Novartis reported two major late-stage setbacks in rapid succession, including the Phase III failure of delpacibart etedesiran (del-desiran) in myotonic dystrophy type 1 and the Phase III failure of pelacarsen in lipoprotein(a) cardiology outcomes. In DM1, the HARBOR trial missed its primary endpoint of statistically significant improvement versus placebo in video Hand Opening Time through week 54. Novartis said it is evaluating the full dataset and will engage with authorities on the program’s development path, with Shreeram Aradhye, president of development and CMO, noting that setbacks are part of scientific progress. For pelacarsen, Novartis and Ionis acknowledged that the Phase III Lp(a)HORIZON trial failed to reduce the risk of cardiovascular events compared with placebo. The outcome adds to pressure on Lp(a)-lowering strategies after other cardiovascular outcomes failures, sharpening scrutiny on whether biomarker reductions can reliably translate into clinical benefit. Together, the two Phase III misses mark a heavy hit to Novartis’ late-stage risk profile and increase uncertainty around both antisense-led and antibody–oligonucleotide conjugate approaches in complex disease areas.