Emerging Treatment Options in ATTR-CM: Near-Complete TTR Silencers and Amyloid Depleters

Abstract Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive and increasingly recognized cause of restrictive cardiomyopathy, heart failure, and premature mortality. Therapeutic advances have transformed management from supportive care to disease-modifying intervention, with demonstrated survival benefit. Current therapies include TTR stabilizers, which prevent tetramer dissociation, and TTR silencers, which suppress hepatic TTR synthesis and reduce circulating amyloidogenic protein by 80–90%. Nonetheless, residual TTR production and established amyloid deposits continue to drive disease progression. Emerging therapies seek to overcome these limitations through near-complete TTR silencing and direct amyloid removal. Next-generation silencers, including nucresiran and the CRISPR-Cas9–based agent nexiguran ziclumeran, have demonstrated sustained TTR suppression exceeding 90%, and are being evaluated in large phase III trials. Amyloid-depleting monoclonal antibodies, such as cliramitug, coramitug, and AT-02, act downstream by targeting misfolded TTR and deposited amyloid fibrils, facilitating immune-mediated clearance. Associated clinical studies suggest these agents may reduce cardiac amyloid burden and improve biomarkers of myocardial stress, with acceptable tolerability. This review outlines the mechanisms of action, emerging clinical evidence, and therapeutic implications of near-complete silencers and amyloid depleters in ATTR-CM. These strategies introduce the possibility of disease modification beyond stabilization and may be particularly relevant for patients with advanced disease. Ongoing trials will clarify their role within evolving treatment paradigms, including optimal sequencing, combination strategies, and comparative effectiveness.