Eplontersen Misses Primary End Point in Phase 3 ATTR-CM Cardiovascular Outcomes Trial

Eplontersen (Wainua) failed to meet its primary efficacy end point in a phase 3 cardiovascular outcomes trial in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), AstraZeneca and Ionis Pharmaceuticals announced earlier this month.¹ The trial showed no statistically significant benefit of eplontersen over placebo on the composite outcome of cardiovascular mortality and recurrent cardiovascular events, AstraZeneca and Ionis Pharmaceuticals announced earlier this month.

“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,” Sharon Barr, executive vice president, BioPharmaceuticals R&D, said in a statement.¹ “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.”

A Large Outcomes Trial in an Evolving Standard of Care Landscape

ATTR-CM is a progressive, often fatal condition driven by cardiac deposition of misfolded transthyretin amyloid fibrils, and it remains an underrecognized contributor to heart failure due to its nonspecific presenting symptoms, including dyspnea, edema, and fatigue. Eplontersen, a once-monthly, subcutaneously administered antisense oligonucleotide that reduces hepatic transthyretin production, is already approved as Wainzua for polyneuropathy of hereditary transthyretin-mediated amyloidosis in more than 20 countries.

CARDIO-TTRansform (NCT04136171), described by the companies as the largest ATTR-CM trial conducted to date, was a global, randomized, double-blind, placebo-controlled phase 3 study enrolling 1432 participants across 130 sites in 20 countries. Participants with wild-type or hereditary ATTR-CM receiving standard of care were randomized 1:1 to eplontersen 45 mg or placebo via subcutaneous injection every 4 weeks, with the primary end point defined as a composite of cardiovascular mortality and recurrent cardiovascular clinical events through week 140. Reflecting current practice patterns, 57% of patients in each arm were already receiving a transthyretin stabilizer at baseline, and an additional 24% in each arm initiated stabilizer therapy during the trial.

Monotherapy Subgroup Signal Contrasts With No Effect Among Stabilizer Users

In the overall population, adding eplontersen to standard of care did not produce a statistically significant reduction in the risk of the composite primary end point compared with placebo. However, in a prespecified subgroup analysis of patients treated with eplontersen monotherapy, fewer primary composite events were observed relative to placebo, a result described as nominally significant. Among patients already receiving a stabilizer at baseline, no incremental treatment effect from eplontersen was observed. The safety profile was described as generally well tolerated and consistent with prior data on the therapy.

The stabilizer-heavy comparator arm echoes the treatment landscape established by tafamidis (Vyndamax and Vyndaqel; Pfizer), which became the first approved transthyretin stabilizer after the ATTR-ACT (NCT01994889) trial demonstrated reductions in all-cause mortality and cardiovascular hospitalization vs placebo, fundamentally reshaping the standard of care for ATTR-CM in the years since.²

AstraZeneca and Ionis said they plan to conduct a full analysis of the CARDIO-TTRansform data set, with results to be presented at the European Society of Cardiology Congress (ESC) in August 2026.¹

Managed Care Implications

For payers and health systems, a missed primary end point in the largest ATTR-CM outcomes trial to date suggests eplontersen is unlikely to gain a near-term cardiovascular outcomes indication or displace stabilizer therapy as first-line treatment, tempering anticipated utilization growth and formulary pressure in this space. The nominally significant monotherapy subgroup signal, however, means plans should watch the full ESC 2026 data presentation closely in August, as it could inform future combination therapy positioning, prior authorization criteria, or step-therapy sequencing relative to stabilizers for appropriate ATTR-CM candidates.

References

1. Update on CARDIO-TTRansform Phase III trial for Wainua (eplontersen) in adults with transthyretin-mediated amyloid cardiomyopathy. News release. AstraZeneca. July 9, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/update-cardio-ttransform-phase-iii-trial.html
2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689