Transthyretin is primarily synthesized in the liver and transports thyroxine and vitamin A in the body. The transthyretin when dissociated into monomers can misfold and ultimately form amyloid fibrils. There are two types of ATTR amyloidosis: hereditary (caused by mutations in the TTR gene) and wild-type (also referred to as senile systemic amyloidosis). Amyloid cardiomyopathy can develop in patients with both types of ATTR amyloidosis, has a later onset and is characterized by progressive heart failure leading to death within a few years after diagnosis. Tafamidis is an oral-administered small molecule that binds to transthyretin and inhibits transthyretin tetramer dissociation, the rate-limiting step in the amyloidosis. Long-term efficacy and safety of tafamidis were shown in patients with transthyretin familial amyloid polyneuropathy. The objective of the phase 3 international, multicenter, double-blind, placebo-controlled, randomized ATTR-ACT study was to evaluate the efficacy, safety, and tolerability of tafamidis (20 or 80 mg orally QD) in comparison with placebo in 441 patients with hereditary and nonhereditary transthyretin cardiomyopathy (median age 75 years, 90% of males). At month 30, treatment with tafamidis was associated with a lower risk of all-cause mortality (by 30%) and a lower rate of cardiovascular related hospitalizations (by 32%) than placebo and resulted in a lower rate of decline in distance for the 6-minute walk test and a lower rate of decline in KCCQ-OS score. The data from extension study supports tafamidis 80 mg as the optimal dose (bioequivalent to tafamidis free acid 61 mg).
ATTR-amyloidosis, cardiomyopathy, tafami- dis, ATTR-ACT clinical trial.