Novartis’s pelacarsen misses Phase III endpoint despite deep Lp(a) lowering

Novartis’s pelacarsen failed to reduce major cardiovascular events in the Phase III Lp(a)HORIZON trial despite substantially lowering lipoprotein(a) [Lp(a)], delivering the first major outcomes setback for a drug specifically targeting the inherited cardiovascular risk factor. The result raises fresh questions for the Lp(a)-lowering hypothesis while increasing scrutiny on competing Phase III siRNA programs from Amgen and Eli Lilly.

Lp(a)HORIZON enrolled 8,323 patients with established cardiovascular disease (CVD) and Lp(a) ≥70 mg/dL, all receiving guideline-directed background therapy including lipid-lowering and antihypertensive agents. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, evaluated in both the overall population and a pre-specified subpopulation with Lp(a) ≥90 mg/dL. Pelacarsen demonstrated an acceptable safety profile, Ionis Pharmaceuticals (Nasdaq: IONS) said in a concurrent statement, but the Lp(a) reductions achieved did not translate into a statistically significant reduction in cardiovascular risk in the overall population. No hazard ratios or p-values were disclosed; full data will be presented at an upcoming medical congress.

Pelacarsen is a GalNAc-conjugated ASO that silences hepatic LPA mRNA, blocking Lp(a) particle assembly at its source. Phase II data had shown approximately 80% Lp(a) reduction at the 80 mg monthly dose used in Lp(a)HORIZON, with 98% of patients reaching below 50 mg/dL. The failure therefore does not appear to reflect inadequate pharmacology. Instead, it raises a more fundamental question about whether Lp(a) lowering per se reduces cardiovascular events in patients whose other risk factors are already well managed .

Ahead of the readout, Novartis management had flagged analyst concerns about whether rising use of GLP-1, SGLT2, and PCSK9 inhibitors in the trial population might dilute any cardiovascular benefit attributable to Lp(a) lowering. Chief Medical Officer Shreeram Aradhye acknowledged the result did not demonstrate that Lp(a) lowering translated into reduced cardiovascular risk in the overall study population, while framing the data as advancing scientific understanding of the Lp(a)-outcomes relationship.

Amgen's olpasiran, a quarterly-dosed siRNA also targeting LPA mRNA, is currently in the ongoing OCEAN(a)-Outcomes trial with 7,297 patients and a primary completion date of approximately March 2028. At Amgen's Q2 2026 earnings call, management had explicitly positioned olpasiran against pelacarsen, citing olpasiran's approximately 95% Lp(a) reduction, its quarterly dosing, and a primary endpoint restricted to 3-point MACE — excluding ischemic stroke, which Amgen said had a weaker genetic association with Lp(a) elevation. Eli Lilly's lepodisiran, an annual-dosing siRNA, is in the ACCLAIM-Lp(a) Phase III outcomes trial. Both companies will now face intensified scrutiny over whether their deeper Lp(a) reductions, different patient selection thresholds, or modified endpoint structures are sufficient to produce a different outcome.

The pelacarsen failure also ends Novartis's ambition to deploy the drug through its existing Leqvio (inclisiran) cardiovascular sales infrastructure — a commercial rationale management had cited as recently as July 2026. Royalty Pharma (Nasdaq: RPRX), which acquired a royalty interest in pelacarsen as part of a January 2023 funding agreement with Ionis, said it does not anticipate making any milestone payments to Ionis and expects its total investment to return only a modest positive result through its retained Spinraza royalty position.

For Ionis, which discovered and conducted early development of pelacarsen before licensing global rights to Novartis in February 2019, the failure removes a major 2026 pipeline catalyst and revenue generator.

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