AstraZeneca and Ionis' Wainua Misses Primary Endpoint in Phase III ATTR-CM Trial

AstraZeneca and Ionis Pharmaceuticals announced that the Phase III CARDIO-TTRansform trial of Wainua (eplontersen) did not meet its primary efficacy endpoint in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). The composite endpoint measured cardiovascular mortality and recurrent cardiovascular clinical events through week 140 compared with placebo, and the trial did not reach statistical significance on that measure.¹ Wainua's safety profile was consistent with prior studies, with no new tolerability concerns reported.

Wainua is a once-monthly RNA-targeted antisense oligonucleotide that suppresses hepatic production of transthyretin (TTR) protein at its source, administered subcutaneously via autoinjector or pre-filled syringe.² It is already approved in more than 20 countries for the polyneuropathy of hereditary transthyretin-mediated amyloidosis, marketed as Wainzua in the EU, but ATTR-CM represented a substantially larger potential patient population, with an estimated 300,000 to 500,000 people living with the cardiac form of the disease worldwide.³

What did the subgroup and design data show?

CARDIO-TTRansform enrolled 1,432 participants across 130 sites in 20 countries, making it the largest ATTR-CM trial conducted to date, and randomized patients 1:1 to eplontersen 45 mg or placebo.⁴ Most participants were also receiving background standard of care, with 57% on a TTR stabilizer such as tafamidis at baseline and another 24% initiating one during the trial. In a prespecified subgroup analysis limited to patients on Wainua monotherapy without a stabilizer, researchers observed fewer primary composite events compared with placebo, a result the companies described as nominally significant. Among patients already on a stabilizer at baseline, no incremental treatment effect from Wainua was observed, raising questions about whether TTR silencing adds benefit on top of stabilization or primarily helps patients not otherwise treated.

Sharon Barr, executive vice president of BioPharmaceuticals R&D at AstraZeneca, said the trial results add to the field's understanding of treatment approaches for ATTR-CM despite missing the primary objective. "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," Barr said. "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."

How does this fit into the broader ATTR-CM treatment area?

ATTR-CM has historically been managed with TTR stabilizers, and gene-silencing approaches, including both antisense oligonucleotides and small interfering RNA agents, have been positioned as a mechanistically distinct alternative that reduces TTR production rather than stabilizing the misfolded protein.⁵ Other modalities are also advancing in the space, including CRISPR-based gene editing approaches designed to permanently silence the TTR gene, though those remain earlier in clinical development.⁵ The CARDIO-TTRansform result suggests that translating TTR reduction into a measurable cardiovascular outcome benefit, on top of modern background therapy, may be more complex than the polyneuropathy setting where TTR-silencing therapies have already shown clear efficacy.

What happens next?

AstraZeneca and Ionis said they will conduct a full analysis of the CARDIO-TTRansform dataset, with results to be presented at the European Society of Cardiology Congress in August 2026. That presentation should clarify whether the monotherapy signal holds up under further scrutiny and inform how, or whether, eplontersen's development in ATTR-CM proceeds.

References

1. CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04136171
2. Coelho T, et al. (2023 Oct 17). Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. https://pubmed.ncbi.nlm.nih.gov/37768671/
3. Kittleson MM, et al. (2026 Feb 10). Transthyretin Cardiac Amyloidosis Evaluation and Management: 2025 ACC Concise Clinical Guidance. J Am Coll Cardiol. https://pubmed.ncbi.nlm.nih.gov/41171219/
4. Masri A, et al. (2026 Jun). Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail. https://pubmed.ncbi.nlm.nih.gov/42104840/
5. Ang, S. P., Chia, J. E., & Mukherjee, D. (2025 Jul). Emerging, novel gene-modulating therapies for transthyretin amyloid cardiomyopathy. Heart Fail Rev. https://pubmed.ncbi.nlm.nih.gov/40056371/