REDEFINE 4: CagriSema 23% vs Tirzepatide 25.5% — Primary Non‑Inferiority Not Met

Novo Nordisk’s press release reports topline findings from REDEFINE 4, a head-to-head comparison of once-weekly CagriSema (cagrilintide 2.4 mg plus semaglutide 2.4 mg) versus tirzepatide 15 mg in adults with obesity. The company says the trial’s prespecified primary objective—demonstrating non-inferiority on percent weight loss at 84 weeks—was not met.

The release provides two sets of 84-week percent weight-loss estimates using different estimands. For the analysis described as assuming all people adhered to treatment, the company reported mean percent weight loss of 23.0% with CagriSema and 25.5% with tirzepatide 15 mg; it also noted that this efficacy estimand was defined as “according to the trial protocol, regardless of dose modification.” On the treatment-regimen estimand, described as treatment effect regardless of treatment adherence, the corresponding values were reported as 20.2% and 23.6%. After outlining both estimands, the company reiterates that the prespecified primary non-inferiority test on percent weight loss at 84 weeks was not achieved.

The press release describes REDEFINE 4 as an open-label, phase 3 trial with an 84-week treatment duration. The company reports that 809 participants were randomized and that the study enrolled adults with obesity and at least one comorbidity. Baseline characteristics highlighted in the release include a mean baseline body weight of 114.2 kg. The open-label design is described as meaning investigators and participants were aware of the assigned drug throughout the trial. These are the main design and population details provided alongside the 84-week percent weight-loss comparison.

In the announcement, the company characterized CagriSema as having appeared safe and well tolerated in the trial, with the most common adverse events reported as gastrointestinal in nature. The company states that the vast majority of these events were mild to moderate, diminished over time, and were consistent with the GLP-1 receptor agonist class.

The update also outlines upcoming milestones: initiation of a higher-dose CagriSema 2.4/7.2 mg phase 3 trial is planned for the second half of 2026, REDEFINE 11 data are expected during the first half of 2027, and a US FDA submission for CagriSema for weight management is stated as having been made in December 2025 with an anticipated decision by late 2026. The release presents these timelines as the next development and regulatory steps following the REDEFINE 4 readout.

Key Takeaways:

• The company reports that REDEFINE 4 did not meet its prespecified primary non-inferiority objective on percent weight loss at 84 weeks.
• Two estimands were reported for 84-week percent weight loss (efficacy and treatment-regimen), with different point estimates for CagriSema and tirzepatide.
• The press release describes predominantly gastrointestinal adverse events that were mostly mild to moderate and diminished over time, and it lists forthcoming programme and regulatory milestones spanning late 2025 through 2027.