ZEUS delivers a bolt of pain to Novo Nordisk

An experimental Novo Nordisk drug for cardiovascular diseases, the IL-6 inhibitor ziltivekimab, has failed the phase 3 ZEUS trial, denting the company's plans to expand its pipeline outside diabetes and obesity.

Shares in Novo Nordisk lost around 7% of their value after it revealed ziltivekimab failed to reduce the risk of major adverse cardiovascular events (MACE) – death, non-fatal heart attack and non-fatal stroke – compared to placebo, in patients with atherosclerotic cardiovascular disease (ASCVD) compounded by chronic kidney disease (CKD) and inflammation.

The 6,300-patient study tested a once-monthly 15 mg dose of the anti-IL-6 drug, and while lab analyses showed it was acting as expected on the IL-6 pathway, it did not translate into clinical benefit. The hazard ratio in the trial ranged from a 12% reduction in MACE compared with placebo to an 11% increase.

"ZEUS was designed to test whether inhibition of the IL-6 pathway could translate reductions in cardiovascular inflammation into fewer major cardiovascular events," said Novo Nordisk's R&D chief Martin Holst Lange.

"Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population. This does not change our strategic commitment to cardiovascular disease."

Novo Nordisk has invested quite heavily in the ziltivekimab programme, and is running two more cardiovascular outcome trials – HERMES in heart failure and ARTEMIS in post-heart attack patients – that are due to reach out in the first half of next year.

Analysts said the ZEUS failure makes ziltivekimab a high-risk asset and increases the pressure on Novo Nordisk to carry out licensing deals and/or acquisitions to bolster its pipeline outside obesity and diabetes, which has been driving growth in recent years but where it is facing increasing pressure from rival Eli Lilly.

One of the drugs that Novo Nordisk hoped would help it fight back in the injectable weight-loss category, CagriSema (cagrilintide and semaglutide), has generated disappointing results in phase 3 trials, although there have been signs that its move into the oral weight-loss category with the Wegovy (semaglutide) pill is paying dividends. So far, oral Wegovy is outselling Lilly's rival pill Foundayo (orforglipron).

Novo Nordisk said the ZEUS setback will not affect it profit outlook for the year but will result in a non-cash impairment charge in its third-quarter results.

Novo Nordisk acquired ziltivekimab as part of its $725 million takeover of AstraZeneca spin-out Corvidia Therapeutics in 2020.

Photo by Michał Mancewicz on Unsplash