CARDIO-TTRansform: Eplontersen Misses Primary Endpoint in ATTR-CM

The phase 3 CARDIO-TTRansform trial investigating eplontersen (Wainua) in transthyretin amyloid cardiomyopathy (ATTR-CM) did not meet its primary efficacy end point, according to results presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.¹

Results showed that among 1432 patients with wild-type or hereditary ATTR-CM, the composite rate of cardiovascular mortality and recurrent cardiovascular events did not differ significantly between eplontersen and placebo through 140 weeks (rate ratio, 0.89; 95% CI, 0.73-1.09; P = .277).¹ The result comes despite robust suppression of circulating serum transthyretin with eplontersen, consistent with its mechanism of action.

Eplontersen Efficacy and CARDIO-TTRansform Trial Design

Eplontersen is currently approved as Wainua for polyneuropathy of hereditary TTR-mediated amyloidosis but does not carry an ATTR-CM indication.² The negative result contrasts with vutrisiran, an RNA interference agent meeting its primary composite end point against placebo in the HELIOS-B trial and gaining US Food and Drug Administration approval for ATTR-CM in March 2025, joining tafamidis and acoramidis as disease-modifying options for clinicians managing this population.³

“ATTR-CM is an under-recognised cause of heart failure,” Mathew Maurer, MD, from Columbia University Irving Medical Center, said in a statement. “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.”

CARDIO-TTRansform was a double-blind, phase III trial conducted across 130 centers in 20 countries.¹ Investigators enrolled 1432 patients with wild-type or hereditary ATTR-CM already receiving available standard of care.¹

Participants underwent randomization in a 1:1 ratio to eplontersen 45 mg or placebo, administered by subcutaneous injection every 4 weeks.¹ Among the study population, the mean age was 72 years and 9.4% of participants were female.¹

The primary endpoint was a composite of cardiovascular mortality and recurrent cardiovascular events. Parent companies Ionis and AstraZeneca announced that the study had missed its primary endpoint on July 9, 2026, describing plans to present the results at ESC 2026.

According to data presented at the Congress, investigators recorded 381 primary end point events among 210 patients receiving eplontersen, compared with 392 events among 231 patients receiving placebo (rate ratio, 0.89; 95% CI, 0.73-1.09; P = .277).¹ A prespecified exploratory analysis confirmed suppression of circulating serum TTR through week 140, consistent with the expected pharmacodynamic effect of TTR gene silencing.¹

Eplontersen Safety and Stabilizer Subgroup Findings in ATTR-CM

A prespecified subgroup analysis examined whether background stabiliser therapy, used by 57% of participants at baseline, influenced the treatment effect.¹ Among patients not receiving a stabiliser at baseline, eplontersen monotherapy produced fewer primary composite end point events than placebo, a difference reaching nominal statistical significance.¹ Among patients already receiving stabiliser therapy, investigators observed no additional treatment benefit for the primary end point with eplontersen added on top.¹

According to the trial presenters, eplontersen was generally well tolerated, with a safety profile consistent with previous studies of the agent.¹ No new safety signals were reported in the release. The findings raise questions about whether TTR gene silencing offers incremental benefit on top of tetramer stabilization, a question with direct relevance for treatment sequencing and combination strategies in ATTR-CM.

“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,” Maurer said. “Baseline stabiliser use appeared to influence the primary results. No additional benefit was observed in patients receiving background stabiliser therapy, while fewer primary endpoint events were observed with eplontersen in patients not receiving a stabiliser. These findings will inform clinical practice and the evaluation of TTR-lowering treatment strategies in ATTR-CM.”

References:

1. European Society of Cardiology. Eplontersen trial did not meet its primary endpoint in transthyretin-mediated amyloid cardiomyopathy. Presented at: ESC Congress 2026, Hot Line 1; August 28, 2026; Munich, Germany. Accessed August 28, 2026.

2. WAINUA (eplontersen) granted first-ever regulatory approval in the US for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis. Ionis Pharmaceuticals. Published December 22, 2023. Accessed August 28, 2026. https://www.astrazeneca.com/media-centre/press-releases/2023/wainua-eplontersen-granted-first-ever-regulatory-approval-us-treatment-of-adults-with-polyneuropathy-hereditary-transthyretin-mediated-amyloidosis.html#

3. Alnylam Pharmaceuticals. Alnylam Announces FDA Approval of AMVUTTRA® (vutrisiran), the First RNAi Therapeutic to Reduce Cardiovascular Death, Hospitalizations and Urgent Heart Failure Visits in Adults with ATTR Amyloidosis with Cardiomyopathy (ATTR-CM). Published March 20, 2025. Accessed August 28, 2026. https://investors.alnylam.com/press-release?id=28831

4. Ionis. Update on CARDIO-TTRansform Phase 3 trial of eplontersen in adults with transthyretin-mediated amyloid cardiomyopathy. July 9, 2026. Accessed August 28, 2026. https://ir.ionis.com/news-releases/news-release-details/update-cardio-ttransform-phase-3-trial-eplontersen-adults