Acoramidis for the Treatment of Transthyretin Cardiac Amyloidosis.

Transthyretin (ATTR) cardiac amyloidosis is an infiltrative, restrictive cardiomyopathy that causes heart failure with both preserved and reduced ejection fraction. Historically considered a disease without treatment, the approval of transthyretin stabilizers brought about a major shift in the paradigm. Following closely on the heels of tafamidis, the United States Food and Drug Administration approved acoramidis for patients with ATTR cardiac amyloidosis in 2024. Similar approvals were also seen across Japan, the European Union, and the United Kingdom. Acoramidis is a highly potent transthyretin (TTR) stabilizer. The mechanism of action of acoramidis centers around its interaction with the unique ultrastructure of the TTR tetramer. The TTR tetramer comprises 2 linked homodimers that are stabilized by the binding of a thyroxine molecule. Acoramidis mimics the transthyretin-stabilizing T119M mutation, stabilizing the tetramer by 2 mechanisms. First, by binding to the TTR thyroxine-binding site to serve as a bridging molecule between the 2 dimeric subcomponents of the tetramer, it dramatically improves its kinetic stability. Second, it engages in hydrogen bond-based enthalpic binding. Cumulatively, this helps achieve TTR stabilization to the order of >90%. In clinical trials, acoramidis has demonstrated a robust safety profile. Acoramidis also improved clinical outcomes such as all-cause mortality and cardiovascular hospitalizations; improved biomechanistic parameters such as 6-minute walk distances, n-terminal pro B-type natriuretic peptide levels, stabilization of myocardial thickness; as well as improved patient-reported outcomes through improved Kansas City Cardiomyopathy Questionnaire scores. The results of the ACT-EARLY trial exploring the preventive benefits of acoramidis are eagerly awaited.