Cardiac amyloidosis is an infiltrative cardiomyopathy characterized by the progressive accumulation of misfolded proteins. Transthyretin amyloidosis (ATTR) is one of the most common forms of cardiac amyloidosis, and is caused by the aggregation of misfolded transthyretin, a protein encoded by the TTN gene. Transthyretin is largely secreted by the liver and, in the form of homotetramers, acts as a transporter for thyroid hormone and vitamin A. Variant ATTR amyloidosis is due to genetic variants in TTR and manifests as cardiomyopathy, polyneuropathy or a mixture of both phenotypes. Wild-type ATTR amyloidosis occurs in the absence of evident genetic variation, usually in older male patients, and prevalently affects the heart. Current therapeutic options are limited. In 2019, the FDA approved the use of two drugs, both containing the same active moiety, tafamidis, based on results from the ATTCR-ACT trial showing reductions in death from any cause and reduced cardiovascular-related hospitalizations in patients treated with the drugs compared with placebo for 30 months. Tafamidis binds and stabilizes transthyretin, preventing its unfolding.
Patisiran is an RNA interference therapeutic agent designed to reduce the circulating levels of transthyretin. It has recently been approved for the treatment of variant ATTR amyloidosis in patients with polyneuropathy, based on results of the APOLLO trial. Maurer et al. now report the results of the APOLLO-B, a phase 3, double-blind, placebo-controlled clinical trial aimed to show whether the reduction in amyloidogenic transthyretin protein can provide a therapeutic benefit in patients with ATTR cardiac amyloidosis.
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