Therapy of amyloidosis: stabilizers and silencers

Transthyretin amyloidosis (ATTR) is a systemic disease characterized by the deposition of misfolded transthyretin (TTR) fibrils. It most commonly presents as cardiomyopathy (ATTR-CM), particularly in elderly patients with the wild-type form, whereas hereditary variants may manifest with polyneuropathy (ATTRv-PN) and/or cardiac involvement. The widespread adoption of non-invasive diagnostic pathways has increased disease recognition and facilitated the early initiation of disease-modifying therapies. Stabilizers limit dissociation of the TTR tetramer and the formation of new amyloid fibrils. Tafamidis demonstrated a benefit on mortality and cardiovascular hospitalizations in the ATTR-ACT trial and remains the treatment supported by the most robust evidence, with greater efficacy when initiated at earlier disease stages. Acoramidis, a next-generation stabilizer, improved a hierarchical composite end-point in the ATTRibute-CM trial and has been approved for ATTR-CM treatment, too. Gene-silencing therapies (small interfering RNA and antisense oligonucleotides) reduce hepatic TTR synthesis and circulating protein levels. Patisiran is approved for ATTRv-PN and, in the APOLLO-B trial, showed a functional benefit in ATTR-CM, although it has not been approved for this indication in the United States. Vutrisiran, a subcutaneously administered siRNA given every 12 weeks, reduced mortality and recurrent cardiovascular events in the HELIOS-B trial and has been approved for ATTR-CM treatment. This review summarizes the rationale and principal clinical evidence supporting tetramer stabilizers and gene-silencing therapies, which are now central to the management of ATTR-CM.