FDA Declines Approval for Tafamidis in TTR-FAP

Susan Jeffrey

June 19, 2012

June 19, 2012 — The US Food and Drug Administration (FDA) has declined approval of tafamidis meglumine (Vyndaqel, Pfizer Inc) for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP).

In a Complete Response Letter, the FDA is requesting completion of a second efficacy trial to establish "substantial evidence of effectiveness," before approval of the company's New Drug Application (NDA), as well as additional information on data included in the current NDA, a statement from Pfizer notes.

"Pfizer will work with the FDA to address the content of the letter," the release said.

TTR-FAP is a rare, progressive, and fatal neurodegenerative disease that affects approximately 8000 patients worldwide; in the United States, the incidence is approximately 1 in 100,000, the company notes. It is caused by mutation of the TTR gene, leading to misfolded proteins that form amyloid fibrils in peripheral and autonomic nerves, as well as other organs, including the gastrointestinal tract, kidneys, and heart.

Onset of symptoms, including polyneuropathy and problems related to impairment of the autonomic nervous system, typically occurs during active adult years in the early 30s, reaching the terminal stage in an average of 10 years.

Tafamidis is a stabilizer of the transthyretin protein. It was approved in November 2011 in the European Union for the treatment of TTR amyloidosis in adults with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment.

Last month, in a 13 to 4 vote, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee decided that findings of a single study assessing tafamidis in patients with TTR-FAP didn't meet criteria for efficacy on a clinical endpoint.

However, the committee did decide — in a complete vote reversal — that the study had substantial evidence of effectiveness for a biomarker or surrogate marker endpoint, in this case, tests of muscle strength and small fiber function.

A drug can be approved on the basis of its effect on a surrogate marker that is reasonably likely to, but not necessarily known to, predict the desired clinical effect. A drug can also be considered for approval with a single adequate and well-controlled clinical investigation, along with confirmatory evidence, but the findings from that single study are expected to be particularly robust.

In advance of the meeting, the FDA's own reviewers had suggested the committee recommend against approval of the drug.

"TTR-FAP is a relentless and debilitating disease. We understand the urgent need within the patient community and stand firmly behind this innovative medicine," said Yvonne Greenstreet, MD, senior vice president and head of Medicines Development Group for Pfizer's Specialty Care Business Unit in the company statement. "It is our intention to request a meeting as soon as possible with the Agency in order to discuss a potential path forward."

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