Novartis’ pelacarsen program took a hit as a large clinical trial failed to protect heart health despite lowering Lp(a). The negative result adds pressure on the broader strategy of using RNA-targeting approaches to modulate circulating biomarkers and could reshape how late-stage Lp(a) programs are prioritized in cardiometabolic pipelines. The finding also highlights a recurring translational problem in cardiovascular drug development: lowering a molecular target does not guarantee clinical benefit, even when earlier signals suggested the target was causal. Companies are likely to scrutinize study designs, endpoints, and responder definitions more tightly going forward. For biotech, the read-through is less about Lp(a) biology broadly and more about execution and evidentiary standards for biomarker-driven claims—especially when trials are intended to stand on their own for regulatory and reimbursement decisions.