Tafamidis: a review of its use in familial amyloid polyneuropathy.

Oral tafamidis (Vyndaqel(®)) is indicated in the EU for the treatment of transthyretin (TTR) amyloidosis in adult patients with early stage symptomatic polyneuropathy to delay peripheral neurologic impairment and, in Argentina, Japan and Mexico, for delaying the peripheral neurological impairment of TTR familial amyloid polyneuropathy (TTR-FAP). It is the first disease-modifying pharmacotherapy to be approved for use in adult patients with early-stage TTR-FAP. The drug acts to kinetically stabilize the variant TTR tetramer and thereby prevent tetramer dissociation, the rate-limiting step in TTR misfolding and amyloidogenesis. In the 18-month Fx-005 study in adult patients with early-stage V30M TTR-FAP, there were no statistically significant differences between tafamidis and placebo recipients for the coprimary endpoints, the Neuropathy Impairment Score-Lower Limb (NIS-LL) response rate (increase in NIS-LL score of <2) and the least-square mean change in Norfolk Quality-of-Life (QOL) Diabetic-Neuropathy Questionnaire total scores at 18 months, based on modified intent-to-treat analyses. However, in prespecified per-protocol analyses of efficacy evaluable patients, tafamidis recipients experienced significantly better outcomes in terms of these coprimary endpoints, with most (98%) tafamidis recipients showing stabilization of TTR tetramers at study end. Secondary endpoint outcomes also favoured tafamidis treatment over placebo. The beneficial effects of tafamidis in slowing deterioration of neurological function and health-related-QOL were maintained in long-term extension studies (up to 66 months). Tafamidis also stabilized TTR tetramers in patients with non-V30M TTR-FAP. Tafamidis was generally well tolerated, with most treatment-emergent adverse events being of mild to moderate intensity and very few patients discontinuing treatment because of these events. No new safety signals have emerged during long-term extension studies and post-marketing experience.