When Novo Nordisk recently reported that its experimental heart drug ziltivekimab failed to reduce the risk of heart attacks and strokes in a late-stage trial, the market reaction was swift. Novo’s stock fell as much as 10%, while shares of several other companies also tumbled amid fears the results cast doubt on whether targeting inflammation could reduce the risk of serious cardiovascular events.
The phase 3 Zeus trial enrolled over 6,300 people with atherosclerotic cardiovascular disease, chronic kidney disease and inflammation, following participants for up to four years. Although ziltivekimab produced the expected biological effect, lowering interleukin-6 and high-sensitivity C-reactive protein (hsCRP), it failed to reduce major adverse cardiovascular events (MACE) — cardiovascular death, nonfatal heart attack or stroke — compared with placebo.
While investors may have been spooked by the failure, it didn’t necessarily mark a death knell for the inflammation hypothesis, according to William Blair analyst Andy Hsieh. Instead, he said, the result may say more about IL-6 inhibition (and hsCRP as a surrogate marker) than it does about inflammation itself.
“In our view, the bearish read-through is more limited to hsCRP's surrogacy for cardio protection in the context of IL-6 inhibition,” he said in an email.
The better approach to reducing cardiovascular events might involve targeting a different protein, interleukin-1beta (IL-1β). In Novartis’ Cantos trial, for instance, a 150-mg dose of the drugmaker’s IL-1β inhibitor Ilaris significantly reduced recurrent cardiovascular events compared with placebo.
“We have validation that IL-1beta inhibition leads to MACE reduction,” Hsieh said. “This effect was dependent on hsCRP reduction magnitude (2 mg/L cutoff). So I wouldn't say the data invalidates the inflammatory hypothesis in its entirety.”
The Novo readout’s ripple effect
While the inflammation hypothesis may not be dead, Novo’s phase 3 results could dampen enthusiasm for NLRP3 inhibitors, a broader anti-inflammatory approach that can also affect IL-6 expression. For instance, BioAge Labs’ shares fell roughly 60% in premarket trading after Novo’s Zeus readout, according to the William Blair note.
BioAge is testing BGE-102 in the phase 2 Quell-Cv trial in patients at elevated cardiovascular risk and plans a phase 1b/2a study in diabetic macular edema.
“Despite plans to examine BGE-102 in ophthalmology indications, we believe the approach remains high-risk and difficult to build an investment thesis around,” Hsieh and William Blair colleagues wrote in a biotech note.
Neumora, which is developing the preclinical NLRP3 inhibitor NMRA-215 for obesity and cardiometabolic disease, saw a 5% premarket drop after the ziltivekimab failure. William Blair sees less read-through to the program, however, because NLRP3 inhibition acts more broadly than IL-6 blockade and NMRA-215’s lead indication is obesity.
Ziltivekimab’s story may not be over. Novo acquired the drug in its 2020 acquisition of Corvidia Therapeutics, and it remains in two additional phase 3 trials: Hermes in heart failure and Artemis in patients following an acute heart attack. Readouts for those trials are expected in the first half of 2027.
“While ziltivekimab did not achieve the MACE benefit we had hoped for, this does not change our strategic commitment to cardiovascular disease,” said Martin Holst Lange, Novo’s executive vice president, chief scientific officer and head of research and development, in a press release. “The study provides important scientific evidence that will inform our ongoing cardiovascular research and the development of treatments for patients who continue to face substantial unmet need.
