Disease-modifying therapies for amyloid transthyretin cardiomyopathy: Current and emerging medications

Abstract

Transthyretin amyloidosis (ATTR) is a rare disease that results in amyloid fibril misfolding and deposition in multiple organs, including the heart, leading to the development of ATTR cardiomyopathy (ATTR-CM), which is associated with poor outcomes. In the last decade, several disease-modifying medications are in advanced stages of clinical development or have been approved to treat ATTR-CM. The purpose of this review is to critically evaluate clinical trial data investigating the use of approved and investigational medications for the treatment of ATTR-CM. We performed a comprehensive literature search via PubMed and EMBASE to identify randomized controlled trials evaluating medications for the treatment of ATTR-CM published through August 2024. This narrative review describes the pathophysiology of ATTR-CM, highlights important screening and diagnostic work-up, and summarizes the existing clinical evidence resulting from our literature search. Several classes of disease-modifying medications are in development for ATTR-CM. The tetramer stabilizers and transthyretin silencers have proven to be the most effective therapies to date. Tafamidis and acoramidis are currently approved for ATTR-CM while vutrisiran approval for ATTR-CM may be forthcoming. Other disease-modifying medication classes in development include antisense oligonucleotides, gene editing therapies, and monoclonal antibodies. However, several unmet needs exist including the lack of cost-effectiveness due to the extremely high acquisition costs of these medications. Disease-modifying medications approved and in development to treat ATTR-CM offer hope for patients with this disease, but their lack of affordability is the biggest barrier to their use.

Keywords: RNA; amyloidosis; antisense; cardiomyopathies; eplontersen; human; oligonucleotides; patisiran; small interfering; tafamidis; transthyretin‐related amyloid fibril protein.

FIGURE 1

Clinical manifestations of transthyretin amyloidosis. Reproduced from Ref. which is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium. The original work was a U.S. government work and not under copyright protection in the United States.

FIGURE 2

Pathophysiology of transthyretin amyloidosis. BNP, B‐type natriuretic peptide; HF, heart failure; NTproBNP, N‐terminal‐pro B‐type natriuretic peptide; TTR, transthyretin. Reproduced from Ref. which is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium. ©The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

FIGURE 3

Pharmacotherapy options for patients with confirmed ATTR‐CM. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; ATTR‐CM, transthyretin amyloid cardiomyopathy; BB, beta‐blocker; FDA, United States Food and Drug Administration; GDMT, guideline‐directed medical therapy; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association; OAC, oral anticoagulant; SGLT2i, sodium‐glucose co‐transporter‐2 inhibitor. ^aEvidence limited to observational studies; no randomized controlled trials to demonstrate safety and efficacy. ^bPhase III randomized controlled trials have demonstrated favorable results but are not currently FDA‐approved to treat ATTR‐CM. ^cIn consultation with a neurologist.