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CagriSema misses non-inferiority goal against tirzepatide in 84-week head-to-head trial

CagriSema produced 23% weight loss but fell short of tirzepatide and missed its non-inferiority goal, a result that does not change what is available to US patients today.

By the Semaglutides news desk··Zepbound

On Feb. 23, 2026, Novo Nordisk reported that CagriSema, its experimental combination of cagrilintide and semaglutide, produced 23.0% average weight loss after 84 weeks but failed the trial's main goal of showing it was at least as effective as tirzepatide 15 mg, which produced 25.5% [1][5].

The trial, called REDEFINE 4, enrolled 809 adults with obesity and at least one related health condition, with an average starting weight of 114.2 kg, or about 252 pounds [1][3][5]. Participants received either CagriSema 2.4 mg/2.4 mg or tirzepatide 15 mg, both given as once-weekly injections under the skin [1]. It was an open-label study, meaning participants and their doctors knew which drug was being given [1][4]. Tirzepatide is the active ingredient in Eli Lilly's Mounjaro and Zepbound [6].

Novo reported two sets of weight-loss numbers, depending on how it accounted for people who stopped or changed treatment. Assuming everyone stayed on treatment, CagriSema produced 23.0% weight loss versus 25.5% for tirzepatide. Counting the treatment effect regardless of whether people adhered, the figures were 20.2% versus 23.6% [1][4][5]. Novo said the prespecified non-inferiority test was not met [1].

Side effects with CagriSema were mostly gastrointestinal, and the vast majority were mild to moderate and eased over time, the company said, describing the profile as consistent with the GLP-1 receptor agonist class [1][4].

Novo's chief scientific officer, Martin Holst Lange, said in the announcement, "We are pleased with the weight loss of 23% for CagriSema in this open-label trial" [1][5]. He told CNBC that an open-label design can introduce a risk of bias in favor of a well-known product when it is compared with an investigational one [6].

Investors reacted sharply. Novo Nordisk shares listed in Copenhagen closed down 16.5% at 251 Danish kroner, their lowest level since June 2021, while Eli Lilly shares closed 4.9% higher [6]. Lilly also launched a new form of its Zepbound pen that holds a month of doses, and a Lilly spokesperson pointed to Zepbound's efficacy and to the company's pill orforglipron, which the spokesperson said is expected to launch in the second quarter of this year [6].

Jefferies analyst Michael Leuchten said the miss adds uncertainty and leaves CagriSema's commercial positioning unclear. He estimates the drug could account for 15% to 25% of Novo's revenue by 2030 [6].

Why it matters for patients

Nothing changes about which obesity drugs are available in the US today. CagriSema is not approved. Novo submitted it to the FDA for weight management in December 2025 based on two other trials, REDEFINE 1 and REDEFINE 2, and an FDA decision is anticipated by late 2026 [1][4][5].

The result is a missed endpoint, not evidence that CagriSema does not work. People taking it lost an average of 23% of their body weight under one analysis and 20.2% under the other, which is substantial. But the trial was designed to test whether it was at least as good as tirzepatide 15 mg, and it did not clear that bar [1][4].

The two numbers reflect different questions. The efficacy estimand estimates the effect if all people adhered to treatment, according to the protocol, regardless of dose modification. The treatment-regimen estimand estimates the treatment effect regardless of adherence [1][4]. Novo has not disclosed how these results might affect its pending FDA application, whether REDEFINE 4 data would appear on a label, or what CagriSema would cost.

What happens next

  • Novo plans to start a phase 3 trial of a higher-dose CagriSema combination, 2.4 mg/7.2 mg, in adults with obesity in the second half of 2026 [1][4].
  • REDEFINE 11, an 80-week phase 3 trial of CagriSema 2.4/2.4 mg versus placebo in 600 adults with obesity, is expected to report data in the first half of 2027 [1][4].
  • An FDA decision on CagriSema for weight management is anticipated by late 2026 [1][4][5].
  • In the same week, Novo said it cut US list prices for Wegovy by 50% and Ozempic by 35% [2].
  • Lilly's orforglipron is expected to launch in the second quarter of 2026, according to a Lilly spokesperson [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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