Levadex (MAP0004) Orally Inhaled Aerosol for Treating Migraine Headaches

Dihydroergotamine (DHE) is an ergot alkaloid used for the acute treatment of migraine headache since Novartis International AG (Basel, Switzerland) introduced it to the United States in 1946.1,2 While DHE's exact mechanism of action is unclear, it is proposed to act as an activator of various 5-hydroxytryptamine (i.e., 5-HT or serotonin receptors), which may relieve migraine symptoms by causing meningeal vasoconstriction and trigeminal inhibition of pro-inflammatory neuropeptide release.3 DHE is available as an injectable solution and as a nasal spray.1 Levadex (MAP0004), a novel, orally inhaled formulation of DHE, is developed by MAP Pharmaceuticals (Mountain View, CA, USA) and Allergan, Inc. (Irvine, CA, USA) to treat migraines.2 The drug is delivered by its developer's proprietary Tempo breath-activated metered dose inhaler.1,4 Compared with the current injectable formulations that cannot be administered at home, Levadex may offer faster relief and fewer side effects and may be a more convenient option for patients who respond to DHE.5  In addition, preliminary data indicate that patients using Levadex experience less nausea and vomiting than patients treated with intravenous DHE.5 Since Levadex is an orally inhaled therapy, the developer claims that users will avoid the local nasal irritation and inconsistent absorption often associated with nasal spray delivery of the drug.6 If approved, Levadex would be indicated for treating acute migraine headaches in adults.7,8

The formulation has not yet been approved for marketing in the United States or elsewhere.8 The U.S. Patent and Trademark Office has issued three pharmacokinetics-related patents for Levadex, which expire in 2028.8,9 Allergan is copromoting Levadex to neurologists and pain specialists in Canada.8 MAP Pharmaceuticals is also working with potential partners to market Levadex in other countries outside the United States.10

In December 2010, MAP Pharmaceuticals completed the clinical trials required for a 505(b)(2) submission to the U.S. Food and Drug Administration (FDA).1 In May 2011, the company submitted a New Drug Application (NDA) for Levadex to treat acute migraines in adults, which FDA accepted in August 2011.8,11 MAP Pharmaceuticals is addressing issues pertaining to chemistry, manufacturing, and controls, as requested in the Complete Response Letter (CRL) that FDA issued on March 26, 2012.12 FDA was unable to complete review of inhaler usability information that it requested late in the review cycle but did not cite any clinical safety or efficacy issues with the drug or request that any additional clinical studies for approval.12 MAP Pharmaceuticals plans to resubmit its NDA to...