ACO-SWITCH Trial to Track Serum Transthyretin After Tafamidis-to-Acoramidis Switch

Researchers have laid out the full blueprint of ACO-SWITCH, a phase 4 study that will follow 50 adults with transthyretin amyloid cardiomyopathy (ATTR-CM) as they switch from the TTR stabilizer tafamidis to the newer stabilizer acoramidis. The protocol article, published in Cardiology and Therapy, describes an ongoing, prospective, open-label, multicenter, single-arm interventional study registered as NCT07298044. Its central question is deliberately narrow: how much does serum transthyretin (sTTR), a transport protein also known as prealbumin, change over six months of acoramidis treatment in patients who were previously stabilized on tafamidis? Because the study is still enrolling and no results have been reported, everything described here concerns planned methods and expected measurements rather than demonstrated effects of switching.

ATTR-CM is a progressive disease in which tetrameric transthyretin destabilizes and dissociates into monomers that aggregate as amyloid fibrils deposited in the myocardial extracellular space. That deposition drives progressive heart failure and repeated cardiovascular hospitalizations. The condition is frequently underdiagnosed and carries a poor quality of life; a 2019 study of roughly 1,000 patients with variant or wild-type ATTR-CM reported median survival of approximately three to six years without disease-modifying therapy, while patients with early-stage disease (stage 1a and 1b) generally have a higher median survival expectancy ranging from six to more than eight years. Despite better diagnostic tools, a US-based multicenter study found that the proportion of patients diagnosed at earlier versus later stages has not significantly improved in recent years.

Both tafamidis and acoramidis belong to a class of TTR stabilizers that bind to and stabilize the TTR tetramer, preventing its dissociation into amyloidogenic monomers. Stabilization raises sTTR levels, which may be lower than normal in patients with ATTR-CM, especially in the hereditary form. Acoramidis achieves near-complete stabilization of at least 90 percent through enthalpically driven binding, forming hydrogen bonds at the thyroxine binding site that mimic the stabilizing effects of the disease-protective T119M TTR variant. Other therapeutic classes work differently: TTR silencers such as patisiran and vutrisiran reduce TTR synthesis and sTTR levels, and TTR depleters, including monoclonal antibodies that promote clearance of TTR amyloid fibrils, remain under investigation.

The rationale for choosing sTTR as the primary readout rests on earlier trial data. In the pivotal randomized phase 3 ATTRibute-CM study, which supported acoramidis approvals in the United States, European Union, Japan, United Kingdom, and Switzerland, participants treated with acoramidis showed a better four-step hierarchical outcome than placebo through month 30, covering death from any cause, cardiovascular hospitalization, change in NT-proBNP, and change in six-minute walking distance. Acoramidis also produced an early and sustained rise in sTTR compared with placebo through month 30. A logistic regression analysis of that trial found strong evidence of a direct and independent association between acoramidis-driven increases in sTTR and improved survival, even after adjustment for factors known to influence survival, with every 5 mg/dl increase in sTTR predicting a 31.6 percent relative reduction in the odds of all-cause mortality among acoramidis-treated participants; no such association was seen in the placebo arm. These are associations from a randomized trial analysis, not proof that raising sTTR causally improves survival, and the authors note that further validation is required before sTTR can serve as a biomarker of drug efficacy.

The switching question arises from preliminary observations in the open-label extension of ATTRibute-CM. Participants who switched from placebo plus tafamidis to acoramidis showed a mean sTTR increase of 3.0 mg/dl at month 1 and 3.4 mg/dl at month 6. The authors write that these findings may suggest a higher TTR-stabilizing potential of acoramidis compared with tafamidis, but they emphasize that confirmation requires a prospective, standardized setting, which is precisely what ACO-SWITCH is designed to provide.

The study will run at up to 20 sites across Europe, with total participation lasting up to 7.75 months: a 21-day screening period on tafamidis, a six-month acoramidis treatment period, and a 30-day follow-up. Eligible participants are aged 18 to 90 with a variant or wild-type ATTR-CM diagnosis made within the previous 24 months, at least three months of tafamidis treatment before enrollment, and good adherence, defined as no more than six missed tafamidis days per month before enrollment and tafamidis intake on at least 80 percent of screening days. Additional requirements include an estimated glomerular filtration rate of at least 30 ml/min/1.73 m², an NT-proBNP above 300 pg/ml and at or below 7000 pg/ml, New York Heart Association class II or better, and stable disease for at least three months. Exclusions include ATTR-CM-related or cardiovascular hospitalization within three months, heart failure due to ischemic heart disease, recent myocardial infarction, cardiovascular surgery, or unstable angina within 90 days, light-chain amyloidosis, renal impairment or suspected liver disorder, recent diuretic initiation or intensification, and current or recent use of sodium-glucose cotransporter 2 inhibitors, TTR silencers, other antisense or siRNA agents, unproven therapies, or investigational drugs.

The day after the last tafamidis dose, participants begin self-administered acoramidis at home at the licensed dose of two 356 mg tablets twice daily for six months. Nine visits are planned per participant, with weekly visits during the first treatment month; most visits apart from screening and end of treatment are conducted remotely by a home care nurse to reduce participant burden. Blood and urine samples are collected at screening and treatment visits to measure TTR levels by immunoturbidimetry, assess TTR stabilization using the fluorescent probe exclusion assay and Western blot, and track routine laboratory parameters and biomarkers. All cardiovascular and noncardiovascular adverse events are systematically recorded.

The primary endpoint is the change in sTTR from baseline to month 6, or to the time of premature treatment discontinuation, analyzed with a one-sided paired Wilcoxon signed-rank test. Secondary endpoints, analyzed exploratively and descriptively, include sTTR levels at baseline, weeks 1 through 4, and month 3; changes from baseline to month 6 in cardiovascular biomarkers (NT-proBNP, high-sensitivity troponin T, and retinol-binding protein 4), kidney markers (eGFR, creatinine, cystatin C, and urinary albumin-to-creatinine ratio), and the thyroid marker thyroid-stimulating hormone; echocardiographic results; six-minute walking distance; quality of life measured by the Kansas City Cardiomyopathy Questionnaire overall summary score and the EuroQol 5-dimension 5-level index; and treatment-emergent adverse events. Further objectives include ex vivo TTR stabilization assays and exploratory biomarkers. The sample size calculation assumes a conservative mean sTTR improvement of 3 mg/dl with a standard deviation of paired differences of 6 mg/dl, giving 92 percent power at a one-sided significance level of 2.5 percent with 50 participants.

The investigators acknowledge the design’s limits. As a single-arm study without a concurrent control group, ACO-SWITCH cannot compare switching against uninterrupted tafamidis treatment or switching in the reverse direction, and enrollment limited to European sites may restrict generalizability to a global patient population. The chosen treatment durations are relatively short for assessing downstream clinical and biomarker outcomes, although they were selected because sTTR changes are expected to occur rapidly, typically within the first four weeks of treatment. On the strengths side, the inclusion criteria mirror those of ATTRibute-CM, and participants in that and other randomized trials have shown only minor baseline differences from the real-world ATTR-CM population. If the planned measurements bear out the anticipated sTTR dynamics, the authors argue, the data could help guide clinical decision-making and optimize management for patients with ATTR-CM; until then, the study stands as a carefully specified test of a biomarker hypothesis, not yet evidence about the outcome of switching therapies.

Subject of Research: A phase 4 study protocol evaluating serum transthyretin changes in patients with ATTR-CM switching from tafamidis to acoramidis

Article Title: ACO-SWITCH: Rationale and Design of a Phase 4 Study Evaluating Serum Transthyretin in ATTR-CM After Switching from Tafamidis to Acoramidis

Article References: Pfister, R., Michel, L., Schulze, M., Vogtländer, K., Ciaccia, A., Merz, M., & Hengstenberg, C. (2026). ACO-SWITCH: Rationale and Design of a Phase 4 Study Evaluating Serum Transthyretin in ATTR-CM After Switching from Tafamidis to Acoramidis. Cardiology and Therapy, 15(3), 529-542. https://doi.org/10.1007/s40119-026-00466-4

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00466-4

Keywords: ATTR-CM, acoramidis, tafamidis, transthyretin, TTR stabilizers, phase 4 study, study design, serum transthyretin, biomarker, cardiac amyloidosis, clinical trial protocol, heart failure