Heading into the American Heart Association’s Scientific Sessions, the cardiovascular space was full of optimism—and disappointment. In the past few months, several failures of innovative assets in late-stage trials have called into question the value of targets like IL-6 and lipoprotein(a) in the treatment of heart disease.
But Eli Lilly delivered good news in August when the FDA approved its blockbuster Mounjaro as the first GIP and GLP-1 agonist indicated to lower the risk of heart attack, stroke or cardiovascular death in adults with type 2 diabetes. Meanwhile, the company’s investigational base editor, VERVE-102, lowered LDL cholesterol levels in patients with an inherited form of high cholesterol by 62% in an early-stage trial, and Merck secured the first FDA approval for an oral PCSK9 inhibitor for high cholesterol.
Targets in trouble
Oppenheimer analysts issued a report on Sept. 8 calling out “six fails in nine weeks” in the cardiovascular space.
First on the firm’s list was Novo’s IL-6 inhibitor ziltivekimab, which in July failed to lower the risk of cardiovascular complications in a late-stage trial. Five weeks later, the company shuttered two more late-stage studies of the asset, leading Oppenheimer to say that IL-6 “now looks like an invalid target in chronic cardiovascular disease.”
Lipoprotein(a) levels were then called into question as a CV target after Novartis’ antisense therapy pelacarsen was unable to generate clinical benefit despite successfully lowering Lp(a).
This outcome “marks a meaningful setback for dedicated Lp(a)-lowering therapies,” BMO Capital Markets said in a Sept. 4 note following the readout. Meanwhile, Oppenheimer left the book open on the target. “We continue to resist the urge of marking the entire class to a single ASO readout,” the analysts wrote to investors.
These misses followed the surprising failure of AstraZeneca and Ionis Pharmaceuticals’ TTR silencer Wainua in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). Adding insult to injury, the partners later revealed that the Phase 3 result was worse than initially thought. In this case, Oppenheimer doesn’t see this miss as quite as dire for the class, but the late-stage failure nevertheless cast doubt on Alnylam’s ATTR programs. Like Wainua, both the biotech’s FDA-approved Amvuttra and its next-generation RNAi candidate nucresiran work by silencing transthyretin.
Cardio catalysts on deck
But all hope is not lost. The fourth quarter holds some important catalysts—including for another drug seeking to address high cholesterol.
NewAmsterdam Pharma is expecting data from the Phase 3 RUBENS trial, which is studying its CETP inhibitor obicetrapib alone or in combination with the cholesterol-lowering drug ezetimibe in patients with type 2 diabetes or metabolic syndrome. Lp(a) change from baseline is a secondary outcome in RUBENS.
Oppenheimer had once thought the data pointed to the obicetrapib’s benefit stemming mostly from the lowering of LDL cholesterol but characterized Lp(a) reduction as a “meaningful secondary contributor.” But after pelacarsen’s Phase 3 flop, the analysts said they “would now discount the Lp(a) contribution heavily.”
Meanwhile, Johnson & Johnson and Bristol Myers Squibb are anticipating data from a Phase 3 trial of their partnered investigational oral Factor XIa inhibitor milvexian in secondary stroke prevention by the end of this year. The partners halted a separate Phase 3 test for milvexian last year in acute coronary syndrome after an independent data committee said the trial was unlikely to meet its efficacy goal, so the program has a lot riding on this upcoming readout.
Editor’s note: A version of this article was originally published as a special edition of ClinicaSpace on October 13, 2026. The American Heart Association’s annual conference has since taken place.