The CARDIO-TTRansform trial investigating eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy did not meet its primary efficacy endpoint, according to results presented in a Hot Line session today at ESC Congress 2026.
Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease characterized by misfolded transthyretin (TTR) amyloid deposits in the heart muscle. The deposits can lead to a reduction in cardiac function, worsening symptoms of heart failure and recurrent cardiovascular events.
ATTR-CM is an under-recognized cause of heart failure. With an estimated 300,000 to 500,000 people living with ATTR-CM worldwide, greater awareness, earlier diagnosis and appropriate targeted treatment are critical to improving outcomes and quality of life for patients," he said.
Doctor Mathew Maurer, presenter, Columbia University Irving Medical Center, New York, USA
Eplontersen is a once-monthly RNA-targeted silencer designed to reduce TTR production by the liver. Eplontersen is approved for the treatment of hereditary/variant TTR amyloid polyneuropathy. The CARDIO-TTRansform trial investigated the efficacy and safety of eplontersen in patients with ATTR-CM.
This was a double-blind phase III trial conducted in 130 centres in 20 countries worldwide. A total of 1,432 patients with wild-type or hereditary ATTR-CM were enrolled who were receiving available standard of care. Participants were randomized (1:1) to receive eplontersen 45 mg or placebo by subcutaneous injection every four weeks. The mean age of the study population was 72 years and 9.4% were women.
The primary endpoint was a composite of cardiovascular mortality and recurrent cardiovascular events. There were 381 primary endpoint events in 210 patients receiving eplontersen compared with 392 events in 231 patients receiving placebo (rate ratio 0.89; 95% confidence interval 0.73 to 1.09; p=0.277).
Eplontersen produced suppression of circulating serum TTR, consistent with the expected pharmacodynamic effect of TTR gene silencing, as assessed by a prespecified exploratory endpoint through Week 140.
The majority of participants (57%) were receiving stabilizer therapy at baseline. In a prespecified subgroup analysis, the observed treatment effect differed according to baseline stabilizer use. Among patients not receiving stabilizer therapy at baseline, fewer primary composite endpoint events were observed with eplontersen monotherapy than with placebo, with the result reaching nominal statistical significance. Among patients receiving stabilizer therapy at baseline, no additional treatment benefit was observed for the primary endpoint.
Eplontersen was generally well tolerated, with a safety profile consistent with previous results.
"In CARDIO-TTRansform, the largest ATTR-CM trial to date, eplontersen achieved reductions in circulating serum TTR, although the trial did not demonstrate a significant reduction in the primary endpoint in the overall population," concluded Doctor Maurer. "Baseline stabilizer use appeared to influence the primary results. No additional benefit was observed in patients receiving background stabilizer therapy, while fewer primary endpoint events were observed with eplontersen in patients not receiving a stabilizer. These findings will inform clinical practice and the evaluation of TTR-lowering treatment strategies in ATTR-CM."
Facts Only
* The CARDIO-TTRansform trial investigated eplontersen in patients with ATTR-CM.
* ATTR-CM is a progressive, fatal disease characterized by TTR amyloid deposits in the heart muscle.
* Eplontersen is a once-monthly RNA-targeted silencer designed to reduce TTR production by the liver.
* The trial was a double-blind phase III study conducted in 130 centers across 20 countries.
* 1,432 patients with wild-type or hereditary ATTR-CM were enrolled and received standard of care.
* Participants were randomized 1:1 to receive eplontersen 45 mg or placebo every four weeks.
* The primary endpoint was cardiovascular mortality and recurrent cardiovascular events.
* 381 primary endpoint events occurred in 210 patients receiving eplontersen versus 392 events in 231 patients receiving placebo.
* The rate ratio for the primary endpoint events was 0.89 (95% CI 0.73 to 1.09; p=0.277).
* Eplontersen produced suppression of circulating serum TTR by Week 140.
* 57% of participants were receiving stabilizer therapy at baseline.
* Fewer primary composite endpoint events were observed with eplontersen monotherapy than with placebo among patients not receiving baseline stabilizer therapy, reaching nominal statistical significance.
Executive Summary
The CARDIO-TTRansform trial investigated the efficacy and safety of eplontersen in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is a progressive, fatal disease caused by misfolded transthyretin (TTR) amyloid deposits in the heart muscle, leading to reduced cardiac function. The study involved 1,432 patients with wild-type or hereditary ATTR-CM across 130 centers in 20 countries. Participants were randomized to receive eplontersen 45 mg or a placebo via subcutaneous injection every four weeks.
The primary endpoint was a composite of cardiovascular mortality and recurrent cardiovascular events. In the eplontersen group, 381 primary endpoint events occurred in 210 patients, compared to 392 events in the placebo group. The rate ratio for these events was 0.89 (95% CI 0.73 to 1.09; p=0.277). Eplontersen demonstrated suppression of circulating serum TTR, consistent with the expected biological effect.
Analysis based on baseline stabilizer use showed differential results: among patients not receiving baseline stabilizer therapy, eplontersen monotherapy resulted in fewer primary composite endpoint events than placebo, reaching nominal statistical significance. However, no additional benefit was observed for the primary endpoint in patients who were already receiving background stabilizer therapy. Eplontersen was generally well tolerated with a safety profile consistent with prior results.
Full Take
The trial yields a nuanced result where the overall population analysis failed to meet the primary efficacy goal, yet subgroup analysis revealed context-dependent effects tied to existing treatment strategies. The failure of the overall population to demonstrate a significant reduction in cardiovascular events suggests that eplontersen's benefit is highly conditional, not universal. The observation that baseline stabilizer use moderates the outcome points toward a critical gap in understanding how TTR-lowering therapies interact with established cardiomyopathy management protocols.
The differential results concerning patients receiving background stabilizer therapy versus those not receiving it imply that the true therapeutic value of reducing circulating TTR might be dependent on the underlying disease severity or the concomitant use of existing stabilizing measures. This forces a reconsideration of whether a single efficacy endpoint is sufficient when dealing with a complex, progressive pathology like ATTR-CM. The scientific pursuit must shift from simply assessing overall mortality rates to determining which patient subgroups—defined by baseline treatment status—experience meaningful clinical benefit from TTR suppression.
The pattern suggests that the mechanism (TTR reduction) is achieved, but translating that biochemical change into a significant clinical event reduction requires considering the holistic context of care. This calls for further research not just on efficacy versus placebo, but on optimizing sequencing and combination strategies based on patient stratification. What assumptions about treatment adherence or disease progression might be masking the true potential for these interventions in different cohorts?