Top-line results previously showed that pelacarsen dramatically lowered lipoprotein(a) but did not reduce serious cardiovascular outcomes in the HORIZON phase 3 trial. The reported update underscores the gap between biomarker change and clinical event reduction in Lp(a)-targeted therapy. The drug’s lack of effect on heart attacks, strokes, urgent coronary revascularization, or deaths over nearly five years creates new questions for the cardiovascular risk-reduction strategy, even as Lp(a) remains a strong genetic risk factor. The report also highlights the broader challenge of validating mechanism-driven therapeutics in outcomes trials rather than relying on Lp(a) lowering alone.