cotadutide (MEDI0382) / AstraZeneca - LARVOL DELTA

Comparative Effectiveness of Semaglutide, Liraglutide, Orlistat, and Phentermine for Weight Loss in Obese Individuals: A Systematic Review. (PubMed, Cureus) - "This literature review evaluates and compares the effectiveness of four pharmacological agents semaglutide, liraglutide, orlistat, phentermine, and emerging agents like setmelanotide, amycretin, retatrutide, cagrilintide, and cotadutide in managing weight loss among obese. A detailed analysis was conducted on their mechanisms of action, dosing regimens, efficacy in weight loss, safety profiles, and their impact on obesity-related comorbidities. Although all agents presented distinct benefits, side effects such as gastrointestinal discomfort with orlistat and GLP-1 receptor agonists, and potential dependency with phentermine, necessitate tailored treatment approaches. This review highlights the importance of integrating pharmacotherapy with lifestyle interventions to achieve sustainable weight management and identifies areas for future research to optimize therapeutic outcomes for individuals with obesity."

HEOR • Journal • Review • Cardiovascular • Gastrointestinal Disorder • Genetic Disorders • Obesity

Potential New Treatments for Chronic Kidney Diseases: A Concise Review. (PubMed, Curr Pharm Des) - "This concise review will shed light on the clinical trials of runcaciguat, cotadutide, osocimab, and Endothelin Receptor Antagonists (ERAs) in patients with CKD and/or ESKD. These drugs were retrieved following surveying the Clinical Trial database as well as the Pubmed database, both maintained by the US National Library of Medicine."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Transplantation

Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release. (PubMed, J Control Release) - "This extended-release formulation also maintains smaller peak and trough fluctuation within therapeutic window, and PK modelling of repeated dose indicates this formulation could enable a possible dose frequency of 14 days in rat with assumed therapeutic concentration (ratios of the maximum concentration and the trough concentration) Cmax/Ctrough window. This new long-acting injectable (LAI) method could open the door to transforming short-life peptides with sub-optimal half-life into candidates for weekly or even monthly dosing regimens, potentially leading to novel drug products which and increased patient comfort."

Journal • Metabolic Disorders

A Study of Cotadutide in Participants Who Have Chronic Kidney Disease With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=248 | Completed | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2

Phase classification • Chronic Kidney Disease • Diabetes • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Glucagon-like Peptide-1 Receptor Agonists for Adult Obesity: Where Next? (ISPOR-EU 2024) - "The most commonly assessed GLP-1 RAs were liraglutide and semaglutide (48%), followed by exenatide (24%) and dulaglutide (21%). Other less commonly identified agents included danuglipron, cotadutide, taspoglutide and mazdutide (2% each)... This research highlights growing interest and evidence in GLP-1 RAs for obesity management. Further research is needed to continue evaluating the long-term efficacy and safety of these interventions."

Clinical • Cardiovascular • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Polycystic Ovary Syndrome • Type 2 Diabetes Mellitus

Safety and Pharmacokinetics of AZD9550, a GLP-1R/GCGR Dual Agonist, in a First-in-Human Study (OBESITY WEEK 2024) - "Background: Cotadutide was a synthetic once-daily GLP-1R/GCGR dual peptide agonist with a relative potency ratio of approximately 5:1... AZD9550 led to dose-dependent reductions in body weight in obese mice. In healthy participants, there were no safety or tolerability concerns with a pharmacokinetic profile supporting once-weekly dosing. AZD9550 is a novel, investigational drug for obesity with an optimized ratio of glucagon and GLP-1R agonism that is being studied further as a treatment to maximize weight loss and end-organ protection."

Clinical • P1 data • PK/PD data • Genetic Disorders • Obesity • Pain

Glucagon and glucagon-like peptide-1 dual agonist therapy: A possible future towards fatty kidney disease. (PubMed, Eur J Clin Invest) - "Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Vascular Neurology

A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease. (PubMed, Kidney Int) - "Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study."

Journal • P2b data • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Exposure-response modeling for nausea incidence for cotadutide using a Markov modeling approach. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The simulations indicated that the biweekly titration with twofold dose escalation is superior to other titration schemes with a relatively low predicted nausea event rate at 600 μg (25%) and a shorter titration interval (8 weeks) to reach the therapeutic dose. The model can be utilized to optimize starting dose and titration schemes for other therapeutics in clinical trials to achieve an optimal risk-benefit balance and reach the therapeutic dose with minimal titration steps."

Journal • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Obesity

CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. (PubMed, Adv Sci (Weinh)) - "Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis."

Journal • Metabolic Disorders • Targeted Protein Degradation • CD9 • CFD • FLI1

Safety and efficacy of GLP-1 and glucagon receptor dual agonist for the treatment of type 2 diabetes and obesity: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Endocrine) - "These results suggest that mazdutide and cotadutide are effective for glycaemic control and weight reduction in individuals with T2DM, obesity, or both."

Journal • Retrospective data • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

PROXYMO-ADV: A Study to Evaluate the Safety and Efficacy of Cotadutide Given by Subcutaneous Injection in Adult Participants With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis (clinicaltrials.gov) - P2 | N=54 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Non-cirrhotic MASH with Fibrosis. (PubMed, Clin Gastroenterol Hepatol) - "PROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven non-cirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH."

Biopsy • Journal • Diabetes • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • GCG

Advancing Diabetes Care: Novel Drug Interventions in the Management and Control of Type 2 Diabetes Mellitus (ISPOR 2024) - " The study examines ongoing clinical trials evaluating the efficacy and safety of drugs like Cotadutide, Enavogliflozin, Retatrutide, ORMD-0801, and Imeglimin for T2DM, and reported data for at least 1 outcome of interest...Cotadutide, an insulinotropic drug, has shown promising results in improving glycemic control and weight loss in T2DM patients through delayed gastric emptying. Enavogliflozin had a slightly larger reduction in HbA1c levels (-0.99%) than Bexagliflozin...As monotherapy or adjunctive therapy (with metformin), it is found to be effective, has low risk of hypoglycemia, and enhances insulin action and sensitivity. Over the past decade, numerous glucose-lowering medications have been approved, requiring careful consideration of their risks and benefits. It is critical to establish the strongest evidence for improving glycemic control and reducing the risk of complications ."

Diabetes • Gastroenterology • Gastrointestinal Disorder • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity. (PubMed, Diabetes Obes Metab) - "Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

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. (PubMed, Br J Pharmacol) - P1/2 | "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."

Journal • Preclinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Population Pharmacokinetic Modeling of Cotadutide: A Dual Agonist Peptide of Glucagon-Like Peptide and Glucagon Receptors Administered to Participants with Type II Diabetes Mellitus, Chronic Kidney Disease, Obesity and Non-Alcoholic Steatohepatitis. (PubMed, Clin Pharmacokinet) - "A popPK model was developed for cotadutide with cotadutide clinical data, and the impact of the statistically significant covariates identified was not considered clinically meaningful. The popPK model will be used to evaluate exposure-response relationships for cotadutide clinical data."

Journal • PK/PD data • Chronic Kidney Disease • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • GCG

Polyagonists in Type 2 Diabetes Management. (PubMed, Curr Diab Rep) - "Tirzepatide, cotadutide, BI456906, ritatrutide, and CagriSema have entered phase 3 clinical trials...Polyagonism has become a key strategy to address the complex pathogenesis of type 2 diabetes and co-morbidities and increasing number of agents are moving through clinical trials. Heterogeneity in efficacy-safety profiles calls for application of precision medicine and need for judicious personalization of care."

Journal • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice. (PubMed, Peptides) - "The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment."

Journal • Preclinical • Genetic Disorders • Obesity • POMC-null Obesity • CALCR • LEP • LEPR • SOCS3

Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes. (PubMed, Nat Metab) - P2 | "We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 ."

Journal • Chronic Kidney Disease • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Nephrology • Non-alcoholic Steatohepatitis • Obesity • Renal Disease • Type 2 Diabetes Mellitus

OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes. (PubMed, Eur J Pharmacol) - "These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH."

Journal • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

How can we pharmacologically mimic the mechanisms that make gastric bypass so effective? Are we close to a "medical bypass"? (PubMed, Metabolism) - "Apart from weight loss, this approach ought to be put to the test also regarding other clinical outcomes, such as liver steatosis and steatohepatitis, cardiovascular disease, and overall prognosis, on which MS has a robustly demonstrated impact. Besides, a medical bypass as an alternative, salvage, or combination strategy to MS may promote precision medicine in obesity therapeutics."

Bariatric surgery • Journal • Addiction (Opioid and Alcohol) • Cardiovascular • Diabetes • Genetic Disorders • Hepatitis C • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

Cotadutide improves brown adipose tissue thermogenesis in obese mice. (PubMed, Biochem Pharmacol) - "Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I α1, collagen type VI α3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits."

Journal • Preclinical • Genetic Disorders • Obesity • Targeted Protein Degradation • ATF4 • IL6 • NRF1 • PLIN2 • TCF4 • UBR5

Efficacy of cotadutide dual GLP1-glucagon receptor agonist on albuminuria and glycaemic control in patients with diabetic kidney disease (EASD 2023) - P2b | "In patients with DKD, cotadutide promoted clinically important effects on UACR, glycaemic control, and body weight. The results suggest cotadutide has a potential to provide benefit on renal outcomes with holistic benefits on body weight and glycaemic control in patients with DKD, but larger studies are warranted."

Clinical • Hypoglycemia • Metabolic Disorders • Non-alcoholic Steatohepatitis

The role of gastric function in control of food intake (and body weight) in relation to obesity, as well as pharmacological and surgical interventions. (PubMed, Neurogastroenterol Motil) - "The motor functions of the stomach are relevant to postprandial fullness and to interventions aimed at weight loss in people with obesity."

Journal • Review • Gastrointestinal Disorder • Genetic Disorders • Obesity