maridebart cafraglutide (AMG 133) / Amgen - LARVOL DELTA

Future GLP-1 receptor co-agonists and their cardiac effects. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Agonists at glucagon-like-peptide-1 receptors (GLP-1R) are becoming approved drugs to treat not only type 2 diabetes and obesity but also cardiac diseases such as coronary heart disease, myocardial infarction and heart failure...We discuss here the known (for tirzepatide and retatrutide) or predicted contractile effects of such co-agonists on isolated cardiac preparations of experimental animals, mainly in mice and compare these results with data in isolated human cardiac preparations...We will discuss not only receptor agonists but also a receptor antagonist (AMG133). We identify research needs and controversies in the literature. We make suggestions for further preclinical research and what improvements in drug design for treatment may lie ahead."

Journal • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Myocardial Infarction • Obesity • Type 2 Diabetes Mellitus

Effect of Maridebart Cafraglutide on the Heart's Electrical Activity (clinicaltrials.gov) - P1 | N=81 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

Comparing the Extent to Which Two Maridebart Cafraglutide Drug Products Are Made Available in the Body After a Single Subcutaneous Dose (clinicaltrials.gov) - P1 | N=340 | Not yet recruiting | Sponsor: Amgen

New P1 trial • Genetic Disorders • Obesity

MARITIME-OSA-1: Maridebart Cafraglutide Versus Placebo in Adult Participants With Obstructive Sleep Apnea on Positive Airway Pressure Therapy (clinicaltrials.gov) - P3 | N=250 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Opposing effects of GIPR antagonism vs agonism on GLP-1R—GIPR heteromerisation reveal distinct incretin receptor crosstalk by maridebart cafraglutide and tirzepatide (EASD 2026) - "GIPR antagonism combined with GLP-1R agonism by MariTide and dual GIPR/GLP-1R agonism by tirzepatide result in distinct receptor-level effects involving GLP-1R-GIPR crosstalk. MariTide enhances receptor heteromerization and biases signaling toward GLP-1R, whereas tirzepatide reduces heteromerization and, despite dual agonism, behaves similarly to GIP by promoting GIPR desensitization with sustained exposure. Despite these mechanistic differences, both strategies ultimately attenuate GIPR signaling while maintaining robust GLP-1R pathway activation."

Metabolic Disorders

Extension Trial to Evaluate the Long-term Efficacy, Safety, and Tolerability of Maridebart Cafraglutide (MARITIME-2-EXTENSION) (clinicaltrials.gov) - P3 | N=950 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

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

Small molecule GIPR antagonist clinical candidate PF-07976016 as a treatment for obesity (ACS-Fall 2026) - "This is supported by human genetics along with clinical data with MariTide, a GIPR antagonist antibody conjugated to a GLP-1R agonist peptide. This molecule demonstrated excellent potency in human-derived cells and showed glucose- and weight-related efficacy in mouse models. PF-07976016 is the first known selective small molecule GIPR antagonist that has proceeded into clinical studies and is being studied as a treatment for obesity."

Clinical • Genetic Disorders • Obesity

Design and therapeutic rationale of antibody-peptide conjugates: insights from maridebart cafraglutide (AMG133) and emerging applications. (PubMed, Antib Ther) - "Collectively, antibody-peptide conjugates represent a biology-driven and strategically important therapeutic modality that bridges antibody engineering and peptide medicinal chemistry. When guided by strong mechanistic rationale, antibody-peptide conjugates offer a powerful solution for therapeutic challenges that cannot be adequately addressed by peptides or antibodies alone."

Journal • Review • Infectious Disease • Metabolic Disorders • Oncology • Pain

Incretin analogues as cardiovascular agents: a state-of-the-art review. (PubMed, Front Endocrinol (Lausanne)) - "We summarize the evidence in five clinical scenarios: type 2 diabetes with established atherosclerotic cardiovascular disease or high cardiovascular risk; overweight or obesity with established cardiovascular disease but without diabetes; obesity-related heart failure with preserved ejection fraction; chronic kidney disease; and symptomatic peripheral artery disease. Pipeline agents (retatrutide, CagriSema, survodutide, orforglipron, zenagamtide, and MariTide) are reviewed alongside their ongoing cardiovascular outcome trials. A dedicated section examines the global access perspective, including the disproportionately high burden of cardiometabolic disease in LMICs, the limited representation of regional populations in pivotal trials, and the structural barriers of cost and reimbursement that constrain access. We close with a practical algorithm for the clinician, an honest assessment of evidence gaps, and a calibrated outlook on the next generation of incretin-based..."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Inflammation • Metabolic Disorders • Nephrology • Obesity • Peripheral Arterial Disease • Renal Disease • Type 2 Diabetes Mellitus

Extension Trial to Evaluate the Long-term Efficacy, Safety, and Tolerability of Maridebart Cafraglutide (MARITIME-1-EXTENSION) (clinicaltrials.gov) - P3 | N=3200 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

One receptor, two opposite approaches: efficacy and tolerability of GIPR agonism and antagonism in obesity pharmacotherapy. (PubMed, Appetite) - "In this review, we examine the mechanistic basis underlying the GIPR agonism-antagonism paradox and discuss how GIPR signaling may regulate the balance between metabolic efficacy and treatment tolerability. Understanding these mechanisms may guide the rational design of next-generation incretin-based therapies that maximize weight loss while minimizing adverse effects."

Journal • Genetic Disorders • Obesity

A Sequential Dual GLP-1R/GIPR Agonist-To-Antagonist Molecule Achieves Superior Weight Loss in Obese Mice. (PubMed, Diabetes Obes Metab) - "Together, these findings validate a peptide-based inhibitory strategy for synergistic weight loss and provide insights into the differential metabolic roles of GIPR activation versus inhibition, guiding the development of novel anti-obesity therapeutics."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity

A Trial to Assess Bioavailability of AMG 133 in Participants With Overweight or Obesity (clinicaltrials.gov) - P1 | N=154 | Completed | Sponsor: Amgen

New P1 trial • Genetic Disorders • Obesity

Effect of Maridebart Cafraglutide on How Oral Contraceptives Are Absorbed and Processed in the Body in Postmenopausal Female Participants Living With Overweight or Obesity (clinicaltrials.gov) - P1 | N=49 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

A Trial to Compare the Extent to Which Maridebart Cafraglutide (AMG 133) is Made Available in the Body When Administered Using Two Subcutaneous Presentations (clinicaltrials.gov) - P1 | N=349 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

MARITIME-CV: Evaluating the Impact of Maridebart Cafraglutide on Cardiovascular Outcomes in Participants With Atherosclerotic Cardiovascular Disease and Overweight or Obesity (clinicaltrials.gov) - P3 | N=12800 | Not yet recruiting | Sponsor: Amgen

New P3 trial • Atherosclerosis • Cardiovascular • Genetic Disorders • Obesity

MARITIME-CV: Evaluating the Impact of Maridebart Cafraglutide on Cardiovascular Outcomes in Participants With Atherosclerotic Cardiovascular Disease and Overweight or Obesity (clinicaltrials.gov) - P3 | N=12800 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • Atherosclerosis • Cardiovascular • Genetic Disorders • Obesity

Extension Trial to Evaluate the Long-term Efficacy, Safety, and Tolerability of Maridebart Cafraglutide (MARITIME-1-EXTENSION) (clinicaltrials.gov) - P3 | N=3200 | Not yet recruiting | Sponsor: Amgen

New P3 trial • Genetic Disorders • Obesity

Extension Trial to Evaluate the Long-term Efficacy, Safety, and Tolerability of Maridebart Cafraglutide (MARITIME-2-EXTENSION) (clinicaltrials.gov) - P3 | N=950 | Not yet recruiting | Sponsor: Amgen

New P3 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Comparing the Extent to Which Maridebart Cafraglutide (AMG 133) is Made Available in the Body When Administered Using Two Subcutaneous (SC) Presentations (clinicaltrials.gov) - P1 | N=348 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

A Study to Evaluate the Effect of Maridebart Cafraglutide on Insulin Sensitivity and β-cell Function in Participants With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P1 | N=56 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Efficacy, Safety and Tolerability of Switching From Glucagon-like Peptide-1 Receptor Agonists (GLP-1RA) to Maridebart Cafraglutide in Adults With Obesity or Overweight (MARITIME-SWITCH) (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

ABK-GIPR-1, an Oral Small-Molecule GIPR Antagonist, Enhanced GLP-1RA's Efficacy in Reducing Body Weight and Improving Metabolic Profile in Preclinical Obesity Models (ADA 2026) - "While small‑molecule glucagon-like peptide-1 receptor agonists (GLP‑1RAs), such as Orforglipron, demonstrate meaningful clinical efficacy, evidence from MariTide indicates that simultaneously agonizing GLP‑1R and antagonizing glucose-dependent insulinotropic polypeptide receptor (GIPR) pathways can provide more robust outcomes than targeting GLP‑1R alone. In summary, ABK-GIPR-1 is a promising selective orally bioavailable GIPR antagonist to enhance weight loss and improve metabolic profile when combining with GLP1-RA.Its superior profile supports fast-track preclinical development."

Late-breaking abstract • Preclinical • Metabolic Disorders • Obesity

A β-klotho Antibody Conjugated to GLP-1/GCG/GIP Triple Agonist Demonstrates Robust Body Weight Reduction and Metabolic Improvement in Obese Rodents and Nonhuman Primates (ADA 2026) - "XWDAPC-1 demonstrates strong in vitro potency, robust in vivo metabolic efficacy, and favorable pharmacokinetic properties. These findings support XWDAPC-1 as a promising therapeutic candidate for the treatment of obesity and related metabolic liver diseases, including MASLD and MASH."

Preclinical • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • GCG • KL

Diabetes Mellitus and Stroke: Pathophysiological Connections and Therapeutic Potential of GLP-1 and GLP-1/GIP Receptor Agonists. (PubMed, Pharmaceutics) - "Findings suggest that semaglutide and liraglutide may reduce non-fatal stroke incidence, decrease hospitalizations, and improve neurological outcomes in patients with prior stroke...Novel therapies, including orforglipron and retatrutide, as well as combinations like Maridebart cafraglutide and CagriSema, may expand future therapeutic options for individuals at high cerebrovascular risk...Future studies should aim to identify the patient subgroups most likely to benefit and to determine whether specific agents confer advantages in acute cerebrovascular contexts. A better understanding of the mechanisms underlying potential neuroprotection will be essential to determine whether these therapies can be effectively integrated into stroke management strategies."

Journal • Review • Cardiovascular • Diabetes • Metabolic Disorders