Efficacy and safety of ervogastat alone and in combination with clesacostat in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis (MIRNA): results from a phase 2, randomised, double-blind, double-dummy study.

Background: Ervogastat, a diacylglycerol acyltransferase 2 (DGAT2) inhibitor, and clesacostat, an acetyl-coenzyme A carboxylase (ACC) inhibitor, have shown promise in reducing hepatic steatosis. Increased circulating triglycerides, a mechanistic consequence of ACC inhibitors, has been shown to be downregulated by DGAT2 inhibitor co-administration. We assessed the efficacy and safety of ervogastat alone and ervogastat plus clesacostat in adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 2 or 3.

Modeling Reductions in Liver Fat: Comparing Noninvasive Tests to Magnetic Resonance Imaging-Proton Density Fat Fraction.

Background And Aims: Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) is an accurate, noninvasive tool for diagnosing metabolic dysfunction-associated steatotic liver disease, but its feasibility is limited in routine clinical practice. We aimed to assess the clinical utility of alternative, cost-efficient approaches for assessing liver fat changes and their relationship with MRI-PDFF changes.

Methods: This is a secondary analysis of a phase 2a study that included adults with metabolic dysfunction-associated steatotic liver disease who received clesacostat, a selective, reversible inhibitor of acetyl-CoA carboxylase.

Exposure-response modeling of liver fat imaging endpoints in non-alcoholic fatty liver disease populations administered ervogastat alone and co-administered with clesacostat.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis describe a collection of liver conditions characterized by the accumulation of liver fat. Despite biopsy being the reference standard for determining the severity of disease, non-invasive measures such as magnetic resonance imaging proton density fat fraction (MRI-PDFF) and FibroScan® controlled attenuation parameter (CAP™) can be used to understand longitudinal changes in steatosis. The aim of this work was to describe the exposure-response relationship of ervogastat with or without clesacostat on steatosis, through population pharmacokinetic/pharmacodynamic (PK/PD) modeling of both liver fat measurements simultaneously.

Evaluation of an oral small-molecule glucagon-like peptide-1 receptor agonist, lotiglipron, for type 2 diabetes and obesity: A dose-ranging, phase 2, randomized, placebo-controlled study.

Aim: The aim was to investigate the effects of lotiglipron, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity.

Materials And Methods: A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review.

SomaLogic proteomics reveals new biomarkers and provides mechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH).

Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH) are major metabolic diseases with increasing global prevalence and no approved therapies. There is a mounting need to develop biomarkers of diagnosis, prognosis and treatment response that can effectively replace current requirements for liver biopsies, which are invasive, error-prone and expensive. We performed SomaLogic serum proteome profiling with baseline (n = 231) and on-treatment (n = 72, Weeks 12 and 16, Placebo and 25 mg PF-05221304) samples from a Phase 2a trial (NCT03248882) with Clesacostat (PF-05221304), an acetyl coA carboxylase inhibitor (ACCi) in patients with NAFLD/NASH.

Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60).

Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology.

Purpose: Hepatic steatosis due to altered lipid metabolism and accumulation of hepatic triglycerides is a hallmark of nonalcoholic fatty liver disease (NAFLD). Diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, catalyze the terminal reaction in triglyceride synthesis, making them attractive targets for pharmacologic intervention. There is a common misconception that these enzymes are related; however, despite their similar names, DGAT1 and DGAT2 differ significantly on multiple levels.

Pharmacokinetics, mass balance, metabolism, and excretion of the liver-targeted acetyl-CoA carboxylase inhibitor PF-05221304 (clesacostat) in humans.

The disposition of the hepatoselective ACC inhibitor PF-05221304 (Clesacostat) was studied after a single 50-mg oral dose of [14C]-PF-05221304 to healthy human subjects.Mass balance was achieved with 89.9% of the administered dose recovered in urine and faeces, over the 11-day study period.

Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study.

Introduction: Small molecule inhibitors of the terminal step in intrahepatic triglyceride synthesis (diacylglycerol acyltransferase 2 inhibitor (DGAT2i, PF-06865571, ervogastat)) and upstream blockade of lipogenesis via acetyl-coenzyme A carboxylase inhibitor (ACCi, PF-05221304, clesacostat) showed promise in reducing hepatic steatosis in early clinical trials. This study assesses efficacy and safety of these metabolic interventions to resolve non-alcoholic steatohepatitis (NASH) with fibrosis.

Methods And Analysis: This phase II, randomised, dose-ranging, dose-finding study evaluates DGAT2i 25-300 mg two times per day (BID) or 150-300 mg once a day, DGAT2i 150-300 mg BID+ACCi 5-10 mg BID coadministration or matching placebo in a planned 450 adults with biopsy-confirmed NASH and liver fibrosis stages 2-3 from approximately 220 sites in 11 countries across North America, Europe and Asia.

ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD.

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor.

Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study.

PF-05221304 is a liver-targeted inhibitor of acetyl-CoA carboxylase, an enzyme that catalyzes the first committed step in de novo lipogenesis (DNL). This first-in-human study investigated safety/tolerability and pharmacokinetics of single and multiple ascending oral PF-05221304 doses, and fructose-stimulated DNL inhibition with repeated oral doses. Healthy subjects (n = 96) received single (1-240 mg) or repeated (2-200 mg daily) doses for 14 days or single 100-mg doses with and without food.

Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatocyte triglycerides, the synthesis of which is catalyzed by diacylglycerol acyltransferases (DGATs). Here, we investigate DGAT2 as a potential therapeutic target using an orally administered, selective DGAT2 inhibitor, PF-06427878. Treatment with PF-06427878 resulted in the reduction of hepatic and circulating plasma triglyceride concentrations and decreased lipogenic gene expression in rats maintained on a Western-type diet.

Glycemic Effect and Safety of a Systemic, Partial Glucokinase Activator, PF-04937319, in Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Metformin-A Randomized, Crossover, Active-Controlled Study.

Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic β cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily).

Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator.

The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms.

Influence of i.v. haloperidol on ventricular repolarization and monophasic action potential duration in anesthetized dogs.

Introduction: i.v. haloperidol is used commonly for sedation in critically ill patients.