monlunabant (NN9440) / Novo Nordisk - LARVOL DELTA

Peripheral cannabinoid-1 receptor antagonists in clinical development: therapeutic potential for the management of obesity and related metabolic disorders for the management of obesity and related metabolic disorders. (PubMed, Expert Opin Investig Drugs) - "Peripherally restricted CB1R antagonists aim to deliver the metabolic benefits of CB1R blockade while avoiding the toxicity that ended development of centrally acting agents such as rimonabant. Recent phase 2 data with monlunabant demonstrated dose-dependent psychiatric adverse events and high discontinuation rates. Nimacimab, an antibody-based approach, has shown only marginal efficacy. The future of this drug class will therefore likely depend on rigorous long-term safety evaluation, biased CB1R pharmacology, and multitarget strategies including combinations with incretin-based therapies."

Journal • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry

Baseline lung function in adults with obesity and metabolic syndrome: Exploratory analysis of oscillometry data from a phase 2 trial (ECO 2026) - P2 | " In this phase 2a weight loss trial (NCT05891834)³, adults in Canada with BMI ≥30 kg/m² and metabolic syndrome were randomised to receive monlunabant (10, 20, or 50 mg) or placebo once-daily oral tablets for 16 weeks... This study is, to our knowledge, the largest clinical trial to date that incorporates oscillometry measurements in a population of adults with obesity and metabolic syndrome. In this trial population, almost two-thirds had IAF at baseline. IAF was linked to higher weight, BMI, waist circumference, HbA1c, and leptin levels, and lower ghrelin levels."

Clinical • P2 data • Asthma • CNS Disorders • Diabetes • Genetic Disorders • Immunology • Inflammation • Mental Retardation • Metabolic Disorders • Obesity • Respiratory Diseases • LEP

Establishment of the International Genetic Obesity (iGO) Registry: Background and Structure (ECO 2026) - P, P2 | "The International Genetic Obesity (iGO) Registry provides a robust platform for improved cross-sectional and longitudinal research in genetic obesity. Physicians and clinical centers caring for individuals with genetic obesity are invited to participate in the iGO Registry. 16 weeks in people with obesity and metabolic syndrome demonstrated statistically and clinically significant weight loss²."

CNS Disorders • Diabetes • Genetic Disorders • Mental Retardation • Obesity • Rare Diseases • LEP

Lung function after 16 weeks of monlunabant in adults with obesity and metabolic syndrome: Exploratory analysis of oscillometry data from a phase 2 trial (ECO 2026) - "This is the first randomised trial to use oscillometry to assess lung function during medical weight loss therapy in people with obesity and metabolic syndrome. Sixteen weeks of monlunabant led to improvements in lung function, especially in AX which reflects lung stiffness and has been associated with dyspnoea³–⁴. Effects on AX and R5-R20 in the 20 and 50 mg groups may be clinically meaningful, suggesting that airway dysfunction in this population may be treatable with medical weight loss therapy."

Clinical • P2 data • Asthma • Genetic Disorders • Immunology • Metabolic Disorders • Obesity • Respiratory Diseases

Monlunabant in adults with obesity and metabolic syndrome: Open-label extension of a phase 2a trial. (PubMed, Diabetes Obes Metab) - No abstract available

Journal • P2a data • Genetic Disorders • Metabolic Disorders • Obesity

A double-blind, randomized, placebo-controlled, phase 2 trial examined the efficacy and safety of monlunabant in adults with diabetic kidney disease. (PubMed, Kidney Int) - "Our study failed to establish proof of concept of monlunabant in DKD, as the effect on UACR at week 16 was not significantly different from placebo. However, greater than anticipated variability and a large placebo response affect interpretation."

Clinical • Journal • P2 data • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Gastroenterology • Gastrointestinal Disorder • Glomerulonephritis • Metabolic Disorders • Nephrology • Renal Disease

Efficacy and safety of monlunabant in adults with obesity and metabolic syndrome: a double-blind, randomised, placebo-controlled, phase 2a trial. (PubMed, Lancet Diabetes Endocrinol) - P2 | "Participants receiving monlunabant showed statistically significant and clinically meaningful weight loss compared with those receiving placebo for all tested doses. Only slightly greater weight loss was observed at higher doses, whereas adverse events appeared dose dependent. Further investigation is needed to assess the safety and efficacy of lower doses of monlunabant, to evaluate its potential as a medication for obesity."

Journal • P2a data • CNS Disorders • Genetic Disorders • Mental Retardation • Metabolic Disorders • Mood Disorders • Obesity • Psychiatry • Sleep Disorder

Blockade of cannabinoid CB1 receptors potentiates the anti-fibrotic effects mediated by SGLT2 inhibition in a mouse model of diabetic nephropathy. (PubMed, Br J Pharmacol) - "Taken together, these data strongly suggest that a poly-pharmacological approach combining both SGLT2 inhibitors and CB1 receptor inverse agonism represents a promising therapeutic strategy for managing DN, with better reno-protection than mono-therapies."

Journal • Preclinical • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • ANGPT1

A cannabinoid receptor 1 inverse agonist induces weight loss and reduces airway hyperresponsiveness in a mouse model of obese asthma. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Phosphatidylglycerol in BALF increased with INV-202, which significantly correlated with compliance in LFD mice. This study supports a significant contribution of metabolic factors related to the endocannabinoid system in lung compliance and airway reactivity, in part through effects on surfactant lipid composition, and demonstrates the potential of CB1R inverse agonists to treat obese asthma."

Journal • Preclinical • Asthma • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Obesity • Pulmonary Disease • Respiratory Diseases • CCL20

Demonstrating the sufficiency of peripheral CB1 inhibition to promote weight loss using clinical pharmacokinetic (PK) and pharmacodynamic (PD) models (ECO 2025) - " We compared clinical PK profiles of rimonabant, monlunabant, and nimacimab using PK/PD modeling to analyze their target engagement and distribution in the brain and periphery. Our findings suggest that peripheral CB1 inhibition, rather than central CB1 inhibition, is sufficient to drive weight loss, minimizing the potential for neuropsychiatric AEs associated with central CB1 inhibition. This work supports further development of novel mAb-based CB1 inhibitors with superior peripheral restriction to promote weight loss with reduced centrally mediated neuropsychiatric effects which continues to be a hurdle for the less restricted small molecule inhibitors. Conflict of Interest: The author is a consultant for Skye Bioscience, a biopharmaceutical company developing therapies for obesity and metabolic diseases."

Clinical • PK/PD data • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry

Skye Bioscience Clinical Model Demonstrating Necessity of Peripheral CB1 Inhibition for Weight Loss Presented at European Congress on Obesity (Skye Bioscience Press Release) - "Skye Bioscience, Inc...presented a clinical pharmacokinetic ('PK') and pharmacodynamic ('PD') model that underscores the fundamental relationship between biodistribution and efficacy of CB1 inhibitors...Published clinical PK and potency data coupled with Phase 2 ('P2') and Phase 3 efficacy data from Novo Nordisk’s monlunabant and Sanofi’s rimonabant, respectively, as well as Phase 1 data from nimacimab were used to develop a model to determine whether peripheral CB1 inhibition alone is sufficient for weight loss, or if central inhibition is also required for optimal efficacy. The results showed that central inhibition of CB1 alone was not sufficient for weight loss with P2 data for monlunabant, and demonstrated that increasing drug levels in the brain did not improve efficacy."

Clinical data • PK/PD data • Obesity

A Study to Explore the PK and PD of INV-202 in Metabolic Syndrome (clinicaltrials.gov) - P1 | N=37 | Completed | Sponsor: Inversago Pharma Inc. | Phase classification: P1b ➔ P1

Phase classification • Dyslipidemia • Genetic Disorders • Hypertriglyceridemia • Metabolic Disorders • Obesity

Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability. (PubMed, eGastroenterology) - "Additionally, a peripheral CB1R antagonist, (S)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates...Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease. Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability."

Journal • Gastroenterology • Gastrointestinal Disorder • Hepatology

Study of INV-202 in Patients With Obesity and Metabolic Syndrome (clinicaltrials.gov) - P2 | N=243 | Completed | Sponsor: Inversago Pharma Inc. | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Metabolic Disorders • Obesity

Monlunabant suppresses appetite through a central mechanism. (PubMed, Behav Pharmacol) - "These findings suggest that monlunabant suppresses appetite mainly through antagonism of central CB1 receptors. Consequently, monlunabant and other second-generation CB1 antagonists being developed for obesity may carry a similar risk of adverse psychiatric effects, as previously observed with rimonabant."

Journal • Genetic Disorders • Obesity • Psychiatry

A Research Study Investigating Safety and Concentration in the Blood After One Dose Tablet of the New Medicine Monlunabant in Healthy Weight Japanese and Caucasian Men (clinicaltrials.gov) - P1 | N=73 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

Phase 2 Study of INV-202 in Patients With Diabetic Kidney Disease (clinicaltrials.gov) - P2 | N=265 | Completed | Sponsor: Inversago Pharma Inc. | Active, not recruiting ➔ Completed

Trial completion • Diabetic Nephropathy • Nephrology • Renal Disease

A Research Study Investigating Safety and Concentration in the Blood After One Dose Tablet of the New Medicine Monlunabant in Healthy Weight Japanese and Caucasian Men (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

A Research Study Investigating Safety and Concentration in the Blood After One Dose Tablet of the New Medicine Monlunabant in Healthy Weight Japanese and Caucasian Men (clinicaltrials.gov) - P1 | N=72 | Not yet recruiting | Sponsor: Novo Nordisk A/S

New P1 trial • Genetic Disorders • Obesity

Cannabinoid Receptor 1 Inverse Agonist, INV-202, Increases Surfactant Phosphatidylcholines and Improves Lung Compliance in a Mouse Model of Asthma (ATS 2024) - "The peripherally acting CB1R inverse agonist INV-202 reduces airway reactivity in allergically inflamed mice and increases lung compliance by restoring airway surfactant phosphatidylcholines. This supports a significant role for the cannabinoid system on lung function. [1] Ackerman et al."

Compliance • Late-breaking abstract • Preclinical • Surfactant • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Phase 2 Study of INV-202 in Patients With Diabetic Kidney Disease (clinicaltrials.gov) - P2 | N=265 | Active, not recruiting | Sponsor: Inversago Pharma Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetic Nephropathy • Nephrology • Renal Disease

Advancements in Diabetic Kidney Disease Management: Integrating Innovative Therapies and Targeted Drug Development. (PubMed, Am J Physiol Endocrinol Metab) - "Emerging agents including GLP-1 agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, Lixudebart, and tozorakimab, mesenchymal stem/stromal cell infusion, and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Hypertension • Immunology • Inflammation • Metabolic Disorders • Nephrology • Oncology • Renal Disease

Study of INV-202 in Patients With Obesity and Metabolic Syndrome (clinicaltrials.gov) - P2 | N=243 | Active, not recruiting | Sponsor: Inversago Pharma Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Metabolic Disorders • Obesity

Phase 2 Study of INV-202 in Patients With Diabetic Kidney Disease (clinicaltrials.gov) - P2 | N=240 | Recruiting | Sponsor: Inversago Pharma Inc. | Trial primary completion date: Mar 2024 ➔ Jul 2024

Trial primary completion date • Diabetic Nephropathy • Nephrology • Renal Disease

Effects of CB1R inverse agonist, INV-202, in patients with features of metabolic syndrome. A randomized, placebo-controlled, double-blind phase 1b study. (PubMed, Diabetes Obes Metab) - "INV-202 was well tolerated, producing a signal for rapid weight loss with improvements in other metabolic syndrome markers in this population. These findings support further exploration and long-term assessment of cardiometabolic effects."

Clinical • Journal • P1 data • Gastrointestinal Disorder • Metabolic Disorders