Novartis’ Pelacarsen Misses Primary Endpoint in Landmark Lp(a)HORIZON Trial

Novartis announced that its antisense oligonucleotide pelacarsen failed to meet the primary endpoint of the Phase III Lp(a)HORIZON trial. The double-blind, randomised, multi-centre study enrolled 8,323 patients with established cardiovascular disease and lipoprotein(a) [Lp(a)] levels >= 70 mg/dL. The composite endpoint—cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation—did not differ between pelacarsen and placebo, despite marked Lp(a) reductions. The result was disclosed on September 4.

Novartis’ pelacarsen fails to meet primary endpoint in Lp(a)HORIZON trial PharmaphorumNovartis’ Lp(a) drug misses Phase 3 endpoint Novartis Heart Drug Pelacarsen Fails Phase 3 Trial, Shocking Cardiologists

Elevated Lp(a) is a genetically determined risk factor present in roughly one-in-five people worldwide and is linked to coronary artery disease, stroke, peripheral arterial disease, and aortic stenosis. No approved therapies currently lower Lp(a). Pelacarsen, developed by Ionis Pharmaceuticals and licensed to Novartis in 2019, binds LPA messenger RNA, reducing apolipoprotein(a) production. Phase II work showed 72-80 % Lp(a) reductions, raising expectations of cardiovascular benefit.

Novartis’ Lp(a) drug misses Phase 3 endpoint PharmaphorumNovartis’ pelacarsen fails to meet primary endpoint in Lp(a)HORIZON trial Novartis Heart Drug Pelacarsen Fails Phase 3 Trial, Shocking Cardiologists

• Participants: 8,323 patients (>= 70 mg/dL Lp(a); a sub-group >= 90 mg/dL).

Novartis’ Lp(a) drug misses Phase 3 endpoint

• Intervention: Monthly sub-cutaneous pelacarsen injection versus placebo; all received guideline-directed lipid-lowering and antihypertensive therapy.

Novartis’ Lp(a) drug misses Phase 3 endpoint

• Outcome: No statistically significant difference in the four-point MACE composite.

Novartis’ Lp(a) drug misses Phase 3 endpoint

• Biomarker effect: Lp(a) levels were lowered markedly in the pelacarsen arm.

Novartis’ Lp(a) drug misses Phase 3 endpoint

• Financial impact: Novartis shares fell up to 3.9 % on September 7, the steepest decline in four months; peers Amgen and Eli Lilly also saw price drops.

The Straits Times

Novartis said full results will be presented at an upcoming medical congress and that the data will inform future risk-management strategies.

The Straits Times

Novartis has not released detailed event rates, effect sizes, or subgroup analyses, leaving uncertainty about any patient subsets that might have benefited. The trial’s duration (? seven years) and the lack of disclosed data mean the Lp(a) reduction needed for clinical benefit remains unresolved.

The Straits Times

• “These are not the results we had hoped for, but they provide important evidence that enhances the scientific understanding of the relationship between Lp(a) reduction and cardiovascular outcomes and could help guide future approaches to cardiovascular risk management,” — Shreeram Aradhye, Chief Medical Officer, Novartis

il Sole 24 Ore

• Data presentation: Detailed results are scheduled for the American Heart Association’s annual scientific meeting in November.

Novartis Heart Drug Pelacarsen Fails Phase 3 Trial, Shocking Cardiologists

• Competing programs: Amgen’s siRNA olpasiran (Phase III OCEAN(a)-Outcomes, 7,297 patients) and Eli Lilly’s lepodisiran (Phase III) now face heightened scrutiny.

Novartis’ Lp(a) drug misses Phase 3 endpoint

• Novartis pipeline: The next major late-stage test is del-desiran, targeting myotonic dystrophy type 1, central to its $12 billion Avidity acquisition.

Pharmaphorum