2011: Year in Review

Stephen J. Peroutka, MD, PhD


Headache. 2012;52(1):168-172. 

In This Article

New Therapies: Acute Treatment of Migraine

Possible FDA Approvals in 2012

After the lack of FDA approvals in 2011, 2012 should prove to be a more productive year for new migraine therapies. Specifically, FDA approvals are expected for inhaled dihydroergotamine and a transdermal sumatriptan patch.

Products in the Pipeline

Inhaled Dihydroergotamine (Levadex®[MAP Pharmaceuticals Inc., Mountain View, CA, USA], Formerly Referred to as MAP0004).— In March 2011, MAP Pharmaceuticals Inc. announced the completion of its clinical development program involving inhaled dihydroergotamine for the acute treatment of migraine. This 505(b)(2) clinical development program evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of inhaled dihydroergotamine in approximately 1000 patients.

In August 2011, MAP announced that its New Drug Application (NDA) for orally inhaled dihydroergotamine (Levadex®) for the acute treatment of migraine in adults had been accepted for filing by the FDA with a goal review date of March 26, 2012, under the Prescription Drug User Fee Act (PDUFA).

If approved, Levadex® will be the first new drug approved for the acute treatment of migraine since diclofenac with potassium bicarbonate (Cambia®, MAP Pharmaceuticals, Inc.) in 2009.

Sumatriptan Transdermal (Zelrix®[NuPathe Inc., Conshohocken, PA, USA], Formerly Known as NP101).— In August 2011, NuPathe Inc. announced that it received a Complete Response Letter from the FDA regarding its NDA for transdermal sumatriptan patch (NP101; Zelrix®) for the treatment of acute migraine. The company stated that the FDA acknowledged NuPathe had established the efficacy of the patch but had questions related to the chemistry, manufacturing, and safety of the product. The company stated that it believed that it has, or shortly will have, sufficient data to address the questions raised by the FDA.

As a result, NuPathe announced that it will not be able to market its migraine patch in the first half of 2012, as previously announced. In October 2011, the company reported positive top-line results from NP101–009, its second 12-month/multiple use safety trial. A total of 479 patients were enrolled and applied at least 1 patch. The incidence of adverse events known to be related to triptans (including chest tightness, flushing, and feelings of pressure and numbness) was reportedly low, with only 4 patients (0.8%) reporting such symptoms over the course of the 12-month trial.

The most common adverse events in the NP101–009 study occurred at the patch application site and included: application site pain (19% of patients), application site itching (14%), and application site reaction (6.1%). During the trial, 13% of patients withdrew from the study due to adverse events (primarily related to the patch application site).

The company believes that the complete dataset for the NP101–009 study will be supportive of its NDA resubmission to the FDA. Additional product updates are likely in 2012.

BMS-927711.— Bristol-Myers Squibb planned to initiate a phase 2 study entitled "Dose ranging study of a drug for the treatment of acute migraine" in late 2011. The drug has been designated as "BMS-927711," but its putative mechanism of action has not been reported. The company's website, however, does list a calcitonin gene-related peptide (CGRP) receptor antagonist as being in development for an unknown indication.

This relatively large (ie, n = 720 subjects) study has been projected to complete in June 2012. As such, this study would represent the largest active clinical trial involving migraine.

Nasal Carbon Dioxide.— Despite the failure of earlier studies to demonstrate clear and convincing efficacy data, another phase 2 study of carbon dioxide infused into the nasal cavity for the acute treatment of migraine reportedly was initiated in October 2011.

The study, entitled "The effect of nasal carbon dioxide in the treatment of moderate to severe migraine," is being cosponsored and conducted by Capnia Inc. and the US military. The 450-subject study is expected to conclude in late 2013.

Lasmiditan (Formerly Known as COL-144).— CoLucid Pharmaceuticals Inc. announced in September 2011 their plans to begin phase 3 acute migraine trials toward the end of first quarter of 2012.

The dose-dependent efficacy of lasmiditan, a 5-hydroxytryptamine1F (5-HT1F) agonist, has been reported in 2 previous trials, one involving an intravenous route of administration and the other an oral route. The company has now established an investigational new drug (IND) application to begin clinical studies in the USA.

A comprehensive phase 3 program is expected to start in the first half of 2012. According to the company, the design of the pivotal trials is under discussion with the FDA and is expected to include a wide range of migraine patients with a particular focus on those poorly served by existing triptan therapy. This clinical development program will be supported by a range of clinical pharmacology studies and the final stages of an extensive preclinical safety evaluation program.

Telcagepant (Formerly Called MK-0974).— In July 2011, Merck announced that it was discontinuing the clinical development program for telcagepant, the company's investigational CGRP antagonist, for the treatment of acute migraine. The decision reportedly was based on an assessment of data across the clinical program, including findings from a recently completed 6-month phase 3 study.

This announcement followed an extensive global development program. Although the company did not provide any rationale for its decision to discontinue that program, it reportedly had put its FDA application on hold after finding elevated levels of liver enzymes in subjects who had taken the drug. Increased liver enzyme levels were also believed to be a major factor in the company's 2009 decision to discontinue a similar migraine product ("MK-3207").

Future studies clearly would be needed to determine whether the apparent liver toxicity observed with these agents is unique to their specific chemical class or relates more broadly to CGRP receptor antagonism.

NXN-188.— NXN-188 (a 5-hydroxytryptamine1 [5-HT1] receptor agonist and a neuronal nitric oxide synthase inhibitor) has been in development by NeurAxon for the treatment of acute migraine. Since reporting in late 2010 that its phase 2 trial of the drug failed to meet its primary end-point, there has been no further update on the status of the development program. Attempts to contact the company were unsuccessful.

BGG492.— BGG is an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist and putative anticonvulsant being developed by Novartis. A phase 2 acute migraine study using single doses of the drug was completed in late 2010. Because no results from the study have been released, and there is no mention of the product on that portion of the company's website that describes its clinical development pipeline, it seems likely that the study results were suboptimal and that the drug's development for migraine has been discontinued.


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