CARDIO-TTRansformHot Line 1CardiomyopathyNew England Journal of Medicine
Eplontersen for Transthyretin Amyloid Cardiomyopathy
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Presenting authorMathew MaurerHeart Failure / Cardiomyopathy · Columbia University Irving Medical Center, New York, USAMathew S. Maurer, MD is the Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons. He directs the Clinical Cardiovascular Research Laboratory for the Elderly and the Cardiac Amyloidosis Program at NewYork-Presbyterian Hospital–Columbia Campus. He is a geriatric cardiologist with advanced training in heart failure and cardiac transplantation.
Overview
Eplontersen lacks benefit for cardiovascular outcomes in ATTR-CM; challenges antisense oligonucleotide TTR lowering as add-on therapy in the stabilizer era.
Key result
Eplontersen did not significantly reduce cardiovascular death and recurrent cardiovascular events compared to placebo in ATTR-CM (rate ratio 0.89; 95% CI 0.73-1.09; P=0.28).
Discussion
CARDIO-TTRansform has reported — post the first read.
Expert takes
The CARDIO-TTRansform Phase 3 trial of eplontersen (Wainua) in 1,432 patients with transthyretin amyloid cardiomyopathy (ATTR-CM) missed its primary endpoint of reducing the composite of cardiovascular mortality and recurrent CV events through Week 140. In a prespecified subgroup analysis, eplontersen monotherapy (without a TTR stabilizer) showed a nominally significant HR of 0.71, but no treatment effect was seen in the ~57% of patients already on stabilizer therapy at baseline. Reaction has focused on whether the evolving treatment landscape — with widespread stabilizer use — created an "add-on ceiling" that made it difficult to detect incremental benefit. Full data are expected at ESC Congress in August 2026.
Mathew Maurer
Professor of Cardiology, Columbia University Irving Medical Center
“Over the last decade, multiple advances and increased awareness of ATTR-CM have driven earlier diagnosis, improved management and better outcomes for patients. These data from the largest enrolled study of a contemporary ATTR-CM patient population provide important clarity for the field that will help inform future treatment decisions in ATTR-CM.”
Brett P. Monia
Chief Executive Officer, Ionis Pharmaceuticals
“We believe these findings reflect the rapidly evolving treatment landscape, in which contemporary ATTR-CM patients are widely treated with stabilizers. Although we are disappointed that the study did not meet the primary endpoint, these results have the potential to guide the treatment landscape for ATTR-CM and contribute to advancing future care for patients.”
SB
Sharon Barr
EVP BioPharmaceuticals R&D, AstraZeneca
“The CARDIO-TTRansform trial was designed to examine the role of Wainua, a gene silencer treatment, on top of today's standard of care in reducing recurring cardiovascular events and mortality. Although the trial did not meet its primary objective, we believe the results support greater scientific understanding of treatment approaches for the hundreds of thousands of patients worldwide suffering from this progressive and often fatal condition.”
“Primary results appeared to be influenced by baseline stabiliser use with no clear benefit in patients receiving background stabiliser therapy, while fewer primary endpoint events occurred with eplontersen in patients not receiving a stabiliser.”
Key Points
- Eplontersen did not significantly reduce the composite rate of cardiovascular death and recurrent cardiovascular events in patients with transthyretin amyloid cardiomyopathy.
- The primary composite outcome occurred in 29.4% of eplontersen recipients versus 32.2% of placebo controls, yielding an insignificant rate ratio of 0.89 across 140 weeks.
- In this double-blind trial of 1432 patients, lowering hepatic transthyretin with antisense oligonucleotide therapy failed to demonstrate clinical cardiovascular benefit.
Study Design
Type
RCT (n=1,432)
Blinding
double-blind
Randomization
1:1 ratio
Multicenter
Yes
Structured PICO
Does eplontersen reduce the cumulative composite of cardiovascular death and recurrent cardiovascular clinical events in patients with transthyretin amyloid cardiomyopathy?
P
Population
1,432 patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), mean age 76.4 years, followed for up to 140 weeks.
I
Intervention
Subcutaneous eplontersen 45 mg every 4 weeks for 140 weeks, in addition to standard treatment.
C
Comparator
Placebo every 4 weeks for 140 weeks, in addition to standard treatment.
O
Outcome
Cumulative composite of death from cardiovascular causes and recurrent cardiovascular clinical events up to week 140.composite
Eplontersen did not significantly reduce the risk of cardiovascular death and recurrent cardiovascular events compared to placebo in patients with ATTR-CM over 140 weeks.
Main Result
Relative Risk: 0.89 (95% CI 0.73–1.09)
Absolute Event Rate: 29.4% vs 32.2%
p-value: p=0.28