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.
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