Transthyretin amyloidosis

These are specialist heart drugs for people diagnosed with the disease, chosen with a cardiologist. They show that fixing one named misfolding protein can work; they are not evidence that a healthy person should try to boost protein quality control.

What goes wrong

In transthyretin amyloid cardiomyopathy, transthyretin misfolds and deposits in heart muscle, stiffening it. It is one of the amyloidoses, the diseases in which a normally soluble protein turns into deposits that accumulate in tissue, and it is the cleanest test of the idea behind loss of proteostasis: find the misfolding protein, stop it misfolding, and see whether patients do better.

Stabilisers: holding the protein in shape

Tafamidis is a small molecule that clamps transthyretin into its correct shape so it cannot misfold in the first place. In a randomised trial of 441 patients over 30 months, it cut deaths from any cause from 42.9% to 29.5%, about 13 fewer deaths per 100 patients treated, or roughly 30% lower risk (hazard ratio 0.70, 95% confidence interval 0.51–0.96). That interval is the range where the true effect most plausibly lies; because it sits entirely below 1.0, the benefit is unlikely to be chance. Tafamidis also reduced cardiovascular hospital admissions from 0.70 to 0.48 per patient per year and slowed the decline in both walking distance and quality of life.^[1]

Acoramidis, a second stabiliser working the same way, beat placebo in 632 patients on a combined ranking of death, hospital admission and function over 30 months, but not on deaths alone.^[2] When the placebo group was then switched onto the drug, patients who had taken it from the start had about 45% lower risk of death by four and a half years (hazard ratio 0.55). That compares early with delayed treatment rather than drug with no drug, and the later years were unblinded.^[3]

Silencers: one worked, one missed

Vutrisiran attacks the problem from the other end: instead of fixing the fold, it shuts down production of the protein. Over 42 months it cut deaths from any cause by about 35% (hazard ratio 0.65, 95% confidence interval 0.46–0.90).^[4]

Eplontersen, a second silencing drug, was tested in the largest trial yet: 1,432 patients randomised to the drug or placebo. It did no better on cardiovascular deaths and heart events overall (rate ratio 0.89, with a 95% range of 0.73–1.09 that includes no effect).^[5] A planned breakdown hinted at why: it appeared to help patients who were not already taking a stabiliser, with about 29% fewer events (rate ratio 0.71), and showed no benefit in the 57% who were.^[6] A subgroup from a trial that missed its main goal is a hint, not a finding.

All of these trials were funded by the companies selling the drugs, which is normal for cardiology and worth knowing anyway.

Clearing the deposits: not yet shown to help

Antibodies are being designed to clear existing transthyretin deposits out of the heart muscle rather than prevent new ones. In a randomised trial of 104 patients, most of them already on tafamidis, the higher dose of one such antibody, coramitug, cut a blood marker of heart strain by about half compared with placebo over a year. It did not improve how far patients could walk compared with placebo.^[7] Whether clearing the deposit helps patients live longer or stay out of hospital has not yet been shown. It is the heart's version of the Alzheimer's test, where anti-amyloid drugs strip deposits from the brain with only a small effect on patients.

What it proves, and what it doesn't

These drugs work because there is one culprit protein, with a known misfolding mechanism, causing a specific disease, in patients selected because they have it. Even the silencer, which sidesteps folding entirely, needs the same thing the stabilisers do: a named protein to remove. None of those conditions holds for ordinary aging, where the suspected problem is a diffuse, gradual loss of general folding capacity with no single protein to stabilise. The drug class shows that protein quality control is a real target in a defined disease. It says nothing about whether a healthy 50-year-old should be trying to boost their chaperones.

What to do

1. If you have been diagnosed, treatment is a decision to make with a cardiologist; the clearest survival benefit in randomised trials is for tafamidis and vutrisiran.
2. If you are well, none of this is a reason to take anything. There is no drug or supplement that does for general aging what these drugs do for one protein.

Further reading

• Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2018 — ATTR-ACT trial.^[8]
• Gillmore JD, et al. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2024 — ATTRibute-CM trial.^[9]
• Fontana M, et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med 2025 — HELIOS-B trial.^[10]
• Fontana M, et al. Eplontersen for Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2026 — CARDIO-TTRansform trial.^[11]
• Fontana M, et al. Coramitug, a Humanized Monoclonal Antibody for the Treatment of Transthyretin Amyloid Cardiomyopathy: A Phase 2, Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial. Circulation 2026.^[12]