Inhaled Dihydroergotamine Relieves Migraine Pain in Phase 3 Trial

Allison Gandey

September 23, 2010

September 23, 2010 (San Francisco, California) — A new inhaled formulation of dihydroergotamine is making its way through a phase 3 clinical trial program and investigators say they are encouraged by what they see — improvements in coprimary endpoints of pain relief, photophobia, phonophobia, and nausea.

Presenting here at the American Neurological Association 135th Annual Meeting, researchers showed the latest numbers for the MAP Pharmaceuticals product also known as Levadex.

Dihydroergotamine in a Tempo inhaler.

Despite the availability of many acute migraine medications, including 7 different triptans, an estimated 71% of migraine patients report they are dissatisfied with their treatment. Physicians and patients report inconsistent response, high recurrence rates, and slow onset of action.

Investigators hope an inhaled version of dihydroergotamine, which is currently available as an intravenous agent, will be more convenient and provide faster pain relief. MAP Pharmaceuticals has developed the Tempo inhaler to deliver the drug.

The new study of the inhaled formulation included 792 patients with migraine. Medscape Medical News first reported topline results of this US Food and Drug Administration–required investigation last year. Coauthor Stephen Silberstein, MD, director of the Headache Center at Jefferson Medical College in Philadelphia, Pennsylvania, later presented the findings at a meeting last September (14th International Headache Conference). Dr. Silberstein said he was encouraged to see pain relief as early as 30 minutes.

These latest numbers, which detail the findings over a range of time points, were presented by Shashidhar Kori, MD, from MAP Pharmaceuticals. The team reports the inhaled therapy met the coprimary endpoints of pain relief, photophobia, phonophobia, and nausea 2 hours after treatment.

Table 1. Proportion of Patients With Pain Relief

Time After Treatment Inhaled Dihydroergotamine, % Placebo, % P Value
10 min 9 6 .1584
30 min 29 22 .0245
1 h 48 28 <.0001*
2 h 59 35 <.0001
4 h 65 37 <.0001

* Not adjusted for multiplicity.

Table 2. Proportion of Patients Photophobia Free

Time After Treatment Inhaled Dihydroergotamine, % Placebo, % P Value
10 min 9 7 Not reported
30 min 18 14 Not reported
1 h 31 22 .0032
2 h 47 27 <.0001
4 h 53 30 <.0001*

* Not adjusted for multiplicity.

Table 3. Proportion of Patients Phonophobia Free

Time After Treatment Inhaled Dihydroergotamine, % Placebo, % P Value
10 min 15 13 Not reported
30 min 27 21 .0286
1 h 39 26 <.0001*
2 h 53 34 <.0001
4 h 57 33 <.0001*

* Not adjusted for multiplicity.

Table 4. Proportion of Patients Nausea Free

Time After Treatment Inhaled Dihydroergotamine, % Placebo, % P Value
10 min 36 34 Not reported
30 min 41 48 Not reported
1 h 53 55 Not reported
2 h 67 59 .0210
4 h 64 46 <.0001*

* Not adjusted for multiplicity.

Nausea was the second most common adverse event with inhaled dihydroergotamine (4.5% vs 2% placebo). Complaints about taste were the most common adverse effect (6% vs 2%).

The investigators observed no decline in pulmonary function following therapy. Spirometry measurements were similar between groups. "We feel comfortable at this stage there is no change in lung function," Dr. Kori said during an interview.

Radiolabeled drug distribution in the lungs.

Coauthor Sheena Aurora, MD, director of the Swedish Headache Center at the University of Washington in Seattle, spoke to Medscape Medical News when the topline results were first presented. She emphasized that as with any vasoconstrictor, dihydroergotamine should not be taken by patients who have coronary artery disease, are at risk for stroke, or have blood vessel problems.

This drug, she says, has the potential to become a first-line therapy because, unlike its intravenous counterpart, it is practical and easy to use. "The inhaled preparation gives you the same benefit of the intravenous drug, but you can take it at home," Dr. Aurora said.

Meeting delegates such as Jigar Desai, PhD, a postdoctoral fellow, were skeptical about the safety of this new formulation. Dr. Desai said he is not convinced about this new method of delivery. "We will need to see more data before we can feel confident this is a safe approach," he said. Dr. Desai also voiced concern about the large number of statistically insignificant findings in the trial with weak or unreported P values.

"The authors suggest that pain relief can begin as early as 30 minutes after treatment, but these numbers do not convince me this is the case."

This study was funded by MAP Pharmaceuticals. Lead investigator Dr. Kori is an employee of the company.

American Neurological Association 135th Annual Meeting: Poster M-41. Presented September 13, 2010.


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