Transthyretin is one of a small number of proteins that can misfold and aggregate to cause pathology in tissues, primarily the cardiovascular system, but other organs as well once aggregation becomes very severe. Despite being a universal mechanism that operates in all older individuals, transthyretin amyloidosis is presently treated as a rare condition by the medical, development, and regulatory communities, because only the most severe cases exhibit evident symptoms that are easily diagnosed. Of those patients diagnosed, some have mutations that drive misfolding and aggregation of transthyretin, while some are simply the most severe examples of what is actually a prevalent issue in later later. Evidence from studies involving post-mortem examinations of tissues suggest that many very old people exhibit a degree of transthyretin amyloidosis that is in principle life-threatening, capable of contributing to cardiovascular mortality.
In recent years a number of drugs have been developed that act to reduce transthyretin misfolding and aggregation to a large enough degree to allow natural clearance mechanisms to catch up. As drugs go, they are fairly effective at achieving this outcome and have reasonable safety profiles. They are only used in the most severe, readily diagnosed patients, and thus regulated and priced as though transthyretin amyloidosis is a rare disease, however. Treatment is enormously expensive, as is usual for rare diseases, and will likely remain so until patent protection runs out and the drugs become generic. Before that point arrives there is all too little incentive for the drug owners to branch out and offer greater availability at a lower price point, regardless of the accumulating evidence for transthyretin amyloidosis to be a prevalent late life issue with meaningful effects on cardiovascular disease and mortality.
Nonetheless, it is worth keeping an eye on this part of the field as data accumulates from the long-term use of these transthyretin amyloidosis drugs. It provides an assessment of their value for a future of broadened generic use in the older population, once the market catches up with the science regarding implementation of that broader use. Today's open access paper is of interest in this regard, providing data on long-term use of acoramidis. Transthyretin exists in a dynamic equilibrium between monomer and tetramer forms, and only the monomer form contributes to amyloidosis. The better of the existing drugs, like acoramidis, act by stabilizing the tetramer form and thereby greatly reducing the size of the monomer pool. Clearly this works to reduce both amyloid and pathology.
Long-Term Durability of Acoramidis Efficacy in Transthyretin Amyloid Cardiomyopathy
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder caused by destabilization of serum transthyretin (sTTR). Acoramidis, an approved therapy that achieves near-complete (≥90%) sTTR stabilization, demonstrated clinical benefit through month 30 in ATTRibute-CM, which was incremental through month 42 in the open-label extension (OLE); however, the longer-term durability of outcomes has not been reported.
This OLE of the ATTRibute-CM randomized clinical trial is an international, multicenter, ongoing OLE study. Data accumulated between October 2021 and April 2025 through month 24 of the OLE (month 54) are reported. Participants (aged 18-90 years) who completed ATTRibute-CM and met the OLE eligibility criteria were invited to enroll in the OLE. Data were analyzed from May 2025 through November 2025. All OLE participants received open-label oral acoramidis, 800 mg, twice daily. Acoramidis recipients from ATTRibute-CM continued therapy (continuous acoramidis) and placebo recipients switched to acoramidis (placebo to acoramidis).
The primary outcome was time to event for all-cause mortality (ACM), cardiovascular-related mortality (CVM), and first cardiovascular hospitalization (CVH), which was assessed for both groups. Biomarkers of disease progression (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), sTTR, functional capacity (6-minute walk distance [6MWD]), and heart failure-related health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score) were analyzed.
In ATTRibute-CM, 632 participants were randomized to receive acoramidis (n = 421) or placebo (n = 211); mean (SD) age was 77.3 (6.6) years, and 62 participants (9.8%) were female. Overall, 389 participants enrolled in the OLE (263 in the continuous acoramidis group; 126 in the placebo-to-acoramidis group). Continuous acoramidis treatment reduced risks of ACM (hazard ratio 0.55) and CVM (HR 0.51) through month 54, with consistent efficacy across all prespecified subgroups. Continuous acoramidis reduced time to first CVH (HR 0.53) through month 54. Through month 54, continuous acoramidis stabilized increases in NT-proBNP, sustained higher sTTR levels, and stabilized KCCQ-OS score and 6MWD. Switching from placebo to acoramidis at month 30 was associated with stabilization of NT-proBNP and KCCQ-OS score and improvements in sTTR and 6MWD through month 54. No new long-term safety concerns were identified.
View the full article at FightAging
