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By April 15, 2013, the United States Food and Drug Administration (FDA) will decide whether to approve MAP Pharmaceutical's (MAPP) drug Levadex for the treatment of acute migraine. The FDA previously rejected MAP's new drug application for Levadex due to concerns regarding inhaler usability and the chemistry, manufacturing, and controls section of the application. However, the FDA accepted a resubmitted new drug application for Levadex this past November. Notably, MAP was recently acquired by Allergan (AGN). Based on our analysis, we believe Levadex is highly likely to receive FDA approval, which should benefit Allergan's stock price in the near term.

Background

MAP Pharmaceuticals is a biopharmaceutical company developing innovative therapies for neurological diseases. MAP specifically aims to improve the performance of proven drugs through a novel aerosol delivery platform. Levadex, the company's lead product, is a combination of the drug dihydroergotamine mesylate (DHE) and a proprietary inhaler. This inhaler allows simple, consistent delivery of DHE via the pulmonary route.

DHE treats acute migraine, including migraine recalcitrant to triptans, the standard first-line therapy. Migraine is a common and often disabling neurological disorder with complicated pathological mechanisms that have not yet been thoroughly characterized. Affected patients suffer from recurrent moderate to severe unilateral headaches and a variety of associated symptoms such as nausea, photophobia (sensitivity to light), and phonophobia (sensitivity to sound). Migraine affects more than 10% of people worldwide. In the U.S., about 6% men and 18% women suffer at least one migraine per year, amounting to an annual cost of $13 billion.

When patients become afflicted with migraine, they typically receive a triptan drug as initial therapy. Various classes of triptan drugs exist. In the U.S., triptan drugs account for more than 90% of all migraine prescriptions. If a patient does not respond well to a given triptan, physicians often rotate between triptans before switching to other options such as ergotamine, non-steroidal anti-inflammatory drugs (NSAIDs), or analgesics. Although DHE, a derivative of ergotamine, has been approved for clinical use in the U.S. since the 1940s, it is relatively ineffective in pill form and, consequently, infrequently prescribed. DHE is used quite often in clinical settings to treat acute headache through intravenous administration. When delivered in an effective form (e.g. intravenously), DHE has several advantages over triptans. DHE has faster onset and lasts longer. MAP's inhalable form of DHE now makes this drug suitable for outpatient use.

Orally inhaled Levadex effectively treats acute migraine

MAP has conducted nine clinical trials to evaluate the safety and efficacy of Levadex. Its phase III trial included 903 adult patients with a history of episodic migraine. The trial contrasted Levadex to a placebo lacking an active ingredient. Primary endpoints monitored two hours after treatment assessed the incidence of pain, nausea, photophobia, and phonophobia. Patients receiving Levadex responded significantly better than placebo patients for each of these endpoints. Furthermore, Levadex patients maintained their pain-free state for 24 hours after treatment.

About half of these patients experienced allodynia, a condition where patients perceive pain from mild stimulation of the skin by touch or massage. Notably, triptans ineffectively treat migraine accompanied by allodynia. Levadex, however, is effective at treating migraine regardless of whether allodynia is present. This accomplishment suggests Levadex may have wide market appeal, as it can be used to treat migraine sufferers who have allodynia or otherwise do not respond well to triptans.

Levadex has a favorable safety profile

MAP completed several trials to evaluate the safety of Levadex. No drug-related serious adverse events were observed in Levadex's phase III trial. In both this phase III trial and its associated twelve month open-label extension study, there were no especially salient adverse events. Notably, DHE use was not accompanied by the set of side effects that plague triptans--the so-called triptan sensations--which include chest pain, tingling, and flushing. Moderately common, likely drug-related adverse events include nausea, cough, and vomiting, side effects that appear to be generally mild in nature.

Importantly, clinical studies indicate Levadex may not have the same level of pulmonary side effects as other aerosolized medications, such as Alexza Pharmaceuticals' (ALXA) Adasuve and MannKind Corporation's (MNKD) Afrezza. Levadex affected pulmonary artery pressure less strongly than intravenously delivered DHE and, in this regard, was indistinguishable from the placebo. In fact, the overall incidence of adverse events for Levadex was lower than that for intravenously delivered DHE. Furthermore, adult asthmatics and smokers on Levadex had no pronounced safety issues relative to comparably treated healthy patients.

MAP diligently responded to the FDA's concerns

When the FDA rejected Levadex in March 2012, the agency did not identify any issues related to the drug's efficacy or safety, or request additional clinical studies. Instead, the FDA asked for information on patient experience with the inhaler--information that can be acquired from MAP's existing clinical trial data--and improvements related to the chemistry, manufacturing, and control section of the application. In June 2012, MAP met with the FDA to confirm the suitability of proposed contents for a resubmitted application. This meeting clarified necessary actions for satisfying the chemistry, manufacturing, and control section. Overall, MAP responded to the FDA's concerns in a timely and productive manner. We expect the FDA will view these responses as adequate for approval.

Summary

MAP's clinical trials show that Levadex has a high efficacy-to-safety ratio for the treatment of acute migraine. As a broadly efficacious therapy, Levadex may gain sizeable market adoption, especially for patients non-responsive to triptans. From the FDA's perspective, drug approval requires an evaluation of associated risks and benefits. For Levadex, the risks are low and the benefits are quite clear. We expect Levadex to gain approval by the upcoming FDA action date.

Source: MAP's Levadex Ready For FDA Approval

Additional disclosure: Beacon VP Investments is a team of analysts. This article was written by Wendy Bian, one of our team members.