Novo Nordisk’s CagriSema misses non-inferiority endpoint in head-to-head trial vs. tirzepatide

Edited by Robert McTiernan··3 min read

Novo Nordisk released headline data from the Phase III REDEFINE 4 study for CagriSema in obesity, in which the fixed dose combination failed to achieve the primary endpoint of non-inferiority versus tirzepatide in weight loss terms. CagriSema, a fixed dose combination of the amylin analog cagrilinitide with GLP-1 agonist semaglutide in a 2.4 mg/2.4 mg achieved a weight loss of 23.0% after 84 weeks compared to 25.5% with tirzepatide 15 mg. The Danish giant is awaiting a US FDA regulatory decision for CagriSema later this year, backed by data from the REDEFINE 1 and 2 trials versus placebo.

Trial specifics

REDEFINE 4 was an open-label, randomized Phase III trial enrolling 809 adults with obesity and at least one related comorbidity, and at least 114kg in weight. Participants received once-weekly subcutaneous injections of either CagriSema 2.4 mg/2.4 mg or Eli Lilly’s tirzepatide 15 mg over an 84-week treatment period in a head-to-head comparative design in which investigators and participants were aware of treatment allocation.

The primary endpoint was percentage body weight reduction at week 84 assessed under a non-inferiority framework. According to the company, individuals treated with CagriSema achieved mean weight loss of 23.0% when assuming treatment adherence, compared with 25.5% for tirzepatide. Using the treatment-regimen estimand, mean weight loss was 20.2% versus 23.6% respectively. The study therefore did not meet its primary endpoint of demonstrating non-inferiority to tirzepatide on weight loss at 84 weeks. Novo Nordisk said the safety profile was consistent with that of the GLP-1 receptor agonist class, with gastrointestinal events reported as the most common adverse effects, generally mild to moderate in severity and diminishing over time.

While Novo Nordisk is expecting a US FDA decision on CagriSema by late 2026, additional Phase III work remains ongoing, including the REDEFINE 11 study expected to report data in H1 2027 and the planned initiation of a higher-dose CagriSema trial in H2 2026 designed to further assess weight-loss potential. The REDEFINE 11 study includes an 80-week extension phase to investigate CagriSema’s ability to maintain weight loss.

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Research context

CagriSema combines semaglutide, a GLP-1 receptor agonist that enhances satiety and delays gastric emptying, with cagrilintide, a synthetic analog of the pancreatic hormone amylin that acts on complementary appetite-regulating pathways in the central nervous system. Targeting both GLP-1 and amylin biology is intended to amplify metabolic signaling linked to energy intake and body weight regulation in obesity, a chronic disease for which long-term pharmacologic management remains limited despite recent therapeutic advances.

According to previous publications, if approved, CagriSema is expected to be initiated at a lower dose of 0.6mg weekly for the first month, then increased to 1.2mg weekly for the second month, followed by 1.8mg weekly for the third month, before reaching the maintenance dose of 2.4mg weekly.

The REDEFINE 4 findings therefore reflect a comparison between launch-relevant dosing strategies, with the 2.4 mg/2.4 mg fixed-dose CagriSema regimen used in the trial forming the basis of Novo Nordisk’s obesity filing, and the 15 mg tirzepatide dose representing the highest approved maintenance dose in clinical practice. As such, the outcome provides an early indication of how the currently submitted formulation may perform relative to an established dual incretin therapy at full titration.

Key competitors include:

  • Eli Lilly’s tirzepatide, marketed as Mounjaro and Zepbound, a dual GIP/GLP-1 receptor agonist approved by the US FDA for obesity and type 2 diabetes.
  • Eli Lilly’s retatrutide, a Phase III GLP-1/GIP/glucagon triple agonist under investigation for obesity and metabolic disease.
  • Novo Nordisk’s own amycretin, a dual GLP-1 and amylin receptor agonist currently in clinical development in both oral and injectable formulations.