CagriSema misses non‑inferiority vs tirzepatide in REDEFINE 4; Novo Nordisk shares fall 15% | iPharmaCenter

CagriSema produced large absolute weight loss in REDEFINE 4 but failed its main goal of matching Eli Lilly’s tirzepatide, raising questions about its competitive positioning in obesity.

CagriSema delivers strong weight loss, but not enough vs tirzepatideIn the open‑label phase 3 REDEFINE 4 trial, adults with obesity and at least one comorbidity were randomized to once‑weekly CagriSema (fixed‑dose cagrilintide 2.4 mg plus semaglutide 2.4 mg) or tirzepatide 15 mg, both given subcutaneously over 84 weeks. The study enrolled 809 participants with an average baseline weight of about 114 kg.

Head-to-head comparison of Novo Nordisk’s CagriSema vs Eli Lilly’s tirzepatide in obesity: CagriSema falls short on non-inferiority

Under an analysis assuming full treatment adherence, patients on CagriSema lost 23.0% of baseline body weight at week 84, versus 25.5% for tirzepatide. Using a treatment‑regimen approach that factors in discontinuations and missing data, estimated weight loss was 20.2% for CagriSema compared with 23.6% for tirzepatide.

In both analytic frameworks, tirzepatide maintained a numerical advantage, and CagriSema did not meet the prespecified non‑inferiority margin. In other words, the drug that was meant to compete head‑on with Lilly’s incretin franchise failed to demonstrate that its weight‑loss effect is statistically “close enough” to tirzepatide in a head‑to‑head setting.

From a clinical perspective, a 20–23% reduction in body weight remains a meaningful result. However, for payers and prescribers comparing agents within a crowded obesity landscape, the fact that tirzepatide did better on the primary efficacy endpoint is likely to be viewed as a clear differentiation point in Lilly’s favor.

Regulatory path continues, but strategic value now more uncertain

Despite the setback in REDEFINE 4, Novo Nordisk has already filed CagriSema for a weight‑management indication with the US FDA, using the REDEFINE 1 and REDEFINE 2 pivotal trials as the core evidence package. The filing went in December 2025, and a US decision is expected by late 2026. That application focuses on placebo‑controlled data, where CagriSema clearly drives substantial weight loss, but it does not change the fact that, against tirzepatide, the candidate looks second‑best on weight reduction.

The company is trying to reposition the narrative around “full weight‑loss potential” by running additional studies, including REDEFINE 11 in obesity and a planned phase 3 programme examining higher‑dose CagriSema regimens. REDEFINE 11, which will explore the durability and magnitude of weight loss with CagriSema 2.4/2.4 mg over 80 weeks plus an extension, is expected to read out in the first half of 2027. A phase 3 trial of a higher‑dose combination (2.4 mg cagrilintide plus 7.2 mg semaglutide weekly) is slated to begin in the second half of 2026, signalling that Novo itself recognises the need to push beyond the current dose to stay relevant against Lilly’s pipeline.

About CagriSema

A combination that now looks like a follower, not a leader CagriSema is a fixed‑dose, once‑weekly injectable pairing a long‑acting amylin analogue (cagrilintide 2.4 mg) with semaglutide 2.4 mg. Mechanistically, the combination aims to promote weight loss by dampening appetite and increasing satiety, reducing caloric intake over time. Development is split into two major programmes: REDEFINE for adults with overweight or obesity, and REIMAGINE for adults with type 2 diabetes.