Characterisation of cotadutide's dual GLP‐1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model

Feb 25, 2024British journal of pharmacology

Cotadutide's combined effects on blood sugar control through two hormone receptors studied with a human glucose regulation model

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Abstract

The 4GI model predicted clinical endpoints of cotadutide in overweight and obese individuals with Type 2 diabetes.

Cotadutide demonstrated a positive effect on insulin sensitivity associated with weight loss.
The model indicated that glucagon's effect on glucose production may counteract the decrease in glucose mediated by GLP-1.
A plateau in glucose reduction was observed around a 200-μg dose of cotadutide.
The system effectively captured the dynamics of glucose, insulin, GLP-1, glucagon, and GIP over time.

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BACKGROUND AND PURPOSE: Cotadutide is a dual GLP-1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP-1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585).

EXPERIMENTAL APPROACH: The cotadutide PK-4GI systems model was calibrated to clinical data by re-estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP-1 and glucagon receptor agonistic effects on glucose.

KEY RESULTS: Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP-1 receptor-mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200-μg cotadutide dose.

CONCLUSION AND IMPLICATIONS: The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP-1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds.

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Characterisation of cotadutide's dual GLP‐1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model

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