Eplontersen Fails to Achieve Primary Endpoint, Improves KCCQ and 6MWT in ATTR-CM

Although it failed to meet its primary efficacy endpoint, treatment effects generally favored eplontersen in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).^1,2

These data from the CARDIO-TTRansform trial were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026 in Phoenix, Arizona, by Brett Sperry, MD, co-director of cardiovascular radiologic imaging and nuclear cardiology and associate program director of the advanced heart failure and transplantation fellowship at Saint Luke’s Health System.¹

“The treatment landscape in ATTR-CM has dramatically changed over the past several years,” Sperry said in his presentation at HFSA. “TTR stabilizers, and now TTR silencers, have improved outcomes, but there’s a large unmet need that remains, not only in mortality and hospitalizations, but in health status – how patients feel, their symptoms, their physical and social function and limitations, and their quality of life.”¹

CARDIO-TTRansform was a phase 3 global, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of subcutaneous eplontersen in patients with ATTR-CM compared to placebo. The study enrolled patients with amyloid deposits confirmed by Congo Red staining or technetium scintigraphy, as well as end-diastolic interventricular septum thickness of >12 mm and New York Heart Association (NYHA) class 1-3 heart failure. Those with acute coronary syndrome, unstable angina, stroke, or coronary revascularization, among other criteria, were excluded.³

Patients were randomly assigned in a 1:1 ratio to receive either eplontersen 45 mg or matching placebo once every 4 weeks. The primary endpoint was a composite outcome of cardiovascular mortality and recurrent cardiovascular clinical events from baseline to week 140. Secondary outcomes included change from baseline in 6-minute walk test (6MWT) distance, change in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and each component of the primary endpoint by week 140.³

A total of 1432 patients underwent randomization and received ≥1 dose of their assigned intervention – 715 patients were assigned to the eplontersen arm and 717 to the placebo arm. The mean age of the patients was 76.4 years, and 90.6% were men. Additionally, 85% of the eplontersen arm and 88.5% of the placebo arm had wild-type TTR, with the remaining 15% and 14.5% having variant TTR, respectively.^1,2

By 140 weeks, a total of 381 primary endpoint events occurred in 210 patients in the eplontersen arm, while 392 events occurred in 231 patients in the placebo arm (rate ratio, 0.89; 95% CI, 0.73 to 1.09; P = .28). Cardiovascular mortality occurred in 74 patients in the treatment arm and 70 in the placebo arm, while 307 clinical events took place in the treatment arm and 322 in the placebo arm. The overall rate ratio for the composite primary endpoint was 0.86 (95% CI, 0.71 to 1.04).²

However, secondary endpoints, including change in KCCQ scores, saw some improvement with eplontersen compared to placebo. Patients in the treatment arm saw a change of -5.4 in their scores compared to -9.4 in the placebo arm, for an efficacy of 4.0 versus placebo (95% CI, 2 to 6, P <.001). Patients receiving eplontersen also saw a -27.5 m change in 6MWT at 140 weeks compared with -47.3 m in the placebo arm, for comparative efficacy of 19.7 (95% CI, 9.9 to 29.6; P <.001).¹

Ultimately, while eplontersen did not successfully demonstrate superior efficacy in reducing cardiovascular mortality or clinical events compared to placebo, Sperry and colleagues concluded that treatment did preserve health status, with lower reductions in KCCQ scores and 6MWT distance.¹

“Eplontersen preserved health status compared with placebo, with the largest benefits in those not on a baseline stabilizer, and the treatment effects were consistent across subgroups and domains,” Sperry said in his presentation. “So the data suggest that eplontersen, particularly as monotherapy, may help patients with ATTR-CM maintain how they feel and function over nearly 3 years of follow-up.”¹

References

1. Cappelli F, Chen J, Claggett B, et al. Effect of Eplontersen on Health Status in Patients with Transthyretin Amyloid Cardiomyopathy Enrolled in the CARDIO-TTRansform Trial. Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026, Phoenix, AZ. October 9-12, 2026.

2. Fontana M, Masri A, Solomon SD, et al. Eplontersen for transthyretin amyloid cardiomyopathy. New England Journal of Medicine. Published online August 28, 2026. doi:10.1056/nejmoa2608510

3. Ionis Pharmaceuticals. CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM). ClinicalTrials.gov Identifier: NCT04136171. Updated September 3, 2026. Accessed October 12, 2026. https://clinicaltrials.gov/study/NCT04136171