To Silence or to Stabilize: That is the Question

Transthyretin amyloid cardiomyopathy (ATTR-CM) was previously considered an inescapable progressive disease leading to devastating outcomes. Clinicians often disregarded ATTR-CM, as the therapeutical arsenal available was very limited. Historically, treatments have offered mostly symptomatic relief without altering disease progression. Fortunately, the last decade brought us disease-modifying treatments with the potential to transform the course of ATTR-CM.

At a molecular level, ATTR-CM develops when transthyretin (TTR), usually a stable transport protein for thyroxine and vitamin A, dissociates from its tetrameric configuration into monomers and amyloid fibrils that accumulate in the myocardium. Two key drug classes have been studied for the treatment of ATTR-CM: stabilizers and silencers. Stabilizers, such as tafamidis and acoramidis, act by stabilizing the TTR tetramer configuration, thus preventing its breakdown and subsequent deposition of amyloid fibrils.^, In contrast, silencers, such as patisiran and vutrisiran, inhibit the hepatic production of TTR via RNA interference mechanisms, essentially reducing the source of the amyloid precursor.^, Historically, the ATTR-ACT study was the first Phase III trial to demonstrate that a drug for ATTR-CM, tafamidis, could reduce all-cause mortality, giving stabilizers a competitive edge. However, with newer drug classes, which option is the best for our patients?

[…]