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Overview of Current and Emerging Therapies for Amyloid Transthyretin Cardiomyopathy

Published:November 09, 2022DOI:https://doi.org/10.1016/j.amjcard.2022.10.014
      Recent efforts in basic science have elucidated the pathobiology of amyloid transthyretin (ATTR) amyloidosis, leading to the development of the first generation of transthyretin (TTR)-targeted therapies for this disease. Along with tafamidis, the first approved therapy for ATTR-cardiomyopathy (CM), several other agents are in late-stage clinical development for ATTR-CM. TTR-stabilizing and TTR-silencing agents with various mechanisms target TTR, preventing disaggregation of tetrameric TTR and subsequent misfolding of TTR and formation of amyloid fibrils in the myocardium. These agents, including the TTR-super-stabilizing agent acoramidis, TTR-silencing agents patisiran, vutrisiran, and eplontersen, and TTR gene silencing with clustered, regularly interspaced, short palindromic repeats and associated Cas9 endonuclease–based therapy NTLA-2001, are in varying stages of development. The nonsteroidal anti-inflammatory diflunisal has been shown to have TTR-stabilizing properties and may play a role off-label as treatment in selected patients, particularly allele carriers of TTR variants and patients unable to afford current therapies. Anti-amyloid treatments represent another strategy for treating patients with advanced ATTR amyloidosis. These agents are designed to bind to epitopes on amyloid fibril and extract amyloid by activation of macrophage-medicated phagocytosis addressing amyloid already deposited in organs and tissues. Since many patients with ATTR-CM present with advanced disease and the presence of significant amyloid burden in the heart, anti-amyloid therapy represents an important area of unmet treatment need. Various investigational anti-amyloid therapies are in early-stage clinical development.
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