FDA Panel Sends Mixed Messages on Rare Disease Drug

May 25, 2012— -- WASHINGTON -- An FDA advisory panel considering an investigational drug to treat a rare nerve disorder agreed that a study of the drug, Vyndaqel, did not provide proof of its benefit. But the panel also agreed that, in this instance, proof may not be necessary.

First, the Peripheral and Central Nervous Systems Drug Advisory Committee voted 13-4 that Pfizer's randomized controlled study failed to demonstrate that treatment with tafamidis slows progression of familial amyloid polyneuropathy (FAP), a fatal heritable disease that affects about 2,500 Americans.

The panel then appeared to reverse itself when members voted -- again 13-4 -- that meeting secondary endpoints such as better lower-limb function in some patients -- may provide enough evidence for the FDA to approve the once-daily pill.

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Taken together, the consensus appears to be any medical treatment is better than no medical treatment.

There is no medication currently approved for FAP patients in the U.S., so the only option is liver transplant. The FDA said the 5-year survival rate rate for familial amyloid polyneuropathy after a liver transplant is about 80%.

Against that background tafamidis, which is approved in Europe, may become more palatable, and the panel members did seem to generally favor approval.

The FDA does not have to follow the advice of its advisory committees, but it often does.

FAP is caused by mutations of the transthyretin (TTR) gene, which leads to build up of amyloid primarily in the peripheral nerves, as well as other organs. Symptoms usually start between the ages of 30 and 50 and include sensory loss that can be accompanied by severe pain as well as severe autonomic dysfunction. Ultimately, distal wasting, complete loss of sensory function, and death occur, generally a little more than a decade after symptoms start.

Tafamidis binds to TTR and is meant to stabilize it and prevent the formation of the abnormal amyloid.

The panel spent Thursday reviewing Pfizer's double-blind, randomized, controlled clinical trial testing tafamidis in 125 patients with familial amyloid polyneuropathy and found there was not a statistically significant difference in the number of patients who experienced a delay in disease progression between the tafamidis and placebo groups.

The study lost statistical power because about 20 percent of the patients in each group dropped out to get a liver transplant, Pfizer said. Those discontinuations had nothing to do with the drug, the company argued. After accounting for those dropouts, the tafamidis was statistically better than placebo, Pfizer said in briefing documents released ahead of Thursday's meeting.

While the main study failed on its primary endpoints, patients on tafamidis seemed to perform better on a number of surrogate endpoints, including stabilization of TTR (as measured by blood tests), improvement on a measure that tests lower limb function, and improvement in small nerve fiber function.

In order to approve a new drug, the FDA generally requires proof of efficacy from two large "adequate and well-controlled" clinical trials, or at least one large trial with additional smaller studies that can provide backup.

FDA More Flexible on Drugs for Rare Diseases

But when making decisions on drugs to treat a very rare disease -- known as orphan drugs -- the agency tends to be more flexible. Orphan drugs won't be used in large numbers of people, and often the diseases they treat are fatal, so patients are willing to accept more risk from the drug than would the general population.

Members of the panel heard from a dozen FAP patients urging approval of tafamidis. In some cases, patients' family members -- a grandparent, aunts, uncles, cousins, and a parent -- were all suffering or had already died from FAP, which is highly hereditary.

"This is a disease that wipes out families," one patient told the panel.

Although the tafamidis's efficacy wasn't particularly good, it also doesn't have many side effects, and patients with FAP need some therapeutic option, the patients said.

"If we do approve it, a lot of people will be helped and no one will be hurt," FAP patient Geri O'Brien told the panel. "If we don't approve it, no one will be helped, research will be stymied, and we will have to wait for another 10 years."