said in a June 20 ^FDL-1 memo to the committee.

FDA found that that "the treatment effect size (for sustained relief) of MT 100 over naproxen is very modest (4%-6%)."

In addition, FDA's analysis of the studies (301 and 304) found no statistically significant difference between the MT 100 and naproxen overall in sustained pain response, with p-values of .064 and .063, respectively.

Pozen conducted an alternative analysis that did show a statistically significant difference, but FDA rejected the result because the analysis was not prespecified.

Pozen's "exploratory" subgroup analyses of the 301 and 304 studies did find a statistical benefit for MT 100 over naproxen in migraine patients without nausea, p-values of .009 and .004, respectively.

However, FDA pointed out that there was no difference between MT 100 and naproxen when it came to two-hour pain response in the non-nauseated migraine patients. "So these subgroup analyses failed to establish a contribution of metoclopramide to the two-hour response rate, which is a key migraine endpoint."

In considering a limited indication for MT 100, FDA pointed the committee to surveys that show "90% of all migraineurs" experienced nausea during an attack. The incidence of nausea in the MT 100 trials varied from 45% to 69%, FDA noted. Pozen argues that even 10% of migraine patients is a large number.

FDA said that "if MT 100 is only shown to be effective and indicated for attacks with no nausea, those patients would either need to have a separate treatment for those attacks with nausea at baseline, or would take MT 100 for a condition for which metoclopramide has not demonstrated its contribution, hence they would be exposed to the risks of adverse events with metoclopramide without demonstrated benefit."

An FDA review of its Adverse Events Reporting System database identified 68 unique metoclopramide related cases of tardive dyskinesia, ranging in doses between 5mg-80mg daily. The proposed MT 100 dose is 16 mg and no case of TD was observed in the NDA trials.

The AERS review did not identify cases of movement disorders after intermittent short-term use of metoclopramide. "There is no current indication for chronic/intermittent use, which may explain the absence of cases in AERS," FDA said, although 2% of metoclopramide use in the review was for migraine.

FDA maintained that some animal and some human data suggest that intermittent use of neuroleptics may be no safer than chronic use.

The agency cited a literature review that concluded that "intermittent neuroleptic therapy may increase the risk of persistent tardive dyskinesia and increase dopaminergic sensitivity.

- Christopher Hollis