AstraZeneca and Ionis reported a major Phase 3 setback for eplontersen (Wainua) in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), with the gene-silencing therapy failing to outperform placebo on the composite clinical endpoint of cardiovascular death and events. The outcome came despite large and sustained reductions in transthyretin levels. The result is likely to reshape competitive positioning in a heart-disease category where mechanisms and dosing models have become increasingly differentiated. It also adds pressure to next-generation approaches targeting amyloid cardiomyopathy and related pathways.