CagriSema Leads to Weight Reduction of Approximately 23% in Phase 3 REDEFINE 1 Clinical Trial, Short of the 25% Expected

The phase 3 REDEFINE 1 clinical trial of CagriSema (Novo Nordisk), the fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg, met its primary endpoint - a statistically significant and superior weight loss of 22.7% after 68 weeks of treatment compared with placebo in a cohort of adults with obesity or with overweight and without type 2 diabetes.1

Although meeting its primary endpoint, however, the study's 22.7% reduction in weight across CagriSema dosing fell short of company and analyst expectations, which were set at 25% or more, according to industry outlets.2

“We are encouraged by the weight loss profile of CagriSema demonstrating superiority over both semaglutide and cagrilintide in monotherapy in the REDEFINE 1 trial. This was achieved even though only 57% of patients reached the highest CagriSema dose,” Martin Holst Lange, executive vice president for development at Novo Nordisk, said in the Novo Nordisk December 20 announcement.1

The safety and efficacy REDEFINE 1 trial evaluated once-weekly subcutaneous CagriSema administration against the individual components in addition to placebo. In the analysis of treatment effects based on adherence by all participants, weight loss reached 11.8% for cagrilintide 2.4 mg, 16.1% for semaglutide 2.4 mg, and 2.3% for placebo, when given alone, Novo reported. The fixed-dose combination was also superior to the components and placebo for weight reduction of 25% or more after 68 weeks, a point reached by 40.4% of participants taking CagriSema vs 6.0% taking cagrilintide 2.4 mg, 16.2% taking semaglugide 2.4 mg, and 0.9% of those taking placebo. The mean baseline weight of study participants was 106.9 kg.1

CagriSema combines the long-acting amylin analogue cagrilintide and the glucagon like peptide-1 receptor agonist semaglutide, a novel pairing of peptides that share attributes supporting weight reduction that include slowed gastric emptying, reduced secretion of glucagon, and increased satiety.

A unique, flexible protocol in REDEFINE 1 gave the 3417 participants freedom to modify CagriSema dosing throughout the trial, according to the company. At the 68-week mark, slightly more than half (57.3%) of the combination CagriSema-treated participants were receiving the highest dose. Proportions of those receiving the highest doses of the individual components were a good deal higher, with 82.5% and 70.2% taking cagrilintide 2.4 mg and semaglutide 2.4 mg, respectively.1

Safety and tolerability outcomes in the study were favorable for the 3 active drug treatments, according to Novo Nordisk. The most common adverse events were gastrointestinal and consistent with the GLP-1 receptor agonist class. They were judged mild to moderate and diminished over time.1

Shortfall

The REDEFINE 1 weight loss outcome was critically compared with results for Lilly's tirzepatide (Zepbound), the original expectation being that CagriSema would deliver superior, not equal, reduction.2 When evaluated against placebo in the pivotal phase 3 SURMOUNT-1 trial, tirzepatide led to mean weight loss of approximately 23%.3 Most recently, the head-to-head SURMOUNT-5 trial compared tirzepatide against semaglutide 2.4 mg, with the former delivering mean weight reduction of 20.2% vs 13.7% reached with the latter.4

Novo Nordisk is also internally questioning why just half the study participants were taking the highest dose of CagriSema, according to the Financial Times. It could potentially have been related to side effects or simply because individuals were content with the progress they were making on the lower doses, the FT speculated.2

Novo expects to report the results of REDEFINE 2, the second pivotal phase 3 trial in the company’s REDEFINE clinical development program, during the first half of 2025. The 1200 participants enrolled in the 68-week trial have type 2 diabetes and either obesity or overweight.1

The global clinical trial development program includes 2 additional phase 3 studies:

• REDEFINE 3 – an event-driven cardiovascular outcomes trial of once-weekly CagriSema vs placebo in 7000 adults with established cardiovascular disease with or without type 2 diabetes.
• REDEFINE 4 – a 72-week efficacy and safety trial of once-weekly CagriSema vs once-weekly tirzepatide 15 mg in 800 adults with obesity.

“With the insights obtained from the REDEFINE 1 trial, we plan to further explore the additional weight loss potential of CagriSema,” EVP Lange said.1

References
1. CagriSema demonstrates superior weight loss in adults with obesity or overweight in the REDEFINE 1 trial. News release. Novo Nordisk. December 20, 2024. Accessed December 20, 2024. tps://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html
2. Kuchler H. Novo Nordisk shares tumble as weight-loss drug trial data disappoints. Financial Times. December 20, 2024. https://www.ft.com/content/a91c249f-61f4-4613-96aa-ca8e67b9d21e
3. Halsey G. Tirzepatide treatment leads to weight loss of up to 22.5% in SURMOUNT-1 clinical trial. Patient Care Online. June 4, 2022. https://www.patientcareonline.com/view/tirzepatide-treatment-leads-to-weight-loss-of-up-to-22-5-in-surmount-1-clinical-trial
4. Halsey G. Tirzepatide bests semaglutide for weight loss by 47% in head-to-head trial. Patient Care Online. December 4, 2024. https://www.patientcareonline.com/view/tirzepatide-bests-semaglutide-for-weight-loss-by-47-in-first-head-to-head-trial