No FDA Approval Yet for Levadex, Inhaled Migraine Treatment

Susan Jeffrey


April 16, 2013

The US Food and Drug Administration (FDA) has declined approval for an orally inhaled formulation of dihydroergotamine (DHE; Levadex, Allergan Inc) for acute treatment of migraine in adults.

The hope for the new formulation of DHE, which is already available as an intravenous agent and as an intranasal treatment (Migranal, Valeant Pharmaceuticals), is to provide a rapid onset of action and sustained pain relief with fewer adverse effects compared with intravenous administration.

However, this morning, Allergan released a statement saying the company received a Complete Response Letter (CRL) from FDA on their New Drug Application.

"Allergan is pleased that, in addition to the response, the company has already received draft labelling from the FDA," the statement notes, adding that they anticipated minimal revisions to this labelling. "The company is committed to bringing Levadex to market as a potential new treatment to address a significant unmet need among millions of people with debilitating migraines."

The main issues cited by the FDA in the CRL had been raised in prior discussions, the company writes, and Allergan "has already taken steps to address the concerns."

  1. "Per the FDA's comments in the CRL, during a previous inspection, the agency noted concerns with Exemplar Pharma, LLC, the canister filling unit manufacturer. In accordance with Allergan's overall manufacturing strategy to secure our supply chain, Allergan completed the acquisition of Exemplar on April 12th, 2013, for less than $20 million. Allergan has appointed senior members of Allergan's Global Technical Operations to oversee the facility. Allergan anticipates that the FDA will require a re-inspection of the Exemplar facility prior to approval. "

  2. "The FDA also noted concerns regarding the manufacturing process for the final filled canisters. Allergan has already responded to this concern. As the FDA indicated in the CRL, the Agency has not yet reviewed Allergan's response under the current PDUFA [Prescription Drug User Fee Act] timeline."

The company remains committed to "vigorously address the concerns raised by the FDA in the CRL," the Allergan statement adds. On the basis of their understanding of the letter, they say, "the company estimates that the next FDA action will occur by the end of Q4 2013."

In the meantime, the company reiterates guidance on earnings per share issued previously, noting that even with an approval on the original timeline, the 2013 sales of Levadex would have been "minimal."

Previous Complete Response

This FDA approval application was based on phase 3 findings from the multicenter, randomized, double-blind, placebo-controlled phase 3 trial, FREEDOM-301, reported previously by Medscape Medical News. The trial met all 4 primary endpoints of relief of pain, phonophobia, and photophobia and freedom from nausea at 2 hours. The study was funded by MAP Pharmaceuticals Inc, which developed the Tempo inhaler to deliver the drug, and was acquired by Allergan Inc earlier this year.

The drug showed rapid and sustained efficacy, was well tolerated with minimal adverse effects, and produced a low incidence of triptan-like sensations. It also appeared effective in patients generally thought to be treatment-resistant. The most common adverse event was medication aftertaste, reported in 6% of the treatment group but also in 2% of placebo-treated patients. There were no decreases in lung function.

However, on March 26, 2012, the FDA issued a first CRL, declining approval for this formulation at that time.

"In the Complete Response letter, the 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," a statement from MAP Pharmaceuticals noted at that time. "The FDA also indicated that it had not been able to complete review of inhaler usability information requested late in the review cycle by the FDA."  

The FDA did not cite any clinical safety or efficacy issues, nor did the agency request that any additional clinical studies be conducted before approval, the statement added.