Evaluation of Acoramidis (AG10) in Patients with ATTR-CM in a Phase 3 Randomized, Double-Blind, Placebo-Controlled Clinical Trial: The ATTRibute-CM Study Design

Acoramidis (AG10) is a small-molecule TTR stabilizer that is currently under development for the treatment of transthyretin amyloidosis (ATTR). Daniel Judge, MD, Department of Medicine, Medical University of South Carolina, Charleston, and colleagues published the results of a randomized, double-blind, phase 2 study that evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in patients with symptomatic ATTR cardiomyopathy (ATTR-CM).1

It has been reported that serum TTR levels are predictive of survival in patients with ATTR-CM, and TTR stabilizer treatment improves serum TTR levels, corresponding with their ability to increase tetrameric stability of TTR ex vivo.

The phase 3 study ATTRibute-CM was designed to enroll 510 symptomatic ATTR-CM patients (including patients with wild-type TTR or mutant TTR) with New York Heart Association class I-III symptoms.2 In this multicenter, international trial, patients will be randomized (2:1) to receive AG10 800 mg or placebo twice daily and followed for 30 months. After 1 year, researchers will assess the change in 6-minute walk distance test (6MWD; the primary end point of the study) in the placebo and treatment arms. At this stage, a key secondary end point will be the change in Kansas City Cardiomyopathy Questionnaire quality-of-life scale.

After 30 months, researchers will compare the combination of all-cause mortality and frequency of cardiovascular-related hospitalizations between AG10 and placebo using the Finkelstein-Schoenfeld method.2 Patients may continue in a separate open-label extension study, after conclusion of the double-blind treatment phase.

Male and female participants in the trial must be aged 18 to 90 years with an established diagnosis of ATTR-CM, with either wild-type transthyretin or a variant transthyretin genotype as defined by either positive endomyocardial biopsy or positive technetium bone scan. Participants must possess a history of heart failure evidenced by ≥1 prior hospitalizations for heart failure, or clinical evidence of heart failure (without hospitalization) requiring medical management. Participants must also have NYHA class I-III symptoms attributable to ATTR-CM. With the exception of diuretic dosing, patients must be receiving stable doses of cardiovascular medical therapy (ie, ≤50% dose adjustment and no categorical changes of medications) for at least 2 weeks prior to screening. Before randomization, participants must have left ventricular wall thickness ≥12 mm, have completed ≥150 meters on the 6MWD on at least 2 tests, and have N-terminal-pro B-type natriuretic peptide levels ≥300 pg/mL.

Patients are ineligible to participate in the study if they possess any of the following characteristics: a confirmed diagnosis of light chain amyloidosis, acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days before screening, or stroke or transient ischemic attack. Current therapy for ATTR-CM with tafamidis, diflunisal, green tea, doxycycline, or TUDCA/ursodiol within 14 days prior to dosing is also considered exclusionary. Any hemodynamic instability or abnormalities in clinical laboratory tests or clinically significant ongoing medical condition at screening or randomization that, in the judgment of the principal investigator, would pose too great a risk for participation in the study are to be excluded. Patients who are likely to undergo heart transplantation within a year of screening are not candidates.


  1. Judge DP, Heitner SB, Falk RH, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2019;74:285-295.
  2. Gillmore JD, Garcia-Pavia P, Grogan M, et al. ATTRibute-CM: a randomized, double-blind, placebo-controlled, multi-center, global phase 3 study of AG10 in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Circulation. 2019;140(Suppl 1):A14214.

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