AstraZeneca and Ionis hit a major setback in transthyretin-mediated amyloid cardiomyopathy after eplontersen (Wainua) failed to outperform placebo in the Cardio-TTRransform Phase 3 study, the companies reported. The trial did not meet its primary composite endpoint of reducing cardiovascular death and recurrent cardiovascular events. While the drug produced large and sustained transthyretin-lowering consistent with its gene-silencing mechanism, the lack of clinical benefit reshapes expectations for the gene-silencing class in ATTR-CM. Markets reacted with sharp premarket declines for both companies. The failure also highlights how biomarker engagement does not automatically translate into outcomes in cardiomyopathy, a pattern with growing scrutiny across RNA and oligonucleotide platforms.