Tafamidis

Tafamidis (INN, or Fx-1006A, trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis (familial amyloid polyneuropathy, FAP), approved by the European Medicines Agency. Its meglumine salt has completed an 18 month placebo controlled phase II/III clinical trial, and an 18 month extension study which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy. Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.

Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute using a structure-based drug design strategy and was developed at FoldRx pharmaceuticals, a biotechnology company led by Richard Labaudiniere that was acquired by Pfizer in 2010. Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein. In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. The process of wild type transthyretin amyloidogenesis also appears to cause senile systemic amyloidosis leading to cardiomyopathy as the prominent phenotype Some mutants of transthyretin, including V122I primarily found in individuals of African descent, are destabilizing enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures including amyloid fibrils leading to familial amyloid cardiomyopathy. While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies, this has yet to be demonstrated in a placebo controlled clinical trial.

Tafamidis is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP. The FDA has granted the Tafamidis New Drug Application a priority-review designation and has provided an anticipated Prescription Drug User Fee Act (PDUFA) action date in June of 2012.