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CagriSema misses its head-to-head goal against Zepbound

Novo Nordisk's CagriSema produced 23.0% weight loss over 84 weeks versus 25.5% for tirzepatide 15 mg and missed its non-inferiority goal, but it is still under FDA review with a decision expected by late 2026.

By the Semaglutides news desk··Zepbound

Novo Nordisk said on February 23, 2026 that CagriSema, its experimental combination of cagrilintide and semaglutide, failed to meet the main goal of REDEFINE 4, a head-to-head trial against tirzepatide, the molecule in Eli Lilly's Mounjaro and Zepbound [1]. The drug still produced substantial weight loss — about 23% — but not enough to prove it was no worse than its competitor [1].

REDEFINE 4 was an open-label phase 3 trial that ran 84 weeks and randomized 809 adults with obesity and at least one other health condition [1]. Average starting body weight was 114.2 kg, or roughly 252 pounds [3]. Participants received either CagriSema (a fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg) or tirzepatide 15 mg, both as a weekly injection under the skin [1]. Open-label means everyone — patients and investigators — knew which drug was being given [1].

The numbers

The results depend on how you count. Under the efficacy estimand, which estimates what would happen if everyone stayed on treatment as written in the protocol, CagriSema produced 23.0% weight loss versus 25.5% with tirzepatide [1][5]. Under the treatment-regimen estimand, which measures the effect regardless of whether people kept taking the drug, the figures were 20.2% for CagriSema and 23.6% for tirzepatide [1][5]. Either way, the prespecified primary endpoint of non-inferiority on percent weight loss at 84 weeks was not achieved [1][4].

On safety, Novo said CagriSema "appeared to have a safe and well-tolerated profile," with the most common side effects being gastrointestinal, mostly mild to moderate, diminishing over time and consistent with the GLP-1 class [1]. The company did not release discontinuation rates or side-by-side tolerability numbers in the headline announcement, so those comparisons are not yet known.

Novo's chief scientific officer, Martin Holst Lange, said the company was "pleased with the weight loss of 23% for CagriSema in this open-label trial" and argued the combination shows cagrilintide adds to semaglutide's effect [1]. He told CNBC that an open-label design "can introduce a risk of bias in favor of a well-known product" and called tirzepatide's performance "slightly surprising" [6]. For context, Lilly's own trial of tirzepatide against Wegovy showed 20.2% weight loss over 72 weeks, and a separate 2023 study reported an average 26% over 88 weeks [6].

Investors reacted sharply. Novo's Copenhagen-listed shares closed down 16.5% at 251 Danish kroner, the lowest since June 2021, while Lilly closed 4.9% higher [6]. Jefferies analyst Michael Leuchten said CagriSema's "commercial positioning is increasingly unclear" [6].

Why it matters for patients

Nothing about this result changes what is on pharmacy shelves today. CagriSema is not approved anywhere; it was submitted to the FDA for weight management in December 2025 based on the placebo-controlled REDEFINE 1 and REDEFINE 2 trials, not on REDEFINE 4 [1][5]. A missed non-inferiority test against a competitor does not automatically block approval, but it does shape how the drug would be positioned if cleared.

The practical read for people weighing options: a next-generation injection that many expected to leapfrog tirzepatide instead landed behind it in the only direct comparison run so far, by about 2.5 to 3.4 percentage points depending on the analysis [1]. Both drugs delivered weight loss in the 20% range over 84 weeks in this trial [1]. Individual results vary, and the trial did not report results by subgroup in the headline release.

Separately, in the same week Novo cut US list prices for Wegovy by 50% and Ozempic by 35%, which the company said is aimed at people whose out-of-pocket costs are tied to list price, such as those with high-deductible plans or coinsurance [2]. Lilly also launched a Zepbound pen holding a month's worth of doses on February 23 [6].

What happens next

  • Second half of 2026: Novo plans to start a phase 3 trial of higher-dose CagriSema 2.4 mg/7.2 mg in adults with obesity [1].
  • Late 2026: an FDA decision on CagriSema for weight management is anticipated [1][5].
  • First half of 2027: REDEFINE 11, an 80-week trial in 600 adults with obesity, is expected to report [1].

Lilly's oral orforglipron is expected to launch in the second quarter of 2026 [6].

Sources

  1. https://www.sec.gov/Archives/edgar/data/353278/000117184326000996/f6k_022326.htm
  2. https://www.ddw-online.com/head-to-head-obesity-trial-disappointment-for-novo-nordisk-40644-202602
  3. https://www.hcplive.com/view/cagrisema-demonstrates-weight-loss-fails-to-achieve-primary-endpoint-compared-to-tirzepatide
  4. https://reachmd.com/news/redefine-4-cagrisema-23-vs-tirzepatide-255-primary-noninferiority-not-met/2485794
  5. https://www.empr.com/news/redefine-4-cagrisema-weight-loss-results-compared-with-tirzepatide/
  6. https://www.cnbc.com/2026/02/23/novo-nordisk-stock-cagrisema-trial-fails-weight-loss.html
  7. https://www.biospace.com/drug-development/novos-cagrisema-falls-to-lillys-zepbound-in-daring-head-to-head-test
  8. https://www.biopharmadive.com/news/novo-nordisk-cagrisema-zepbound-head-to-head-results/812810
  9. https://www.drugs.com/history/cagrisema.html
  10. https://www.globenewswire.com/de/news-release/2026/02/23/3242381/0/en/Novo-Nordisk-A-S-CagriSema-demonstrated-23-weight-loss-in-an-open-label-head-to-head-REDEFINE-4-trial-in-people-with-obesity-the-primary-endpoint-was-not-achieved.html

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