maridebart cafraglutide (AMG 133) / Amgen - LARVOL DELTA

A Study of Maridebart Cafraglutide in Adult Participants With Type 2 Diabetes Mellitus (T2DM) (clinicaltrials.gov) - P2 | N=350 | Not yet recruiting | Sponsor: Amgen

New P2 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Study to Evaluate AMG 133 in Chinese Participants With Obesity or Overweight (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. (PubMed, Nat Metab) - "Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • ARRB1

Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity. (PubMed, Diabetes Care) - "The success of GLP-1-based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1-based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine..."

Journal • Review • Alzheimer's Disease • Anesthesia • Cardiovascular • CNS Disorders • Diabetes • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Metabolic Disorders • Movement Disorders • Musculoskeletal Diseases • Obesity • Oncology • Parkinson's Disease • Peripheral Arterial Disease • Type 2 Diabetes Mellitus

A Study to Evaluate AMG 133 in Chinese Participants With Obesity or Overweight (clinicaltrials.gov) - P1 | N=20 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

A Study to Evaluate AMG 133 in Chinese Participants With Obesity or Overweight (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

Antagonizing GIPR adds fire to the GLP-1R flame. (PubMed, Trends Endocrinol Metab) - "Unimolecular co-agonists at the GLP-1/GIP receptors have recently achieved remarkable anti-obesogenic feats; yet, in a recent Phase 1 clinical trial, Véniant and colleagues report astounding body-weight loss, and an appreciable safety profile, in participants with obesity using the GLP-1R agonist/GIPR antagonist AMG 133."

Journal • Genetic Disorders • Obesity

A Study to Evaluate AMG 133 in Chinese Participants With Obesity or Overweight (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Amgen

New P1 trial • Genetic Disorders • Obesity

Phase I results for AMG 133. (PubMed, Nat Rev Endocrinol) - No abstract available

Journal • P1 data

A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. (PubMed, Nat Metab) - P1 | "In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133."

Clinical • Journal • P1 data • Preclinical • Genetic Disorders • Obesity

Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of AMG 133 in Adult Participants With Overweight or Obesity, With or Without Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=592 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CRP

Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of AMG 133 in Adult Participants With Overweight or Obesity, With or Without Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=570 | Recruiting | Sponsor: Amgen | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CRP

AMGEN REPORTS SECOND QUARTER FINANCIAL RESULTS (PRNewswire) - "A Phase 2 study of maridebart cafraglutide, a multispecific molecule that inhibits the gastric inhibitory polypeptide receptor (GIPR) and activates the glucagon like peptide 1 (GLP-1) receptor, in overweight or obese adults with or without type 2 diabetes mellitus continues to enroll patients."

Enrollment status • Metabolic Disorders • Obesity

A Novel GIPR Antagonist Antibody and GLP-1 Peptide Conjugate (AMG 133) for Treatment of Obesity (PEGS 2023) - "In human Phase 1 trial AMG 133 demonstrated weight loss and tolerability. The design, conjugation process, and preclinical activity will be discussed."

Genetic Disorders • Obesity

Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of AMG 133 in Adult Participants With Overweight or Obesity, With or Without Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=570 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CRP

An update on peptide-based therapies for type 2 diabetes and obesity. (PubMed, Peptides) - "Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide...Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized."

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

Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of AMG 133 in Adult Participants With Overweight or Obesity, With or Without Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=570 | Not yet recruiting | Sponsor: Amgen

New P2 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CRP

Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. (PubMed, Nat Rev Endocrinol) - "We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation."

Journal • Review • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Single and Multiple Ascending Dose Study of AMG 133 in Participants With Obesity (clinicaltrials.gov) - P1 | N=110 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

"Still difficult to understand how GIPR agonism (tirzepatide) and antagonism (AMG-133) can both bring additional benefits to GLP-1R agonism…" (@bernardkhoo)

"$AMGN great stuff. AMG133, Olpasarin, Evolocumab. #AHA22." (@princetongb)

Single and Multiple Ascending Dose Study of AMG 133 in Participants With Obesity (clinicaltrials.gov) - P1 | N=110 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

Single and Multiple Ascending Dose Study of AMG 133 in Participants With Obesity (clinicaltrials.gov) - P1 | N=112 | Recruiting | Sponsor: Amgen | Active, not recruiting ➔ Recruiting | Trial completion date: May 2022 ➔ Nov 2022 | Trial primary completion date: May 2022 ➔ Nov 2022

Enrollment open • Trial completion date • Trial primary completion date • Genetic Disorders • Obesity

Study of AMG 133 Administered Subcutaneously in Healthy Japanese and Caucasian Participants (clinicaltrials.gov) - P1 | N=34 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion

Study of AMG 133 Administered Subcutaneously in Healthy Japanese and Caucasian Participants (clinicaltrials.gov) - P1; N=34; Active, not recruiting; Sponsor: Amgen; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed