Rationale and Design of CARDIO-TTRansform: A Phase 3 Trial of Eplontersen for Transthyretin Amyloid Cardiomyopathy

Understanding Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive and fatal disease caused by misfolded transthyretin (TTR) protein depositing as amyloid fibrils in the heart muscle. This leads to heart stiffness, impaired function, and ultimately heart failure. Historically, treatment options were limited, focusing on symptom management. Disease-modifying therapies like TTR stabilizers (tafamidis, diflunisal) have emerged, but mortality remains high, underscoring the need for novel approaches.

Eplontersen: A Targeted Therapeutic Approach

Eplontersen represents a breakthrough as an N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide. It works by specifically binding to TTR messenger RNA (mRNA) in liver cells (hepatocytes). This binding triggers the degradation of the mRNA, significantly reducing the production of both mutant and wild-type TTR protein at its source, thereby lowering the amount available to misfold and form amyloid deposits in the heart.

The CARDIO-TTRansform Trial: Rationale and Design

CARDIO-TTRansform is a pivotal Phase 3, randomized, double-blind, placebo-controlled trial designed to rigorously assess the efficacy and safety of eplontersen in ATTR-CM patients. This landmark study is the largest conducted in this patient population to date.

Patient Population and Eligibility

The trial enrolled 1,432 participants globally. Key inclusion criteria required confirmed ATTR-CM diagnosis, evidenced either by histological proof of amyloid deposits or Grade 2-3 cardiac uptake on technetium-based cardiac scintigraphy (without evidence of plasma cell dyscrasia). Participants had to be in New York Heart Association (NYHA) functional class I-III and have an end-diastolic interventricular septal thickness greater than 12 mm.

Treatment Protocol and Study Structure

Participants were randomized in a 1:1 ratio to receive either eplontersen (45 mg) or matching placebo, administered via subcutaneous injection every four weeks for a core treatment period of up to 140 weeks (approximately 2.7 years). This was followed by either a 20-week post-treatment evaluation period or entry into an open-label extension (OLE) phase. Crucially, all participants received locally available standard of care throughout the trial, which explicitly included unrestricted use of TTR stabilizer medications.

Primary and Secondary Endpoints

The primary endpoint is a composite measure of cardiovascular mortality and recurrent clinical cardiovascular events (such as hospitalizations for heart failure, myocardial infarctions, arrhythmias, or strokes) assessed through the 140-week core period. Secondary endpoints, tested in a predefined hierarchical sequence, include: (1) Change from baseline in the 6-minute walk distance (6MWD), a key measure of functional capacity; (2) Change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, assessing disease-specific health status and quality of life; (3) Analysis of recurrent cardiovascular events; (4) All-cause mortality; (5) The primary composite endpoint specifically in the subgroup of patients receiving TTR stabilizers at the study baseline; and (6) Cardiovascular mortality alone.

Comprehensive Cardiac Assessment

The trial incorporates extensive cardiac monitoring. All participants underwent regular echocardiography to assess heart structure and function. In addition, a subset of participants underwent advanced imaging with cardiovascular magnetic resonance (CMR) to evaluate tissue characterization and amyloid burden, along with serial technetium scintigraphy to monitor cardiac tracer uptake dynamics.

Current Status and Significance

CARDIO-TTRansform has completed enrollment, with all 1432 participants randomized and dosed. Its immense size positions it uniquely to provide definitive evidence on whether adding eplontersen to current standard of care (including stabilizers) can significantly improve major cardiovascular outcomes and survival for patients suffering from ATTR-CM. The results are eagerly anticipated by the cardiology community and could redefine treatment protocols.

Trial Registration Information

CARDIO-TTRansform is registered on major international trial databases: ClinicalTrials.gov identifier: [NCT04136171](https://clinicaltrials.gov/ct2/show/NCT04136171); EU Clinical Trials Register (EudraCT) number: 2019-002835-27.

Source Citation

Masri A, Cappelli F, Davis MK, et al. Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail. 2026;19:e014205. PMID: 42104840. [URL: https://pubmed.ncbi.nlm.nih.gov/42104840/]