AstraZeneca (NYSE: AZN) and Ionis Pharmaceuticals (Nasdaq: IONS) reported that eplontersen (Wainua) failed to meet the primary endpoint of the CARDIO-TTRansform Phase III trial in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), closing off what had been one of the most anticipated cardiovascular readouts of 2026 and casting doubt on what had been viewed by analysts as a near-term revenue driver valued at more than USD 5 billion in peak sales.
The trial — the largest ever conducted in ATTR-CM, enrolling 1,432 patients across 130 sites in 20 countries — evaluated eplontersen 45 mg subcutaneously once monthly versus placebo on top of available standard of care. The primary composite endpoint of cardiovascular mortality and recurrent cardiovascular clinical events through Week 140 was not met. A prespecified subgroup analysis of patients receiving eplontersen without a TTR stabilizer showed nominally significant fewer primary composite events, but in patients already on stabilizer therapy at baseline — 57% of each arm — no treatment effect was observed. An additional 24% of patients in each arm initiated a stabilizer during the trial, meaning the vast majority of participants were exposed to background stabilizer therapy at some point.
Eplontersen is a GalNAc-conjugated antisense oligonucleotide that degrades TTR mRNA in hepatocytes via RNase H1, reducing circulating TTR protein and downstream amyloid fibril deposition. The mechanism is well-validated in the polyneuropathy setting, where eplontersen is approved in more than 20 countries for hereditary transthyretin-mediated amyloid polyneuropathy. The cardiomyopathy indication represented the major commercial expansion opportunity.
The result raises a pointed question about the interaction between gene silencers and TTR stabilizers in ATTR-CM. Pfizer's Vyndaqel and Vyndamax (tafamidis) and BridgeBio's Attruby (acoramidis) stabilize the TTR tetramer to prevent misfolding, while eplontersen reduces TTR production upstream. Whether the two mechanisms are complementary or whether stabilizer-treated patients derive less marginal benefit from TTR knockdown — perhaps because stabilized tetramers are already less amyloidogenic — is a question the full dataset may help clarify. Alnylam's Amvuttra (vutrisiran), an RNAi agent with a similar silencing mechanism, received FDA approval for ATTR-CM in March 2025 based on the HELIOS-B trial, which enrolled patients both with and without background stabilizer use. Cross-trial comparisons are limited by differences in design and patient populations, but vutrisiran's success in a similarly constructed contemporary population will make the CARDIO-TTRansform failure particularly difficult to explain on mechanism alone.