Novartis’ pelacarsen failed to reduce cardiovascular events in the Phase 3 HORIZON trial, after earlier studies showed it could drastically lower Lp(a). The result directly challenges the drug’s core hypothesis—whether lowering the lipoprotein(a) biomarker translates into fewer heart attacks, strokes, or cardiovascular emergencies. The disappointing outcome will likely reverberate across Lp(a)-focused programs and reshape how sponsors design endpoints and confirm target engagement in late-stage trials. For clinicians and investors, it adds pressure to identify which patient subgroups and biomarker strategies, if any, can reliably predict clinical benefit. With Lp(a) positioned as a major cardiovascular risk factor for decades, the trial outcome raises the bar for subsequent disease-modifying approaches targeting the molecule.