Novo Nordisk left praying to Artemis and Hermes to salvage CKD program after phase 3 fail

A phase 3 trial of Novo Nordisk’s ziltivekimab has missed its primary endpoint, denting the prospects of a molecule analysts tipped to generate blockbuster sales and diversify the company’s portfolio. Hope now rests with the ongoing Artemis and Hermes trials—although analysts have their doubts. Today's results come from the Zeus study, which compared the effect of once-monthly subcutaneous doses of ziltivekimab, an antibody against the IL‑6 ligand, to placebo in more than 6,300 people. Subjects had atherosclerotic cardiovascular disease, chronic kidney disease (CKD) and inflammation. Novo bet that inhibiting the IL-6 cytokine could reduce cardiovascular inflammation and, in doing so, prevent outcomes such as heart attack and stroke. However, while Novo generated evidence that ziltivekimab inhibited the IL-6 pathway, the molecule’s effect on the cytokine failed to translate into a significant reduction in major adverse cardiovascular events. The rate of cardiovascular death, non-fatal heart attack or non-fatal stroke was statistically no lower on ziltivekimab than placebo, causing the trial to miss its primary endpoint. Martin Holst Lange, M.D., Ph.D., Novo’s chief scientific officer, has consistently characterized the Zeus readout as high risk on conference calls with investors this year. Yet analysts were optimistic heading into the data drop. Success was highly likely and a clinically significant benefit was probable, Guggenheim Securities analysts assessed in a July 13 note to investors. The analysts defined a clinically significant benefit as a hazard ratio (HR) of 0.85, indicating a 15% benefit. The actual HR was 0.99. BMO Capital Markets analysts put Novo’s chances of achieving at least a 15% benefit at 55% in their own note to investors earlier this week. The failure to live up to those expectations weakens the prospects of an asset that BMO analysts called “an important opportunity for Novo to extend its cardiovascular presence beyond obesity/diabetes, and establish a differentiated position in inflammation-driven cardiovascular disease.” That opportunity was potentially lucrative, with Guggenheim analysts predicting that Zeus “could unlock a multibillion-dollar opportunity in CKD alone.” BMO analysts concurred, estimating that positive data in a cardiovascular outcome trial could represent a multibillion-dollar opportunity. The analysts put consensus peak sales at about $3 billion. Novo still has two chances to rescue ziltivekimab. The Danish drugmaker is testing ziltivekimab in people with heart failure in its Hermes trial and evaluating the drug candidate in patients following an acute heart attack in its Artemis study. Both trials are continuing and scheduled to deliver data in the first half of next year. Speaking on an earnings call in May, Lange said Novo saw “very, very high potential” across the three indications but warned that the program was “high risk until we’ve seen the first readout.” Zeus’ failure leaves Hermes and Artemis looking even riskier than before, with BMO analysts concluding Friday in their latest note to investors that they now “view it as unlikely that either will read out positively.” Novo could step up its interest in M&A following “another higher-profile pipeline failure,” the analysts said. A large deal in the cardiovascular, metabolic or rare disease space could “reignite investor interest” in Novo, “helping to alleviate some of the hyper focus on the company's GLP-1 business,” the analysts said.