CagriSema misses tirzepatide noninferiority

Novo Nordisk said on February 23 that its obesity drug candidate CagriSema delivered 23.0% mean weight loss in the phase 3 REDEFINE 4 study but failed to meet the trial’s primary goal of showing noninferiority to Eli Lilly’s tirzepatide at 84 weeks. The head-to-head study compared once-weekly CagriSema 2.4 mg/2.4 mg with tirzepatide 15 mg in adults with obesity. Novo said the miss came even as CagriSema posted what the company called clinically meaningful weight loss in the open-label trial. ### What exactly did REDEFINE 4 test? REDEFINE 4 enrolled 809 randomized adults with obesity and at least one comorbidity, with a mean baseline body weight of 114.2 kg, according to Novo Nordisk’s results summary. The 84-week phase 3 trial tested a fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg against tirzepatide 15 mg, with both given once weekly by subcutaneous injection. (markets.ft.com) Novo described the study as open-label, meaning investigators and participants knew which drug was being administered. The primary endpoint was noninferiority on percentage weight loss at week 84 versus tirzepatide. ### How far apart were the weight-loss results? Under the analysis Novo used for people who adhered to treatment, CagriSema produced 23.0% weight loss after 84 weeks, compared with 25.5% for tirzepatide 15 mg. (markets.ft.com) Under the treatment-regimen estimand, which counts outcomes regardless of whether people stayed on treatment, CagriSema showed 20.2% weight loss versus 23.6% for tirzepatide. Those figures explain why the headline number and the primary-endpoint result point in different directions. A drug can post large absolute weight loss and still miss a noninferiority test if the comparator performs better than the prespecified margin allowed. That interpretation follows from Novo’s reported efficacy numbers and its statement that the primary endpoint was not achieved. (markets.ft.com) ### What is CagriSema, and how is it different from tirzepatide? CagriSema is an investigational fixed-dose combination of cagrilintide, a long-acting amylin analogue, and semaglutide, a GLP-1 receptor agonist, according to Novo Nordisk. Novo has said the combination is designed to target complementary obesity-related pathways. (markets.ft.com) Tirzepatide, sold in the United States as Zepbound, is Eli Lilly’s once-weekly injectable treatment for chronic weight management in adults with obesity or overweight plus at least one weight-related condition. Lilly’s prescribing information identifies tirzepatide as an approved product, while CagriSema remains investigational and is not FDA-approved. ### Did Novo Nordisk say anything about safety? (prnewswire.com) Novo Nordisk said CagriSema appeared safe and well tolerated in REDEFINE 4. The company said the most common adverse events were gastrointestinal, were mostly mild to moderate, and diminished over time, consistent with the GLP-1 receptor agonist class. Martin Holst Lange, Novo Nordisk’s executive vice president for Development, said in the company statement that Novo was “pleased” with the 23% weight-loss result and said CagriSema could become the first GLP-1/amylin combination product for obesity if approved. (pi.lilly.com) ### What happens next for CagriSema? December 18, 2025 marked Novo Nordisk’s announcement that it had filed a U.S. new drug application for CagriSema for chronic weight management. (markets.ft.com) The company has also said additional trials are exploring the product’s full weight-loss potential, including higher-dose combinations. Novo Nordisk said a high-dose CagriSema 2.4 mg/7.2 mg phase 3 efficacy and safety trial is planned to start in the second half of 2026. That study is the next named milestone the company has put on the program after the REDEFINE 4 readout. (markets.ft.com) (prnewswire.com)