A Triumph for Rare Disease Therapy Development

Amyloid polyneuropathies may be either inherited (familial amyloid polyneuropathy; FAP) or acquired. Autosomal-dominantly inherited mutations in transthyretin (TTR), a thyroxine transport protein, are the most common cause of FAP. Mutations in the TTR gene destabilize its tetrameric structure, promoting dissociation into misfolded amyloidogenic monomers. Knowledge that a second TTR mutation exerts a protective effect by countering the destabilizing effect of pathogenic mutations has led to a search for small molecule kinetic stabilizers of the TTR tetramer as a viable therapeutic alternative to orthotopic liver transplantation. Hot on the heels of promising results published last year for tafamidis, a small molecule that occupies the thyroxine-binding site, investigators now report the results of an international, double-blind, placebo-controlled trial of diflunisal in 130 patients with FAP.

Over a period of 2 years, diflunisal slowed progression of polyneuropathy as measured on a 270-point scale, the Neuropathy Impairment Score plus 7 nerve tests (NIS+7). Using multiple imputation (a statistical approach necessitated by the high rate of loss to follow-up), the NIS+7 score increased (i.e., worsened) significantly more in the placebo group than in the diflunisal group (by 25 points vs. by 8.7 points). The difference of 16.3 points favoring diflunisal exceeds criteria defined by the International Peripheral Nerve Society for clinically meaningfulness. The benefits of diflunisal were also evident on a host of secondary outcome measures, and diflunisal was very well tolerated.