Novo Nordisk was banking on the inflammatory benefits of its investigational therapy ziltivekimab to improve cardiovascular outcomes. Last week’s Phase 3 failure dashed not just the Danish pharma’s hopes but that of other drugmakers working on the same pathway.
Last week, Novo Nordisk’s IL-6 inhibitor ziltivekimab failed to lower the risk of cardiovascular complications in the Phase 3 ZEUS trial—a miss that has sent shock waves across the inflammatory space.
BioAge Labs and Monte Rosa Therapeutics seem to have been hit particularly hard. By the end of the trading session on Friday, BioAge had taken a 63.6% hit, dropping to $9.04 per share, while Monte Rosa crashed 27% to $16.52. To a lesser degree, the ZEUS failure also pulled down the stock of other companies. Neurocrine Biosciences, for instance, dipped 10% to $166.8, while Neumora slid 2.4% to $1.61.
BioAge’s lead asset is an orally available drug called BGE-102, which is being proposed as a treatment to lower cardiovascular risk. Although the asset has a different target from Novo’s ziltivekimab, BioAge is taking the same approach as the Danish pharma, building up BGE-102’s cardiovascular potential by showing its effect on high-sensitivity C-reactive protein (hs-CRP), a biomarker of inflammation.
The heavy blow to BioAge is due to the “negative readthrough from the ZEUS trial that challenges the correlation between significant hsCRP reduction and MACE [major adverse cardiovascular events] protection,” analysts at William Blair explained in a note on Friday.
In April, BioAge released Phase 1 data for BGE-102, touting an 85% reduction in hs-CRP at day 7 for the 60-mg drug dose. At the time, CEO Kristen Fortney said in a statement that these hs-CRP findings position BGE-102 as a potential “single oral therapy to address NLRP3-driven inflammation in cardiovascular, ocular, and CNS diseases.”
ZEUS now “challenges” this assertion, William Blair said, contending that ziltivekimab also lowered hs-CRP in the late-stage trial—though Novo didn’t provide specific numbers—but that this drop failed to translate to cardiovascular benefits. Phase 2 data for ziltivekimab showed an 88% reduction in hs-CRP levels at the 15-mg dose level at 12 weeks, “a magnitude that is comparable” to BGE-102’s Phase 1 results, the firm added.
With the ZEUS disappointment, “we believe investors will remove BioAge’s NLRP3 opportunity from the model,” William Blair said.
Monte Rosa, meanwhile, is advancing the oral molecular glue degrader MRT-8102 for IL-1β/NLRP3-driven inflammation and associated complications, including cardiovascular disease, according to its website.
Interim Phase 1 data in January showed that in patients with heightened cardiovascular disease risk, MRT-8102 suppressed hs-CRP levels by 85% after four weeks—a positive inflammatory signal that CEO Markus Warmuth at the time said could “establish the significant potential opportunity for MRT-8102 in multiple chronic inflammatory diseases, including [atherosclerotic cardiovascular disease].”
The impacts of ZEUS on Neumora and Neurocrine are more “limited,” William Blair said on Friday, because even if the biotechs are advancing assets targeting inflammation, their pipelines don’t heavily rely on these programs.
Neumora, for instance, has programs for obesity, schizophrenia psychosis and Alzheimer’s disease agitation, the firm said. Neurocrine, meanwhile, can lean on its commercial portfolio of the tardive dyskinesia drug Ingrezza, the congenital adrenal hyperplasia therapy Crenessity and the oral medicine Vykat XR for extreme hunger in Prader-Willi syndrome.
