Pivotal trial missed co-primary endpoints, but a secondary analysis along with an extension study showed success.

Pfizer reports that the European Commission has cleared Vyndaqel® (tafamidis) for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with stage 1 symptomatic polyneuropathy.

“Until now, there were no approved medications to treat this degenerative and fatal disease,” says Teresa Coelho, M.D., of the Hospital Santo Antonio in Porto, Portugal, who participated in the clinical trials of Vyndaqel.

In the U.S., Pfizer received a refusal to file letter from the FDA in April. The agency determined that the application, which was submitted in February, was not sufficiently complete to permit a substantive review. The company says that the additional information needed to support this filing is available without further clinical studies, but has not reported any subsequent discussions with FDA.

Mutations of the transthyretin (TTR) gene can result in the production of unstable TTR proteins, which can accumulate as amyloid fibrils. Vyndaqel is a specific transthyretin stabilizer designed to prevent the formation of these misfolded proteins and the subsequent amyloid deposits that induce neurodegeneration and decline of neurologic function. In the pivotal trial (Fx-005), transthyretin stabilization (as demonstrated by an in vitro assay) was observed in 98% of patients on Vyndaqel and in no patients on placebo at 18 months.

The EC approval was based on results from Fx-005 and an open-label, 12-month extension study called Fx-006. Fx-005 was an 18-month, multicenter, randomized, double-blind, placebo-controlled study that evaluated once-daily 20 mg Vyndaqel in 128 patients with TTR amyloid polyneuropathy with the V30M mutation and primarily stage 1 disease.

This study missed its co-primary endpoints of primary outcome measures, which were the Neuropathy Impairment Score – Lower Limb (a physician assessment of the neurologic exam of the lower limbs) and the Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QOL-DN; a patient reported outcome, total quality of life score). Other outcome measures included composite scores of large nerve fiber and small nerve fiber function and nutritional assessments utilizing the modified body mass index (mBMI).

It did, however, meet statistical significance in a predefined secondary analysis, which was designed to adjust for the impact of patient attrition due to liver transplantation. Following 18 months of treatment in a double-blind, placebo-controlled trial, more Vyndaqel-treated patients were NIS-LL responders. The secondary endpoints demonstrated that Vyndaqel treatment resulted in less deterioration of neurologic function and improved nutritional status compared with placebo.

The extension study was conducted over 12 months as an open-label, single-treatment arm study. The rate of change in the NIS-LL was similar to that observed in those patients randomized and treated with Vyndaqel in the previous double-blind, 18-month period.

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