Novo Nordisk shares tumbled last year when obesity candidate CagriSema failed to clear a weight loss bar of 25%. Now, executives are taking another look at the data but steering clear of making hard bets.
Individualized treatment could boost weight loss with Novo Nordisk’s up-and-coming treatment CagriSema, which disappointed investors late last year after failing to meet the company’s own bar of 25% weight reduction.
Novo has recently released two readouts from its closely watched weight loss pipeline. The first was for CagriSema, which combines the active ingredient of Wegovy and Ozempic, semaglutide, with cagrilintide. The second, and more successful readout, was for amycretin, which showed 22% weight loss in results posted in January.
During a fourth quarter earnings call Wednesday, Novo Executive Vice President of Development Martin Holst Lange revisited the CagriSema readout, aiming to boost sentiment toward the Phase III asset, which is further along in the clinic than amycretin, the latter having just wrapped Phase Ib/IIa testing.
Lange himself had set expectations high for CargiSema, saying on a third quarter earnings call last year that the investigational drug could achieve weight loss of 25%. When the December 2024 readout came back showing only 22.8% after 68 weeks, Novo lost $72 billion in market cap. Analysts at the time called this an unforced error.
Lange presented a posthoc analysis of the Phase III REDEFINE 1 trial to investors, who were eager to hear any tidbit of data from the company’s weight loss pipeline. Novo now believes that treatment regimens should be tailored to each patient, and there may need to be a re-calibration of the dose at some point.
“The REDFINE 1 data indicate that a patient-centric and individualized treatment regimen, which takes the initial dose escalation, dose re-escalation and trial duration into account, could potentially enhance efficacy of CagriSema while maintaining a favorable safety profile,” Lange said.
The trial data were split up after the fact into a few subgroups. The first included 57% of the total population on the highest dose of 2.4 mg. This group had 12.7% mean weight loss at 20 weeks and 22.2% at 68 weeks. These participants did not see their weight loss plateau, as has been a concern with existing GLP-1s. This group also had fewer gastrointestinal side effects, which Lange said suggests they could keep going and experience steeper weight loss at the high dose.
The second group, with 29% of the participants, received the lowest doses, on average just 1.1 mg. This cohort experienced 15.9% mean weight loss at 20 weeks and just cleared Novo’s high bar at 25.1% by 68 weeks. These participants were approaching a normal BMI at the end of treatment, according to Lange. This group could titrate up and see further weight loss, he said.
“While it may appear counterintuitive that lower doses of CagriSema leads to more substantial weight loss, this pattern is consistent with the observations from the STEP and STEP UP trials with semaglutide—however, it appears to be more pronounced with the potent biology of CagriSema,” he explained.
Analysts continued to be confused about the inverse dose response on the earnings call, with some asking why this wasn’t more pronounced in earlier trials. CEO Lars Fruergaard Jørgensen pointed to the potency of the product. “These differences will be amplified,” he said.
He brushed off concerns about how physicians will respond to the nuanced dosing requirements in the marketplace, because providers already examine patient characteristics carefully before prescribing.
“It’s perhaps less confusing for physicians than we believe, because they’re actually used to patients responding quite differently on treatment and that goes for obesity,” Jørgensen said. “I think it’s up for the rest of us to acknowledge that this is a new sign we get in large scale clinical development, but it’s really linked to the potency of the product.”
CagriSema is moving into a Phase III trial called REDEFINE 11, where Novo will examine a longer duration, dose escalation and dose re-escalation.
Novo will also put CagriSema head-to-head against Eli Lilly’s rival GLP-1 tirzepatide, which is approved for weight loss as Zepbound, in a trial called REDEFINE 4. The trial will read out in the second half of this year. Lange said the main goal will be non-inferiority to show that CagriSema is at least as good as Lilly’s option. The R&D executive is confident based on existing data that Novo will meet or exceed that bar.
But this time around, Lange resisted the call to set a bar for success. “I think it’s too early to speculate, but we will see the data when we see them.”
