On Sunday, The New England Journal of Medicine (NEJM) published results from Novo Nordisk A/S‘ NVO phase 3 REDEFINE 1 trial of CagriSema plus lifestyle interventions for weight loss in adults with obesity or overweight who have a weight-related medical complication and without diabetes.
CagriSema is being investigated by Novo Nordisk as a once-weekly subcutaneous injectable treatment for adults with overweight or obesity (REDEFINE programme) and as a treatment for adults with type 2 diabetes (REIMAGINE programme).
CagriSema is an investigational product that combines the GLP-1 RA, semaglutide, with an amylin analog, cagrilintide.
Also Read: Novo Nordisk Moves Amycretin Into Phase 3 Trials For Weight Management, Becomes Europe’s Largest Company
REDEFINE 1 Trial
If all patients adhered to treatment, CagriSema resulted in a greater weight loss of 22.7% at 68 weeks versus 2.3% in the placebo group.
When evaluating the treatment effect regardless of adherence, those treated with CagriSema achieved a statistically significant weight loss of 20.4% at 68 weeks versus 3.0% for the placebo group.
In addition, a supportive secondary analysis showed that half (50.7%) of trial participants with obesity treated with CagriSema reached the threshold for non-obesity (BMI < 30 kg/m2) at the end of treatment, from a mean BMI of 38 kg/m2 at the start of treatment.
In the placebo group,10.2% reached that threshold at 68 weeks.
Select confirmatory secondary endpoints showed that if all participants adhered to treatment, 40.4% of those receiving CagriSema achieved a weight reduction of ≥25%.
Additionally, 23.1% lost ≥30% of their body weight.
When applying the treatment policy estimand, 34.7% of participants treated with CagriSema achieved ≥25% body-weight reduction, and 19.3% achieved ≥30%.
In a prespecified analysis of 252 participants, the relative reduction in fat and lean soft-tissue mass from baseline to week 68 was -35.7% (fat mass) and -14.4% (lean soft-tissue mass) for those treated with CagriSema versus –5.7% and –4.3% for the placebo group, respectively.
These data, along with the related phase 3 REDEFINE 2 study conducted in adults with overweight or obesity and type 2 diabetes, were presented at the American Diabetes Association.
REDEFINE 2 Study
If all participants adhered to treatment, the estimated mean change in body weight from baseline to week 68 was –15.7% with CagriSema versus –3.1% with placebo.
When applying the treatment policy estimand, the estimated mean change in body weight from baseline to week 68 was –13.7% with CagriSema versus –3.4% with placebo.
A greater proportion of participants receiving CagriSema, compared with placebo, reduced their body weight by >5% (83.6% vs. 30.8% of participants), ≥10% (65.6% vs. 10.3%), ≥15% (43.9% vs. 2.4%), and ≥20% (22.9% vs. 0.5%;)
The safety results from CagriSema in REDEFINE 2 were similar to those reported in the REDEFINE 1 trial.
Novo Nordisk initiated the REDEFINE 11 trial with the first patient visit in early June 2025. REDEFINE 11 will explore further weight loss potential and safety of CagriSema 2.4 mg / 2.4 mg through a longer trial duration and other protocol changes compared to REDEFINE 1 and 2.
Market Reaction
NVO experienced a decline of over 7% in premarket trading on Monday; the market’s reaction suggests that Novo Nordisk’s CagriSema has been perceived to have a less favorable side effect profile when compared to Eli Lilly And Co’s LLY orforglipron.
In Eli Lilly’s ACHIEVE-1 trial, the most common adverse events for participants treated with orforglipron (3 mg, 12 mg and 36 mg, respectively) were diarrhea (19%, 21% and 26%) vs. 9% with placebo, nausea (13%, 18% and 16%) vs. 2% with placebo, dyspepsia (11%, 20% and 15%) vs. 7% with placebo, constipation (8%, 17% and 14%) vs. 4% with placebo, and vomiting (5%, 7% and 14%) vs. 1% with placebo.
In REDEFINE 1, adverse events were mainly gastrointestinal (79.6% in the CagriSema group vs. 39.9% with placebo), including nausea (55% vs. 12.6 %), constipation (30.7% vs. 11.6%), vomiting (26.1% vs. 4.1%) and mainly were transient and mild-to-moderate in severity.
Adding to the investor concerns, William Blair analysts expressed disappointment, stating, “We had hoped that the amylin component could provide a higher magnitude of weight loss among patients living with type 2 diabetes. Unfortunately, the hypothesis did not come to fruition, and 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.”
Analyst Andy Hsieh further elaborated that 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.”
Price Action: At the last check on Monday, NVO stock was down 7.10% to $68.53 during the premarket session.
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