Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy

Abstract

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from −0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to −0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

Identification of a Misfolded Region in Superoxide Dismutase 1 That Is Exposed in Amyotrophic Lateral Sclerosis

“…6). A similar outcome could potentially be achieved with chemical chaperones, which have been used to mitigate the misfolding and toxicity of other amyloidogenic proteins (52). Either with small molecules or alternative approaches, our results advocate for concealing the C4F6 epitope and/or stabilizing loops IV and VII as rational therapeutic strategies for SOD1-mediated ALS.…”

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

“…At the end of the extension study, neurologic function was better preserved among patients who continuously received tafamidis than among those who received 18 months of placebo followed by 12 months of tafamidis, and underscores the benefit of early intervention [22,23]. A 12-month open-label study in 21 non-ATTRV30M patients further demonstrated the generalizability of the TTR-stabilizing effect, and indicated clinical efficacy of tafamidis for delaying disease progression across several other TTR variants [24].…”

“…An 18-month, double-blind, randomized, placebocontrolled study of tafamidis in 128 ATTRV30M patients with early stage ATTR-FAP and its subsequent 12-month open-label extension study demonstrated the safety and efficacy of tafamidis in delaying the progression of polyneuropathy [21,22]. At the end of the extension study, neurologic function was better preserved among patients who continuously received tafamidis than among those who received 18 months of placebo followed by 12 months of tafamidis, and underscores the benefit of early intervention [22,23].…”

SCA2 predictive testing in Cuba: challenging concepts and protocol evolution

“…In the case of FAP TTR Met 30, there are two therapeutical options that significantly alter the psychological burden imposed by this condition: FAP-I patients are offered Tafamidis (Coelho et al 2013) which may delay the progression of the disease or liver transplantation (Rolim et al 2006). The patients and their families now see FAP-I as being less threatening than other neurodegnerative diseases such as SCA3 and HD (Rolim et al 2006;Paneque et al 2009;Ledo et al 2013), and this may increase the presymptomatic testing uptake.…”