Novo Nordisk's ziltivekimab cut inflammation 76% but not heart outcomes; Novartis's pelacarsen failed too

The full ZEUS results↗, presented at the American Heart Association's Chicago sessions on Saturday and published the same day in the New England Journal of Medicine, settle what the field's biggest biomarker win was worth. Novo Nordisk's·−1.69% — Novo Nordisk, down 1.69 percent as of its last quote ziltivekimab cut interleukin-6, an immune signaling protein, by 76% and high-sensitivity C-reactive protein, the standard blood measure of inflammation, by 64% across 6,376 patients ¹². Heart attacks, strokes and cardiovascular deaths landed where placebo left them: 561 events against 565, a hazard ratio of 0.99 ¹².

Novartis's·−0.91% — Novartis's, down 0.91 percent as of its last quote pelacarsen matched the pattern at a second target, in the same journal the same day: lipoprotein(a), an inherited cholesterol-like particle, fell 78% across 8,323 patients with no change in any cardiovascular outcome ³. Ionis Pharmaceuticals, which discovered pelacarsen and licensed it to Novartis, had its partner's topline null on the record from September 4↗ ⁴. The biomarkers fell by record margins in both trials; the event rate did not move in either.

The drugs changed the blood, not the patient

The null was priced before the weekend. Novo announced the ZEUS topline↗ in August ²; the September futility halts of its companion HERMES and ATHENA trials followed ⁵; Saturday supplied the full detail and the cost. Serious infections ran at 20.4% on the drug against 17.9% on placebo, and blood clots at 1.6% against 0.6% ⁵. Deaths came to 538 on ziltivekimab against 542 on placebo, about 17% of those enrolled ¹.

Participants averaged 69 years old, with both cardiovascular disease and chronic kidney disease ². Lead investigator Paul Ridker of Mass General Brigham allowed that disease this advanced may have been "too little, too late" to modify ¹.

The genetics priced a lifetime; the trial tested two and a half years

Both programs were built on Mendelian randomization, a method that uses inherited gene variants to estimate what a lifetime of lower exposure to a target does to risk ⁵. A trial instead suppresses the marker for about two and a half years in people who already have arterial plaque. ZEUS confirmed both halves of that distinction: patients who started with more inflammation had more events, and lowering it prevented none ⁶.

"Genetic causality is not therapeutic reversibility," Ridker said. "Both the Mendelian randomization and the clinical trials are correct" ⁶. Trial discussant Priscilla Hsue of UC San Francisco named the other suspect: the drug blocks the IL-6 protein itself, and the strongest human genetic evidence points at its receptor ⁵⁶.

The write-down is booked; the spending is not

Novo bought the antibody in 2020 from Corvidia Therapeutics, the AstraZeneca spinoff that developed it, for $725 million upfront and up to $2.1 billion with milestones ⁵. Its third-quarter report↗ then booked DKK 8.7 billion of impairments, DKK 4.6 billion of them on ziltivekimab ⁷.

That is the gap between the 27% rise in adjusted operating profit and the 9% fall in reported profit we covered on November 5 ⁷. NVO closed Friday at $40.31, with price-to-sales and price-to-earnings ratios near half their five-year averages and a 4.46% dividend yield ⁸. At that price the investment case rests on the Wegovy pill's launch, not on this pipeline ⁸.

The same null reprices Novartis, Ionis and the next readouts

Novartis has stopped pelacarsen in atherosclerotic disease, keeping only a study in calcific aortic valve stenosis; its Swiss shares rose 0.3% Monday ¹⁰. Ionis, which licensed the drug to Novartis in 2019 for $150 million upfront, fell 28% on the data and its own lowered guidance↗ ⁹¹⁰. Evan Seigerman, an analyst at BMO Capital Markets, told investors the odds of a clear benefit for the two rival Lp(a) programs are "extremely low" ¹⁰.

ARTEMIS continues; Novo still owes Ventus up to $700 million

The watch list from here is concrete. ARTEMIS, testing the same antibody in acute coronary ischemia, "has been allowed to continue," Ridker said, "so we're optimistic on that" ⁶. Novo owes up to $700 million more to Ventus Therapeutics, the drugmaker behind an NLRP3 inhibitor one step upstream of IL-6, on a cascade whose causal point of intervention Ridker calls uncertain ²⁵.

And the next two readouts, Amgen's·+0.17% — Amgen's, up 0.17 percent as of its last quote olpasiran and Eli Lilly's▲+1.51% — Eli Lilly's, up 1.51 percent today lepodisiran, arrive with analysts expecting $2.3 billion in peak olpasiran sales ¹⁰. If they null as well, that expectation is the next thing repriced.