Head-to-head trials are often reserved for approved therapies as drugmakers try to one-up each other to gain further market share. In this case, Novo Nordisk ran the test at the candidate stage, and the bet did not pay off.
Novo Nordisk’s up-and-coming weight loss combo drug CagriSema elicited 23% weight loss in a late-stage trial—but it wasn’t enough to beat Eli Lilly’s heavyweight Zepbound, which hit 25.5%. The jarring results sent Novo’s shares tumbling 15% to $40.20 in pre-market trading Monday.
CEO Maziar Mike Doustdar rigorously defended CagriSema—and Novo’s broader clinical program—after an analyst referred to the drug as “obsolete” in light of the data on a Monday morning conference call.
“To say it’s obsolete is quite belittling a fantastic drug, in all honesty,” Doustdar said. He then brushed off concerns about CagriSema’s marketability, as it has already been submitted to the FDA based on previous late-stage tests for weight management. The agency is expected to make a decision by late 2026, according to Novo.
“When CagriSema will make it to the market early next year as the first amylin-based product, it will have the best weight loss label than any product marketed at that time,” the CEO asserted.
Novo compared CagriSema, which combines new amylin agent cagrilintide with approved ingredient semglutide, in a head-to-head Phase 3 trial called REDEFINE 4 against Lilly’s approved therapy tirzepatide, marketed as Zepbound.
Head-to-head trials are often reserved for approved therapies as drugmakers try to one-up each other to gain further market share. But in the cutthroat world of obesity care, both Novo and Lilly have resorted to these winner-takes-all tests in an attempt to gain further ground.
In this case, Novo’s bet did not pay off, and the Danish pharma was forced to announce the failure of its own candidate to beat Lilly’s.
Chief Scientific Officer Martin Holst Lange blamed the loss on tirzepatide’s surprisingly strong showing. He declined to offer an explanation as to how the trial measured non-inferiority. Holst Lange also said the open-label nature of the trial may have influenced people who received the better-known product—but at the end of the day, tirzepatide may simply have worked better in the specific trial population.
“That’s maybe why we have seen these surprisingly good data for the comparative drug in part—we probably also have to ascribe this to biology,” Holst Lange said, adding that this level of efficacy has never been shown before with tirzepatide. “So obviously, this is the one off.”
Holst Lange noted that more patients achieved the full 15 mg dose in the tirzepatide cohort than in the CagriSema arm of the test, although not all stayed there.
The Results
In REDEFINE 4, CagriSema achieved an average of 23% weight loss after 84 weeks of treatment. But the combo failed on the primary endpoint of the trial, which was to show non-inferiority to Lilly’s treatment. Tirzepatide achieved 25.5% weight loss.
When treatment adherence was not taken into account, tirzepatide still beat CagriSema, with 23.6% weight loss to Novo’s 20.2%.
Novo executives in a statement announcing the results insisted that the CagriSema’s weight loss achievement was significant and said the asset has the opportunity to be the first GLP-1/amylin-combination product to market. CagriSema appears to add to the achievement of semaglutide alone, according to the press release.
Novo has an expansive clinical program for CagriSema, including the REDEFINE 11 study that will test a higher dose than the REDEFINE 4 trial against placebo. A readout is expected in the first half of 2027.
Earlier readouts from the program had already informed a change in the REDEFINE 4 protocol to try to tease out the best weight loss outcome for CagriSema, Holst Lange explained. The study was extended to 84 weeks to provide a longer runway for weight loss, for example.
Holst Lange declined to provide more specific data on the differences observed between REDEFINE 1, which was one of two studies that made up the FDA application, and REDEFINE 4, but said the weight loss achievement was similar in both studies. Novo believes that more weight loss can be squeezed out of CagriSema, and the REDEFINE 11 trial will test out all the learnings across the program in an attempt to achieve the best possible results for the treatment.
“We are strongly assuming that there is a further weight loss potential to be had when taking all of these learnings into account; we’ve done that in REDEFINE 11,” Holst Lange said.
The chief scientist did not rule out future head-to-head trials between CagriSema and Zepbound, however there is more to be learned from REDEFINE 11 and higher doses before that happens.
Another Good Day For Lilly
While Novo’s shares fell, Lilly got a nice bump with an additional 2.5% for $1,035 in pre-market trading. Truist Securities handed a W to Lilly for the competitor’s data.
“While we do acknowledge that Cagrisema is a potent drug and we continue to keep track of additional trial data, we believe these data maintain LLY’s dominance in obesity landscape at least for the near-future,” the firm wrote in a Monday morning note.
Tirzepatide also beat Novo’s semaglutide, which is marketed as Wegovy for weight loss, in a head-to-head trial sponsored by Lilly.
“Best-in-class profile coupled with improved access and supply, and increasing demand are expected to support LLY’s position in the landscape, in our view,” Truist wrote.
One area where Novo has the edge is in oral weight loss pills. The company launched oral Wegovy after a December 2025 approval and has had considerable success with the launch already. When announcing earnings earlier this month, Doustdar said that more than 100,000 patients are already taking the pill.
Lilly is close behind, however, with an FDA approval of orforglipron expected in the second quarter, Truist noted.
