Transthyretin amyloidosis deposits. Credit: Steve Gschmeissner/Science Photo Library

The first medication for a rare and often fatal protein misfolding disorder has been approved in Europe. On November 16, the EU gave a green light to Pfizer's Vyndaqel (tafamidis) for treating transthyretin amyloidosis in adult patients with stage 1 polyneuropathy symptoms. Chemist Jeffery Kelly, now at the Scripps Research Institute in La Jolla, California, began working on transthyretin amyloidosis, including familial amyloid polyneuropathy (TTR-FAP), in 1989. He later founded FoldRx in Cambridge, Massachusetts, to develop a small-molecule kinetic stabilizer for transthyretin in its correctly folded form (Nat. Biotechnol. 27, 874, 2009), and in 2010, New York–based Pfizer acquired FoldRx. The approval was based on a study of 128 TTR-FAP patients. Although 45% of patients randomized to Vyndaqel showed improved or stabilized nerve function, compared with 30% of patients on placebo, the results fell short of statistical significance, and Vyndaqel also missed its quality-of-life end point. However, a secondary analysis adjusting for patients who left the study early for liver transplant (the only current therapy) met both end points. Nevertheless, Philip Hawkins, clinical director of the National Amyloidosis Centre in London, calls the EU approval “puzzling.” “The clinical results seem disappointing,” he says. Kelly disagrees. “It's unequivocal that the drug works,” he says.

The autosomal dominant disease is most commonly caused by a V30M transthyretin gene mutation. It affects only 5,000–10,000 people worldwide. But Vyndaqel has potential for much wider use, as unstable transthyretin proteins, which can accumulate as amyloid fibrils and deposit in a variety of organs including theheart and kidneys, probably affect millions of people. Pfizer's potential competitors include Alnylam Pharmaceuticals in Cambridge, Massachusetts, with a lipid nanoparticle short interfering RNA for transthyretin, and Isis Pharmaceuticals in Carlsbad, California, with an antisense compound. Both are in phase 1 trials, as is GlaxoSmithKline's ligand to serum amyloid protein. Dolobid (diflunisal), an old nonsteroidal anti-inflammatory drug, is in phase 3. Kelly especially likes Alnylam's approach, which has effectively silenced transthyretin in clinical studies. “The tafamidis drug will be used in combination with RNAi [RNA interference] suppression in the pretty near future,” he predicts. In the US, Pfizer filed a new drug application (NDA) with the Food & Drug Administration in February 2011, but received a Refusal to File letter on the grounds that the application was incomplete. Pfizer spokeswoman Victoria Davis, in an email, says Pfizer “is on track with the NDA refiling.”