Abnormal deposits of misfolded protein, shown in red, accumulate in body organs threatening healthy function. Prion diseases, diabetes, Parkinson's disease, Alzheimer's disease, Huntingdon's disease and transthyretin amyloidosis share misfolded protein deposits as a common feature. Credit: Steve Gschmeissner/Science Photo Library

A new drug candidate has, for the first time, modified disease progression in patients with a rare inherited protein-misfolding neuropathy. Initial results from pivotal phase 2/3 trials released by Cambridge, Massachusetts company FoldRx at the end of July suggest their compound tafamidis meglumine (FX-1006A) could be the first to successfully treat the genetic disorder transthyretin (TTR) amyloid polyneuropathy. The positive findings lend credence to the therapeutic targeting of misfolded protein to treat a raft of human diseases where insoluble protein aggregates known as amyloid are implicated.

The FoldRx trial is the first randomized, controlled trial ever completed in TTR amyloid polyneuropathy, a slow, progressive disease affecting up to 10,000 people worldwide. Pathogenesis is thought to be due to dissociation of a tetramer of the transport protein TTR, which leads to aggregation into toxic amyloid fibrils that subsequently accumulate in nerve, gut and heart tissue. The study enrolled 128 patients with the disease, who carried a confirmed V30M mutation—the most prevalent variant. Over the 18-month study, tafamidis halted disease progression, measured by the neuropathy impairment score, and quality of life—two endpoints which correlate with disease severity and serve as endpoints for neuropathy disease progression—while patients on placebo worsened.

Tafamidis, an oral, small-molecule chaperone, is a modified form of the non-steroidalagent diflusinal. The drug works by stabilizing the TTR protein complex into its normal tetrameric conformation, preventing its dissociation into the fibril-forming monomers. “This is the first drug that's ever done anything in these diseases,” says Joel Buxbaum of the Scripps Institute in La Jolla, California, where the groundwork for the small-molecule tafamidis was performed. “This is clearly a molecule that is first in its class.” Tafamidis may be unique among anti-amyloid agents because rather than target the fibrils, it acts by stabilizing the TTR tetramer, which reduces the availability of dissociated monomers, that are the fibril precursors. But Buxbaum points out that the therapeutic strategy is the same as for other protein-misfolding diseases, including those that do not involve amyloid. The aim is to reduce the amount of a misfolding precursor, whether by stabilization, in the case of TTR, or by inhibiting an enzyme.

“A wide range of protein-misfolding disorders are driven by the overproduction of mutant protein or in some cases, the overproduction of the protein itself,” says John Maraganore, CEO of Alnylam Pharmaceuticals, also in Cambridge. Alnylam, for its part, expects to seek regulatory approval to begin human studies of an siRNA against TTR by the end of 2009, and also has an early-stage siRNA program in Parkinson's. “There are data with synuclein that [indicates that] triplication of the allele leads to pathology in the genetic causes of Parkinson's,” he says, “so there are clearly both quantitative and qualitative changes in these proteins that make them pathogenic.”

Using siRNA to downregulate the expression of a protein that might be important in a misfolding disorder “is a situation that is begging for a trial,” according to John Berk, clinical director of the Amyloid Treatment and Research Program at Boston University School of Medicine, which is conducting a randomized, controlled trial of diflusinal in TTR. In TTR as well as other protein-misfolding diseases, the misfolded protein is probably there from day one, says Scripps' Buxbaum. “As soon as you turn on the gene, it's expressed,” he says, and to that extent, all of these diseases are age dependent. “The phenomenon that goes on in transthyretin amyloid once you start to deal with the misfolded monomer, it's probably going on in all of these diseases.”