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Novartis (NVS) shares are plunging as primary-endpoint failures for pelacarsen and del-desiran, together with recent safety-related pauses involving rap-cel, trigger a broader reassessment of R&D productivity and pipeline value. The company maintained its 5-6% sales CAGR outlook for 2025-2030, but the setbacks increase pressure on newer medicines to offset patent erosion from Entresto and other mature products.

• The 8,323-patient Phase III Lp(a) HORIZON trial showed that pelacarsen lowered Lp(a), but this biomarker effect did not reduce the composite risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularization requiring hospitalization versus placebo. Because participants were already receiving guideline-directed lipid-lowering and antihypertensive therapy, the result raises questions about whether targeting Lp(a) provides additional clinical benefit, although the magnitude of lowering and subgroup outcomes remain undisclosed.
• The approximately 150-patient, 54-week Phase III HARBOR trial failed to significantly improve video hand opening time, a measure of how quickly patients with myotonic dystrophy type 1 can open their hand after making a fist. NVS cited evidence of activity across secondary endpoints and exploratory analyses, but did not disclose effect sizes or statistical significance, leaving an uncertain regulatory path despite safety findings generally consistent with prior data.
• Del-desiran was the centerpiece of NVS’s approximately $12 bln acquisition of Avidity Biosciences and had been viewed as a potential multibillion-dollar product. Its failure therefore challenges both the asset’s commercial outlook and the value assigned to the transaction.
• The market is also digesting NVS’s recent decision to pause eight of ten rapcabtagene autoleucel, or rap-cel, studies following patient deaths. This third setback makes the selloff less about two isolated trial failures and more about confidence in the company’s broader development engine.
• The acquired AOC platform remains active, with delpacibart zotadirsen under FDA Priority Review for DMD44 and regulatory discussions planned for delpacibart braxlosiran in FSHD. Remibrutinib recently succeeded in two Phase III relapsing multiple sclerosis trials, while MRT-6160 has entered a Phase II Sjögren’s disease study.

Briefing.com Analyst Insight

The central issue is that several high-value programs have lost risk-adjusted value within days, even though NVS’s formal medium-term sales outlook is unchanged. Pelacarsen’s failure raises a fundamental target-validation question, while del-desiran’s miss is particularly damaging because it was expected to validate the company’s largest acquisition under CEO Vas Narasimhan. Secondary signals may justify further analysis, but overcoming a failed pivotal endpoint generally requires unusually strong, consistent evidence or another confirmatory study. The next decisive evidence will come from full subgroup and secondary-endpoint data, regulatory feedback on del-desiran, the rap-cel safety investigation, and execution across the remaining AOC portfolio.