azemiglitazone (MSDC-0602K) / Cirius Therap - LARVOL DELTA

Fibroblast activity assessed by PRO-C3 is prognostic for fibrosis progression in MASH patients treated with insulin sensitizer MSDC-0602K during a phase IIb clinical trial (EASL 2025) - P2 | "Lower fibroblast activity (PRO-C3) at baseline was associated with achieving primary endpoint as well as fibrosis regression, while higher baseline PRO-C3 was associated with fibrosis progression. MSDC-0602K significantly reduced PRO-C3, suggesting an anti- fibrotic effect. PRO-C3 can identify MASH patients who are likely to respond to treatment and prognosticate their evolution."

Clinical • P2b data • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Glyceraldehyde-3-Phosphate Dehydrogenase/1,3-Bisphosphoglycerate-NADH as Key Determinants in Controlling Human Retinal Endothelial Cellular Functions: Insights from Glycolytic Screening. (PubMed, J Biol Chem) - "Pharmacological inhibitors targeting lower glycolytic components were tested: heptelidic acid for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), NG-52 for phosphoglycerate kinase (PGK), shikonin for pyruvate kinase M (PKM), galloflavin for lactate dehydrogenase (LDH), AZD3965 for lactate transporter (MCT-1), and MSDC-0160 for the mitochondrial pyruvate carrier (MPC)...GAPDH and its downstream products (1,3-BPG and NADH) are shown to play a pivotal role in maintaining barrier integrity and promoting HREC adhesion and spreading. These findings guide the development of targeted interventions that modulate HREC bioenergetics to treat endothelial dysfunction in various retinal disorders, while minimizing potential adverse effects on healthy endothelial cells."

Journal • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • GAPDH • PKM

Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics. (PubMed, Metabolism) - "These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

METASIGHT'S METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (MASH)-FIBROSIS SCORE: A BLOOD TEST ENABLING PATIENT MONITORING OF LIVER FIBROSIS (AASLD 2024) - P2 | "Patients with biopsy-confirmed MASH, fibrosis stage 1–3, and a Non-alcoholic fatty liver disease Activity Score (NAS) ≥4 were enrolled and randomly assigned for oral daily doses with MSDC-0602K, or placebo, for 12 months... The MetaSight test is a promising accurate approach for diagnosing MASH-fibrosis. Unlike currently utilized NITs, the MetaSight test enables monitoring fibrosis in patients under treatment, making it an option to be considered in clinical practice."

Clinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Potential for New Oral Insulin Sensitizers in Combination with GLP-1 Agonists (ADA 2024) - "MSDC-0602K (azemiglitazone) is a second-generation insulin sensitizer that was designed based on the knowledge of the activity of active metabolites of the first-generation insulin sensitizer pioglitazone...Here we have looked specifically at the 23 subjects with NASH (MASH) and type 2 diabetes who had been enrolled in the trial while on a stable dose of a GLP1 agonist (11 liraglutide, 8 dulaglutide, and 4 exenatide)...Some subjects who had been on a GLP1 continued to lose weight while others did not. Given the major effects of his pharmacology to improve insulin sensitivity Iin skeletal muscle and based on some existing precedent with high dose pioglitazone, maintenance of lean mass could be a component of the overall pharmacology achieved with oral metabolic modulators."

Combination therapy • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Type 2 Diabetes Mellitus

Azemiglitazone in combination with GLP1 agonists increases benefit and could preserve lean body mass (EASL-ILC 2024) - "Background and Aims: Azemiglitazone (0602K) is a second-generation insulin sensitizer designed based on the activity of metabolites of the first-generation insulin sensitizer pioglitazone to specifically bind to the recently identified target of the TZDs, the mitochondrial pyruvate carrier...2020 Apr; 72(4): 613-626) and examined the body composition in db/db mice treated with the combination of 0602K and liraglutide under conditions where there are synergistic improvements in liver histology including ballooning with the 0602K/lira combination (Kamm et al, J Biol Chem 2021: 296: 100807) Analysis of the 23 subjects with NASH (MASH) and type 2 diabetes who had been enrolled in the trial while on a stable dose of a GLP1 receptor agonist (GLP1-RA; 11 liraglutide, 8 dulaglutide, and 4 exenatide) demonstrated that any dose of 0602K was able to further lower fasting glucose, insulin and liver enzymes... Together these results suggest that clinical evaluation of azemiglitazone..."

Combination therapy • Late-breaking abstract • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Serological biomarkers PRO-C3 and PRO-C6 reveal the anti-fibrotic and pro-metabolic effects of MSDC-0602K, an insulin sensitizer, in non-alcoholic steatohepatitis patients during the EMMINENCE phase IIb study (EASL-ILC 2023) - P2 | "MSDC-0602K reduced both PRO-C3 and PRO-C6 levels, indicating an anti-fibrotic and pro- metabolic effect. Furthermore, the biomarkers identified a subgroup of patients with lower baseline PRO-C3 and a F3-F4 diagnosis at BL that had a high likelihood of improvement in fibrosis. Our findings suggest that measuring ECM neo-epitope biomarkers may aid in understanding the pharmacodynamic effects of MSDC- 0602K as well as support future exploration of MSDC-0602K in patients with NASH."

Biomarker • Clinical • P2b data • Fibrosis • Hepatology • Inflammation • Non-alcoholic Steatohepatitis

Inhibition of MPC Simultaneously Mitigates Hyperinflammation and Hyperglycemia in COVID-19 (ATS 2023) - "Therefore, novel interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors known to drive COVID-19 pathophysiology, are urgently needed. We have utilized murine models of influenza and SARS-CoV-2 infection to test whether MSDC-0602K (MSDC), a second-generation insulin sensitizer that targets mitochondrial pyruvate carrier (MPC), can simultaneously dampen pulmonary inflammation and hyperglycemia. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery as well as host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease."

Diabetes • Dyslipidemia • Infectious Disease • Inflammation • Influenza • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Pneumonia • Respiratory Diseases • HIF1A

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism. (PubMed, Mol Metab) - P2 | "These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations."

Clinical • Journal • Addiction (Opioid and Alcohol) • Diabetes • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity • Solid Tumor • Type 2 Diabetes Mellitus • AMPK

[VIRTUAL] Lack of reliability of liver biopsies in nonalcoholic steatohepatitis (NASH) clinical trials - potential implications for developing new therapies for NASH (EASL-ILC-I 2020) - "The average effect of MSDC-0602K 125/250 mg combined versus placebo on 12-month changes in noninvasive markers of fibrosis and liver injury was almost double in terms of standard deviations (0.33 SDs) as compared to histologic endpoints (0.18 SDs), suggesting that the significant lack of reliability in hepatic histology interpretation may have reduced the apparent treatment effect of MSDC- 0602K... Reliability of hepatopathologists’ liver biopsy evaluation using currently accepted criteria is poor. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects."

Clinical • Late-breaking abstract • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Failure • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

[VIRTUAL] Lack of reliability of liver biopsies in non-alcoholic steatohepatitis (NASH) clinical trials - potential implications for developing new therapies for NASH (EASL-ILC-I 2020) - " We evaluated data from the EMMINENCE study examining a novel insulin sensitizer (MSDC-0602 K) in NASH... Reliability of hepatopathologists’ liver biopsy evaluation using currently accepted criteria is poor. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects."

Clinical • Late-breaking abstract • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Failure • Non-alcoholic Steatohepatitis

Effect of MSDC-0602K treatment on the metabolome of a diet-induced murine model (EASL-ILC 2019) - P2; "Administration of MSDC-0602K regulated the levels of triglycerides in the liver, reducing saturated and increasing polyunsaturated species, and reduced the levels of lipotoxic species. The results also revealed metabolites that are specifically altered by MSDC-0602K and that may be used as non-invasive biomarkers reflecting its therapeutic effect on the liver."

Preclinical

Novel mitochondrial pyruvate carrier modulators to treat non-alcoholic steatohepatitis and insulin resistance (EASL-ILC 2019) - P2; "...Indeed, a thiazolidinedione derived MPC inhibitor, MSDC-0602, is completing phase 2 clinical trials for NASH in 2019 (EMMINENCE; NCT02784444)... Use of the BRET reporter system confirmed previous reports of MPC interacting drugs, including other thiazolidinediones (pioglitazone and rosiglitazone), zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), and 7ACC2, which was originally purported to be a lactate transport inhibitor... In conclusion, these data provide proof of concept evidence in a mouse model for the efficacy of novel MPC modulators as insulin sensitizing agents and NASH therapeutics. Moreover, despite differing mechanisms for interacting with the MPC complex, both 7ACC2 and zaprinast had similar effects on insulin sensitivity and NASH end points demonstrating a generalization of the MPC inhibitor mechanism of action."

MSDC-0602K, a PPAR-gamma sparing modulator of the mitochondrial pyruvate carrier, improves NASH outcome in a diet-induced animal model of non-alcoholic steatohepatitis (EASL-ILC 2019) - P2; "Unlike the first generation TZDs pioglitazone and rosiglitazone, MSDC-0602 was designed not to bind We postulated that MSDC-0602K treatment would improve clinical laboratory indices and pathophysiological aspects of NASH in the DIAMONDŽ mouse model. MSDC-0602K met the primary study goal of ameliorating and preventing progression of NASH. The drug treatment improved insulin resistance, LFTs, ballooning, and NASH outcome independently of weight and steatosis. These study results support the biological rationale for use of MPC modulators like MSDC-0602K to treat NASH."

Preclinical

Six month interim results of MSDC-0602K in a large phase 2b NASH study demonstrate significant improvement in liver enzymes and glycemic control (NCT02784444) (EASL-ILC 2019) - P2; "The interim results from 328 of 402 NASH patients in the Phase 2b EMMINENCE study demonstrate significant positive effects on liver enzymes and glycemic control, suggesting that MSDC-0602K may result in improvement of NASH and fibrosis on liver biopsy while also improving glycemic control in type 2 diabetes."

P2b data

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19. (PubMed, Sci Immunol) - "MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease."

Journal • Diabetes • Dyslipidemia • Immunology • Infectious Disease • Inflammation • Influenza • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Pneumonia • Respiratory Diseases • HIF1A

Side effect profile of pharmacologic therapies for liver fibrosis in nonalcoholic fatty liver disease: a systematic review and network meta-analysis. (PubMed, Eur J Gastroenterol Hepatol) - "The risk of side effects significantly varied among different pharmacologic regimens, and evidence showed that lanifibranor, liraglutide, semaglutide, cenicriviroc, MSDC-0602K and obeticholic acid were the pharmacological interventions with the highest risk in patients with NAFLD. This study may guide clinicians and support further research."

Adverse events • Journal • Retrospective data • Review • Constipation • Dermatology • Fatigue • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Pain • Pruritus

Novel thiazolidinedione analog reduces a negative impact on bone and mesenchymal stem cell properties in obese mice compared to classical thiazolidinediones. (PubMed, Mol Metab) - "Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases."

Journal • Preclinical • Genetic Disorders • Musculoskeletal Diseases • Obesity • Orthopedics • Osteoporosis • PPARG

Simultaneously targeting hyperinflammation and hyperglycemia following respiratory viral infection (IMMUNOLOGY 2022) - "Here, we showed that a second-generation thiazolidines drug MSDC-0602K (MSDC), a mitochondrial pyruvate carrier inhibitor, simultaneously decreased excessive pulmonary inflammation and hyperglycemia in normal and obese hosts during influenza infection, as such, reducing host morbidity and mortality. scRNA-seq analysis revealed that MSDC treatment reduced lung macrophage inflammation, and myeloid-specific ablation of MPC2 led to dampened lung inflammation. Further, MSDC inhibited human lung macrophage inflammatory responses following SARS-CoV-2 infection, and dampened inflammation in lung autopsies of COVID-19 patients. Mechanistically, MSDC treatment destabilized HIF-1a protein, a transcription factor promoting inflammatory responses of lung macrophages, by repressing cellular Acetyl-CoA levels and HIF-1a acetylation. Our results suggest that MSDC has the great potential to treat severe COVID-19 or other..."

Diabetes • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Pneumonia • Respiratory Diseases • HIF1A

Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. (PubMed, Drug Des Devel Ther) - "At the time of writing this review, only Zydus Cadila's new drug application for Saroglitazar had been approved (2020) for NASH therapy in India...Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon...Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come."

Clinical • Journal • Review • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

A Study of MSDC-0602K to Assess Glycemic Control and Cardiovascular Outcomes in Patients With Pre-T2D or T2D and NAFLD/NASH (clinicaltrials.gov) - P3; N=1800; Not yet recruiting; Sponsor: Cirius Therapeutics, Inc.; Trial completion date: Nov 2023 ➔ Sep 2024; Trial primary completion date: Nov 2023 ➔ Sep 2024

Clinical • Trial completion date • Trial primary completion date • Cardiovascular • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • KRT18

[VIRTUAL] Mechanisms of Metabolic Cross Talk between Mitochondrial Pyruvate Carrier Inhibition and Branched-Chain Amino Acid Catabolism in Hepatocytes (ADA 2021) - P2 | "BCAA concentrations were assessed in plasma collected in EMMINENCE (NCT02784444), a randomized, placebo-controlled trial of the MPC inhibitor MSDC-0602K in people with NASH...Lean LS-Mpc2-/- mice also exhibited reduced plasma BCAA concentrations after an overnight fast. These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation via the phosphatase PPM1K."

Late-breaking abstract • Diabetes • Metabolic Disorders • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus

[VIRTUAL] MSDC-0602 Is a Direct Mitochondrial Pyruvate Carrier Inhibitor That Modulates Central Carbon Metabolism in Mice and Humans (ADA 2021) - "Similarly, circulating and liver glucose were decreased in HFD mice treated with MSDC-0602. Together, these data are consistent with MSDC-0602 modulating in vivo metabolism in a partially MPC-dependent manner and by additional mechanisms that remain to be understood."

Preclinical • Diabetes • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • PPARG

Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide. (PubMed, J Biol Chem) - "In conclusion, MSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance and liver histology, suggesting that this combination treatment may be an effective therapeutic strategy for diabetes and NASH."

Combination therapy • Journal • Preclinical • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

A Study of MSDC-0602K to Assess Glycemic Control and Cardiovascular Outcomes in Patients With Pre-T2D or T2D and NAFLD/NASH (clinicaltrials.gov) - P3; N=1800; Not yet recruiting; Sponsor: Cirius Therapeutics, Inc.; Trial completion date: Jul 2023 ➔ Nov 2023; Trial primary completion date: Jul 2023 ➔ Nov 2023

Clinical • Trial completion date • Trial primary completion date • Cardiovascular • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus