CagriSema Phase III Results Review

Friday 20th of December, just before Christmas started, Novo Nordisk published the results of their REDEFINE 1 trial announcing CagriSema achieved a weight reduction of 22.7% during the 68 weeks trial.

The results fell short of investor expectations, as many anticipated CagriSema would achieve weight reductions exceeding 25%. Adding to the disappointment, competitor Eli Lilly’s GLP-1 drug tirzapetide has already reported up to 20.9% weight loss at its highest dose of 15 mg.

As a result, Novo Nordisk’s stock dropped 20.71% during the day, closing at 589.2 DKK per share. While the initial reaction may seem discouraging, I believe the results are actually positive. Let me explain why!

DISCLAIMER: This article is not a recommendation to buy or sell any financial instrument, the content is educational and my personal opinion. Each person has to make his own analysis. Any action or decision you take as a result of viewing this article is your sole responsibility.

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What is Cagrisema?

Cagrisema is combination therapy under investigation by Novo Nordisk comprising cagrilintide and semaglutide, developed to enhance weight loss and glycemic control.

1. Cagrilintide

   A long-acting amylin analog. Amylin is a hormone co-secreted with insulin by pancreatic cells. It plays a role in appetite suppression, slowing gastric emptying, and regulating post-meal glucose levels.

2. Semaglutide

   A GLP-1 receptor agonist that enhances insulin secretion, reduces appetite, and delays gastric emptying. It is the active pharmaceutical ingredient (API) of Ozempic and Wegovy.

The goal of combining both is to exploit the benefits from their synergistic effects: while each hormone targets distinct pathways, they work together to enhance satiety, lower calorie intake, and regulate blood sugar. Semaglutide focuses on insulin-related mechanisms, while cagrilintide complements it by suppressing appetite through amylin receptors.

REDEFINE Program

Let´s start from the beginning, what is Novo Nordisk REDEFINE Program?

The REDEFINE program is a clinical research initiative led by Novo Nordisk, designed to evaluate the safety and efficacy of CagriSema. Its purpose is to evaluate the effect, benefits and safety of a once-weekly administered subcutaneous CagriSema.

It comprises four different clinical trials: REDEFINE 1, REDEFINE 2, REDEFINE 3 and Redefine 4.

REDEFINE 1 is focused in assessing the impact of CagriSema on weight loss and metabolic health in individuals with obesity-related comorbidities.

REDEFINE 2 objective is to study CagriSema effect in improving glycemic control and reducing body weight in a population where diabetes management is a primary concern.

REDEFINE 3 is a phase 3, event-driven cardiovascular outcomes trial comparing once-weekly CagriSema to a placebo in 7,000 adults with established cardiovascular disease, with or without type 2 diabetes.

REDEFINE 4 is a phase 3 clinical trial designed to compare the effects of CagriSema with tirzepatide. The trial will last 72 weeks and evaluate the efficacy and safety of once-weekly CagriSema versus once-weekly tirzepatide 15 mg in 800 adults with obesity.

By targeting multiple metabolic pathways, the REDEFINE program aims to set new benchmarks in obesity and diabetes treatment.

REDEFINE 1 Results

As mentioned before, last 20th of December Novo Nordisk published the results of the REDEFINE 1 clinical trial. To understand the results we first need to introduce and explain the study design.

Study Design

Dose

A fixed dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg compared to the individual components cagrilintide 2.4 mg, semaglutide 2.4 mg and placebo, all administered once-weekly. The REDEFINE 1 trial was based on a flexible protocol, allowing patients to modify their dosing throughout the trial.

To put into context, the highest available Wegovy dose is 2.4mg per injection. Although, patients were able to modify dosing. It is not specify if they were able to modify the frequency, dosing or any other relevant parameter.

Structure

A 68 weeks long randomized, double-blind, placebo-controlled study.

This means that neither the patients nor the researchers know who is receiving the CagriSema treatment or the placebo, and the assignment to either group is done randomly.

Population

3,417 randomized adults with obesity or overweight with one or more comorbidities and a mean baseline body weight of 106.9 kg

Reported Results

Firstly, Novo Nordisk reported the study achieved its objective, “proving statistically significant and superior weight loss at week 68 with CagriSema versus placebo”.

Regarding the specific trial results, Novo Nordisk reported:

From the above fragment two things can be noted:

1. Reported weight loss of CagriSema is remarkably superior of both, cagrilintide and semaglutide, alone.

2. Reported weight loss is under 25%, what Novo Nordisk management have repeatedly commented to be the expected efficacy of CagriSema during 2023 and 2024 investors calls.

Regarding its safety profile, it was reported that CagriSema has a safe and well-tolerated profile. Gastrointestinal side-effects were the most commonly reported ones, and in the vast majority of cases they were mild to moderate and they diminished over time, consistent with the GLP-1 receptor agonist class.

Results Analysis

I think the flexible arrangement of the trial makes it more difficult to assess CagriSema based on Novo Nordisk announcement. 42.7% of patients who participated in the trial reduced the 2.4mg cagrilintide and 2.4mg of semaglutide dose.

Since higher doses are associated with greater results, it is reasonable to expect that the efficacy outcomes of CagriSema would align more closely with the set expectations if the entire cohort of patients adhered to the trial design. This is further supported by the fact that over 40% of patients in the trial experienced a weight loss exceeding 25%.

Moreover, criticism on the announced results was also focused in connection with the poor comparative with competitor Eli Lilly´s Zepbound (tirzapetide) efficacy for weight loss. In clinical studies, particularly the SURMOUNT trials, tirzepatide has shown significant weight loss results:

• 5 mg dose: ~15% average body weight reduction.

• 10 mg dose: ~19.5% average body weight reduction.

• 15 mg dose: ~20.9% average body weight reduction.

REDEFINE 1 has shown a scarce 1.8% higher weight loss efficacy than Zepbound highest dose. However, as above mentioned, it will be REDEFINE 4 the trial in which Zepbound vs CagriSema efficacy will be compared.

Conclusion

In my view, the announced results should be interpreted with caution: in a dynamic trial where 57.3% of patients did not maintain the highest dose throughout the entire trial period and, over 40% of participants still achieved a weight loss exceeding 25%.

I understand that the results do not call for an overly enthusiastic reaction, but I don't believe they are negative - especially since the primary objective was achieved, and four additional Phase 3 trials are planned.

Finally, even if CagriSema proves to be less effective than anticipated, the demand for GLP-1 drugs for treating type 2 diabetes and obesity remains so high that supply situation and shortages are frequent topics of discussion. Therefore, in my view, Novo Nordisk's long-term thesis remains unchanged: focusing on expanding manufacturing capacity for its current portfolio, prioritizing oral medications, and extending semaglutide applications to address other unmet health needs, while continuing to develop its Rare Diseases segment.

None of the expansion projects announced during the last two years will fallout due to the REDEFINE 1 trials results not inviting for optimism. The demand will continue outpacing the supply for years. In the meantime, Novo Nordisk will remain focused on scaling up GLP-1 production volumes. Everything else - ziltivekimab, CagriSema, monlunabant, and similar developments - represents additional positive optionality.

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