AstraZeneca and Ionis' Eplontersen Fails Phase 3 CARDIO-TTRansform Trial in ATTR-CM

AstraZeneca and Ionis' Eplontersen Fails Phase 3 CARDIO-TTRansform Trial in ATTR-CM

In a major clinical setback for the transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) therapeutic space, AstraZeneca and Ionis Pharmaceuticals announced that their once-monthly, subcutaneously administered antisense oligonucleotide gene silencer, eplontersen (Wainua), failed to meet its primary efficacy endpoint in the Phase 3 CARDIO-TTRansform trial. The trial was the largest clinical outcomes study conducted in ATTR-CM to date, enrolling 1,432 wild-type or hereditary ATTR-CM patients across 130 sites in 20 countries.

The primary composite endpoint was evaluated through week 140 and consisted of cardiovascular mortality and recurrent cardiovascular clinical events. The trial showed no statistically significant benefit of eplontersen over placebo in the overall study population.

Standard of Care and Real-World Stabilizer Use Confound Efficacy Signal

A major factor influencing the trial's outcome was the high rate of background transthyretin stabilizer therapy (specifically tafamidis), reflecting the current real-world standard of care established by Pfizer's Vyndaqel/Vyndamax.¹ At baseline, 57% of patients in each arm were already receiving a TTR stabilizer, and an additional 24% in each arm initiated stabilizer therapy during follow-up.

A prespecified subgroup analysis showed a stark contrast in clinical benefit:

• Monotherapy Subgroup: Patients treated with eplontersen as a monotherapy showed a nominally significant reduction in primary composite events relative to placebo.
• Combination Subgroup: Patients already receiving a stabilizer at baseline derived no observable incremental treatment effect or clinical benefit from adding eplontersen gene silencing.

The full dataset and detailed subgroup analyses are scheduled for a high-profile "Hot Line" presentation at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, which runs from August 28 to 31, 2026.

"The trial showed no statistically significant benefit of eplontersen over placebo on the composite outcome of cardiovascular mortality and recurrent cardiovascular events." — AJMC Article

"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..." — Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, quoted in AJMC Article