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FDA Delivers CRL for Pfizer's Rare Disease Drug Vyndaqel

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By Karen Pihl-Carey
Staff Writer

Asking for a second efficacy study, the FDA issued a complete response letter (CRL) for Pfizer Inc.'s new drug application for tafamidis meglumine to treat the orphan indication of transthyretin familial amyloid polyneuropathy (TTR-FAP).

New York-based Pfizer, which acquired the drug in 2010 through its acquisition of FoldRx Pharmaceuticals Inc., received approval from the European Commission last November for the novel, selective stabilizer of the transthyretin protein, which is branded there as Vyndaqel, to treat TTR-FAP in adults with Stage I symptomatic polyneuropathy.

The FDA's decision not to follow suit, however, comes without surprise after the Peripheral and Central Nervous System Drugs Advisory Committee delivered a split vote in May, indicating some uncertainty over whether the one pivotal trial was enough for approval. It voted 4-13 against recommending the use of the single study as providing enough efficacy evidence; but it voted 13-4 that the data provided internal consistency and a replication of effect. (See BioWorld Today, May 25, 2012.)

In the CRL, the agency requested a second efficacy study, which is not always necessary for approval of an orphan indication. That additional trial could take another 18 months. The FDA also wants additional information on the data within the current new drug application package.

"It is our intention to request a meeting as soon as possible with the agency in order to discuss a potential path forward," said Pfizer spokeswoman Victoria Davis.

Tafamidis meglumine, which is designed to stabilize the misfolding transthyretin protein to prevent further accumulation of amyloid fibrils on the nerve tissue, was the primary driver for Pfizer's 2010 acquisition of privately held FoldRx, of Cambridge, Mass. (See BioWorld Today, Sept. 2, 2010.)

The pharmaceutical company has built a presence in rare diseases, creating a unit specifically aimed at finding treatments for diseases affecting fewer than 200,000 U.S. patients. It's an area of business that requires less investment, and offers more government incentives and big price tags (sometimes as high as $500,000) to offset the smaller patient populations – an attractive formula for pharmaceutical firms like Pfizer, which lost patent protection last November of its $13 billion-in-peak-annual-sales cholesterol drug Lipitor. (See BioWorld Today, April 16, 2012.)

TTR-FAP is a fatal genetic disease that affects 5,000 to 10,000 people worldwide, with about 2,500 patients in the U.S. and other clusters found in Japan, Portugal and Sweden. Patients experience sensory loss, pain and weakness in the lower limbs, and impairment of the autonomic nervous system, resulting in things like erectile dysfunction, alternating diarrhea and constipation, and orthostatic hypotension. The only available treatment is liver transplant. Many patients die about 10 to 15 years after onset.

FoldRx completed its pivotal Phase II/III trial in 2009 – a year before the Pfizer acquisition. The 18-month trial enrolled 128 patients who received 20 mg of the drug or placebo. Although the study missed its primary endpoints of improvement in neuropathy impairment score – lower limb and quality of life, it did show statistical significance in a secondary endpoint of reducing attrition due to liver transplantation, and it demonstrated transthyretin stabilization in 98 percent of treated patients, compared with none on placebo.

An open-label extension study also showed that patients treated with tafamidis for 30 months had less neurologic deterioration than patients who began tafamidis 18 months later. Secondary endpoints showed treated patients had a significantly improved physiologic performance compared with placebo, and they maintained their quality of life, while placebo patients worsened. The most common adverse events were diarrhea, upper abdominal pain, urinary tract infection and vaginal infection.

Of the patients enrolled in the original study, 58 percent came from a single Portugese site, leaving FDA officials wondering if the findings could be extrapolated to U.S. patients. Another concern has focused on whether the randomized, double-blind, placebo-controlled study was sufficiently powered. It enrolled FAP patients with the V30M genetic mutation – which accounts for the disease in 40 percent of U.S. patients – but it wasn't clear as to whether pivotal results would be applicable to patients without that mutation.

Furthermore, only 91 of the original 128 patients completed the study, with many dropping out to get a liver transplant, although a subset analysis showed the drug significantly improved outcomes compared to placebo.

In April 2011, Pfizer received a refuse-to-file letter from the FDA for the tafamidis meglumine NDA, with the agency saying the application was incomplete. The agency later accepted the NDA for review in February of this year.