SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

Tania D. Strout, PhD, RN, MS

Article

Infant with bilious emesis

Article

Diagnosis of Severe Acute Lower Gastrointestinal Bleeding with CTA