MAP Pharmaceuticals, Inc (MAPP)

[frontiers]

Levadex has shown heart valve changes in P3 trials (3 pts with issues out of 638 pts)


Source : http://www.mappharma.com/file.cfm/124/docs/Cardiac_Web.pdf

Excerpt

Assessment of Cardiac Safety of MAP0004 Orally Inhaled Dihydroergotamine (DHE)
The cardiac safety of MAP0004 was assessed in clinical studies
Echocardiograms and electrocardiograms were reviewed by Board Certified
Cardiologists at a central reading center

Three MAP0004 treated subjects (out of 638) had changes in vavular regurgitation (two of tricuspid valve and one of mitral valve) vs. none in placebo treated subjects (out of 217). Changes were not considered clinically relevant.

Comments

Sounds similar to the phenfen story from Wyeth ? Initial reports were on heart valve changes and ignored till some phenfen users died. The initial reports for Levadex note changes but they are not clinically relevant. The same story happened with Redux. Has MAPP done follow-up biopsy on the affected valves to rule out fibrotic changes ? No, they did not do this.

Both fenfluramine and dihydroergotamine are 5HT 2B agonists, fenfluramine has greater agonist action meaning dihydroergotamine (DHE) is partial agonist, LSD, a compound related to DHE is a full agonist. But fenfluramine and DHE bind 5HT 2B equally well. Like Redux, DHE as Migranal or Dihydergot carry a warning for cardiac valvulopathy (see label for Migranal). The FDA may consider the heart valve findings for Levadex negatively. The issue becomes relevant as Levadex has shown issues in a relatively small number of patients, placebo has no such cases. Effect of exposure is one more thing that the FDA will look at. Levadex, if approved, will increase the use of DHE further than what Migranal has done (Vernalis does not promote as well enough) and the heart valve issue becomes a real concern.

The 6 month dog toxicology study with Levadex did not show any issues. However, the study did not use known heart valve disease causing agents as controls, fenfluramine as positive control and cyproheptadine as negative control. Should controls fail to show expected results, dog model would be invalid for cardiac valve disease. SD rat and cynomolgous monkey have been shown to be meaningful. A good reference for drug induced valvulopathy is a recent GSK presentation. (http://www.toxpathindia.com/docs/fourth_conference_2012/Elangbam_Drug-induced%20Valvulopathy.pdf). It lists DHE as causing Drug Induced Valvulopathy.

Levadex subjects the lung and heart to higher levels of DHE compared to Migranal Nasal Spray as delivery of DHE through Levadex is pulmonary absorption while Migranal is nasal cavity based absorption and more distributed before reaching the heart. Both bypass hepatic extraction. Both are equally effective at treating acute migraine based on P3 data (comparison across trials unfortunately). Levadex is not a big advance over Migranal in this regard.
In the Migranal NDA comments (NDA 20148, documents at FDA site), the FDA notes that while oral, intra-venous, intra-muscular and sub-cutaneous forms of DHE are already marketed, the FDA considers nasal spray different for two reasons. Firstly, the delivery method subjects the nasal cavity to high levels of drug and nasal toxicity becomes relevant. Secondly, DHE is used sparingly in current forms as oral is not very effective and injected forms are delivered by HCP. With a nasal spray approval, use will increase due to convenience and hence, performing rigorous studies to study risks is needed. The FDA gave Novartis a non-approvable letter and noted that nasal delivered carcinogenicity studies in rodents are needed for approval. In the case of Levadex, MAPP has done the 6 month Levadex dog toxicology study but this may not address the relevant lung and heart exposure issue with respect to valve pathology as the dog model is not validated for such effects. The FDA may delay approval till human studies for cardiac valve disease studies are done by MAPP considering that duplication in an animal model may be problematic. A 2 year study with 5000 patients against placebo is a guess.

Zecuity is a far safer option for treating acute migraine and a true advance over sumatriptan oral, sc or nasal. Levadex is another version of Migranal. Novartis has divested Migranal to Vernalis without completing 2 year nasal spray rat carcinogenicity studies that the FDA required as a post market commitment. Novartis submitted a preliminary 2 year nasal carcinogenicity report just prior to approval that the FDA did not review at approval (noted in documents) but Novartis did not provide a full report as needed. The label for Migranal till today notes that rat nasal delivered carcinogenicity studies are not available. This baggage goes with Levadex. MAPP is not submitting these either as they are using the 505 (b) (2) pathway inappropriately, what is needed is a full new NDA through the (505) (b) (1) pathway. Migranal pulmonary and cardiac fibrosis issues will appear on the Levadex label if MAPP used 505 (b) (2) as planned. Removal of pulmonary and cardiac fibrosis will be a gift to the lawyers. This pulmonary and cardiac fibrosis warning for long term use on the Levadex Label will make the clean Zecuity Label appealing for physicians and their patients.

Another recent example of a drug with 5HT 2B binding is lorcaserin. The FDA gave Arena a CRL and called for an Advisory Committee Meeting. One of the issues for discussion at the Advisory Committee Meeting was the heart valve fibrosis (see briefing document). Lorcaserin is a new chemical entity without past experience. DHE in Levadex is an existing drug and has shown cardiac fibrosis and 5HT 2B binding to be as potent as pergolide, an agent withdrawn due to pulmonary and cardiac fibrosis. The FDA cannot ignore considering that heart valve changes were seen in rather small P3 Levadex trials.