Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy

Abstract

Objective: To review the pharmacology, efficacy, and safety of the selective transthyretin inhibitor tafamidis for transthyretin amyloid cardiomyopathy (ATTR-CM). Data Sources: A PubMed (1966 to October 2019) and ClinicalTrials. gov search was conducted using the keywords tafamidis, Fx-1006A, Vyndaqel, and Vyndamax. Additional articles were identified from references. Study Selection and Data Extraction: We included English-language clinical studies evaluating the pharmacology, efficacy, or safety of tafamidis in humans for ATTR-CM. Data Synthesis: Tafamidis binds to the thyroxine-binding sites of the transthyretin tetramer and inhibits its dissociation into monomers, which is the rate-limiting step in the amyloidogenic process. Treatment with tafamidis was significantly associated with a significant reduction in mortality, lowered cardiovascular-related hospitalizations, less functional decline, and improved transthyretin stabilization compared with placebo. Additionally, tafamidis was found to have fewer adverse events, with no difference found compared with placebo. Relevance to Patient Care and Clinical Practice: Historically, symptomatic management for ATTR-CM was the only option, and the treatment of the underlying disease was limited to liver or heart transplantation. Tafamidis is the first medication approved for the treatment of ATTR-CM and the only medication that showed a reduction in all-cause mortality and cardiovascular-related hospitalizations in patients with amyloidosis. However, the role of tafamidis in patients with the New York Heart Association class III/IV heart failure or mutated transthyretin remains unclear. Conclusion: Tafamidis is an effective and safe oral medication for the treatment of the cardiomyopathy of transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

Tafamidis is entering the clinical arena for the treatment of transthyretin‐related cardiomyopathy: certainties and unmet needs

“…Tafamidis inhibits TTR dissociation into monomers in a dose‐dependent manner by binding to the thyroxine‐binding sites, thereby preventing fibril formation. This action occurs at physiologic pH with a comparable efficacy in the case of wild‐type TTR and heterotetramers of TTR mutants 13,14 …”

“…This action occurs at physiologic pH with a comparable efficacy in the case of wild-type TTR and heterotetramers of TTR mutants. 13,14…”

Cardiac Amyloidosis Therapy: A Systematic Review

“…Tafamidis (VYNDAQEL ® ), an approved drug for the treatment of wild-type or hereditary ATTR in adult patients with cardiomyopathy and polyneuropathy, binds selectively to the tiroxine binding sites, stabilizing the tetramer and preventing the dissociation into monomers [39,40].…”

Exploring the occurrence of thioflavin-T-positive insulin amyloid aggregation intermediates

“…Such protein assembly into insoluble aggregates is still not fully understood, despite the significant effort put into figuring out both the mechanism of aggregation ( Meisl et al, 2016 ; Castello et al, 2017 ; Biza et al, 2017 ; Giorgetti et al, 2018 ; Linse, 2019 ), as well as the resulting fibril structural aspects ( Makin & Serpell, 2005 ; Fitzpatrick et al, 2013 ). As a consequence, there are still very few disease modifying drugs available ( Mehta et al, 2017 ; Cummings et al, 2019 ; Maurer et al, 2018 ; Park et al, 2020 ).…”