AstraZeneca Halts Mid-to-Late-Stage GLP-1R/GCGR Agonist Cotadutide Amid Fierce Competition from Novo Nordisk and Eli Lilly

On April 12, according to the foreign media Endpointsnews, AstraZeneca decided to terminate the development of the GLP-1R/GCGR agonist cotadutide (once daily) and will focus resources on developing another GLP-1R/GCGR agonist, AZD9550 (once weekly).

AstraZeneca stated that it is currently concluding patient recruitment for the cotadutide clinical trial, while patients already enrolled have the option to continue treatment. According to the registration information on clinicaltrials.gov, cotadutide is undergoing a Phase II/III clinical trial (PROXYMO-ADV) for non-alcoholic steatohepatitis (NASH) patients with liver fibrosis but without cirrhosis.

Cotadutide (MEDI0382) is an oxyntomodulin (OXM) analog developed by MedImmune (acquired by AstraZeneca) that simultaneously activates glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). Preclinical studies have shown that the plasma half-life of cotadutide in mice is approximately 5 hours, similar to liraglutide (about 7 hours).

The Structure of Cotadutide

(Source: Diabetes Obesity & Metabolism)

To date, cotadutide has completed four Phase II studies. In a Phase IIa study (N=113) involving overweight or obese patients with type 2 diabetes, the cotadutide group showed significant weight loss (-3.84kg vs -1.70kg; P=0.0008) and a significant reduction in HbA1c levels (-0.9% vs -0.6%; P=0.0004).

Source: The Lancet

In a head-to-head Phase IIb study with liraglutide (N=834), cotadutide also demonstrated promising efficacy, with all dose groups showing no less weight loss and glucose-lowering effects compared to the liraglutide group.

Source: Diabetes Care

Although cotadutide has shown fairly good efficacy, it does not possess a competitive edge in the overall GLP-1 market. Currently, there is no shortage of GLP-1 products in the fields of diabetes and obesity/overweight; what’s lacking are products with a sufficiently long half-life and excellent efficacy. This is precisely why semaglutide and tirzepatide, which allow for once-weekly injections, became blockbuster successes upon their market launch. In such a market environment, cotadutide, which requires once-daily injections, appears to be an underperformer with little room to stand out.

AstraZeneca may have also realized this, later shifting the indication development of cotadutide to NASH and diabetic nephropathy. In April 2022, AstraZeneca announced that cotadutide effectively reduced postprandial blood glucose levels in patients with chronic kidney disease and type 2 diabetes, but failed to significantly decrease the urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Based on these results, cotadutide remains a GLP-1R/GCGR product lacking standout features.

Rather than developing a product with limited market potential, it’s better to cut losses early and focus energy on products with brighter prospects. The logic is clear, but making the decision can still be challenging. However, for a big pharma like AstraZeneca, making decisive moves is undoubtedly the best choice. Aside from cotadutide and AZD9550, AstraZeneca's pipeline also includes an oral GLP-1R agonist, AZD0186, currently in development. In the GLP-1 space, although there are powerful diabetes giants like Novo Nordisk and Eli Lilly leading the way, as well as formidable newcomers like Amgen, Pfizer, and Innovent hot on their heels, with AZD9550 and AZD0186, AstraZeneca might still carve out a share of the market.

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