The effect of Novo Nordisk’s amycretin injections on body weight showed no signs of plateauing after 36 weeks, suggesting the Danish drugmaker can improve on the data that triggered a jump in its share price early this year. However, the tolerability data raised questions about the strength of Novo’s hand.
Top-line phase 1b/2a data on the GLP-1 and amylin receptor agonist provided some rare respite for Novo in January. With CagriSema’s disappointing phase 3 data still fresh in the memory, Novo reported 22% weight loss in people who received weekly amycretin injections for 36 weeks. Investors sent Novo’s stock up, but the top-line readout left key questions about the effects of amycretin unanswered.
Novo filled in some of the gaps in a paper in The Lancet. The full data set shows the weight loss trend was unchanged across the 36-week study, with patients shedding pounds as quickly at the end of the trial as at earlier time points.
The researchers said “the mean plots did not indicate any plateauing of weight reduction during dose escalation or maintenance dose periods.” If the trends continue beyond Week 36, Novo could improve on the 22% weight loss seen to date when it runs longer trials. Eli Lilly found weight loss in people taking its GLP-1/GIP drug Zepbound increased (PDF) from 20.9% after 36 weeks to 25.8% after 88 weeks.
While the mean plots suggest amycretin can achieve industry-leading weight loss, they raise questions about which dose Novo should take into phase 3. The dose response part of the study escalated patients up to maintenance doses of 1.25 mg, 5 mg or 20 mg.
Novo reported the highest weight loss at the 20-mg dose, but that cohort also stayed on the treatment for longer. The mean plots show overlapping response curves, with patients on 1.25 mg and 5 mg of the drug candidate losing similar amounts of weight as their counterparts on the top dose before they came off treatment. It is unclear whether weight loss trends would diverge over the course of a longer trial.
There could be tolerability benefits to using lower doses. The proportion of patients with gastrointestinal side effects was the same—94%—in the 5-mg and 20-mg cohorts but fell to 63% on the 1.25-mg dose. The small sizes of the cohorts complicate attempts to compare safety and efficacy between doses and, in particular, between trials. However, the results are worrying some observers.
"We believe the high frequency of adverse events could fuel uncertainty over the asset’s differentiation against approved (Zepbound) or late-stage investigational (retatrutide and MariTide) compounds," analysts at William Blair said in a note to investors.
Zepbound’s advantages over Wegovy, Novo’s GLP-1 drug, have ratcheted up the pressure on the Danish drugmaker to develop a more effective successor to its first-generation obesity treatment. CagriSema, a combination of the active ingredient in Wegovy and a long-acting amylin analog, achieved Zepbound-like efficacy in phase 3 but fell short of Novo’s own weight loss target.
Sunday, Novo shared more data on CagriSema in patients with and without Type 2 diabetes. The New England Journal of Medicine papers support the top-line impression that CagriSema will provide stiffer competition to Zepbound than Wegovy but may lack a clear advantage over Lilly’s blockbuster.
"In our view, there is no evidence to suggest CagriSema should be prescribed over Zepbound in any subpopulation, based on the available data released to date," William Blair analysts said. "In the absence of clinical differentiation against Zepbound, we believe the frequency of injection site reaction adds another commercial headwind to CagriSema, as Zepbound continues to gain market share away from Wegovy."
Amycretin offers Novo another shot at developing a market-leading molecule. The company is preparing to start phase 3 trials of the injectable and oral formulations of the GLP-1 and amylin receptor agonist. On an earnings call last month, Martin Holst Lange, M.D., Ph.D., executive vice president of development at Novo, said the company was aiming to start the phase 3 program in the first quarter of 2026.