Pelacarsen lowered lipoprotein(a) by up to 80 percent in Phase 2, and that number turned out to mean almost nothing for what patients actually care about. Novartis announced September 4 that the Lp(a)HORIZON Phase 3 trial did not meet its primary endpoint, a composite of cardiovascular death, non-fatal heart attack, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, compared to placebo. The gap between a biomarker that drops dramatically and a cardiovascular outcome that moves is the central problem the field now has to explain.
For Ionis, the financial damage is direct. Under its 2019 licensing agreement with Novartis, Ionis was entitled to tiered royalties in the mid-teens to low 20 percent range on net sales, plus $650 million in development, regulatory, and commercial milestones. A failed outcomes trial eliminates the commercial royalty stream entirely and almost certainly voids the portion of milestones tied to approval and launch. Ionis retains whatever development milestones it has already collected, but the future payments are gone.
The failure also lands hard on the broader Lp(a) field. Approved drug options specifically targeting Lp(a) reduction remain absent, with lipoprotein apheresis the only procedure carrying an FDA clearance for Lp(a) lowering. Other antisense and small-molecule programs targeting Lp(a) are still in development, and every one of them now faces a harder question from regulators and trial sponsors: if a therapy cuts Lp(a) by 80 percent and cardiovascular events do not follow, is Lp(a) reduction the right surrogate endpoint to build a program around, or does the relationship between the biomarker and outcomes need to be reconceived before the next large outcomes trial is funded?
The Lp(a)HORIZON dataset, when Novartis releases the full results, will be the document the field studies most carefully. Subgroup analyses, baseline Lp(a) thresholds, and the absolute event rates in the placebo arm will shape whether researchers conclude the hypothesis is wrong or that the trial enrolled the wrong population at the wrong Lp(a) level. That disclosure, not the topline failure itself, is what the competing programs need to see before deciding whether to proceed.
Source link: https://www.sec.gov/Archives/edgar/data/874015/000114036126035802/ef20081690_8k.htm
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
