omesdafexor (MET409) / Organovo - LARVOL DELTA

Aberrant oxidative modifications of neutrophil myeloperoxidase in anti-neutrophil cytoplasmic antibodies-associated vasculitis. (PubMed, J Proteomics) - "These included oxidation of Met577, Phe686, Met688 and Met719, dioxidation of Met409, Phe605, Trp679 and Met719, and kynurenylation of Trp255...Immunization of in vitro oxidized MPO induced autoantibodies to the intact unoxidized MPO, indicating that the increased oxidative modifications of MPO may break the immune tolerance in MPO-AAV. This study suggests a novel trigger mechanism for MPO-ANCA production, which may lead to a curative treatment for AAV."

Journal • ANCA Vasculitis • Glomerulonephritis • Hematological Disorders • Lupus Nephritis • Nephrology • Vasculitis • MPO

Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease. (PubMed, Bioorg Chem) - "MET-409 in clinical phase Ⅲ, has been proven significantly fewer side effects than that of other FXR agonists...In the nonalcoholic steatohepatitis (NASH) model, LH10 significantly improved the pathological characteristics of NASH by regulating several major pathways including lipid metabolism, inflammation, oxidative stress, and fibrosis. With the above attractive results, LH10 is worthy of further evaluation as a novel agent for the treatment of liver disorders."

Journal • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Metacrine Reports First-Quarter 2022 Results (GlobeNewswire) - "R&D Expenses - Research and development expenses were $6.7 million for the three months ended March 31, 2022, as compared to $10.9 million for the prior-year period. The decrease was primarily driven by lower clinical development costs related to the advancement of our MET409 and MET642 programs."

Commercial • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Metacrine to Host Virtual R&D Day for Analysts and Investors on September 15, 2021 (GlobeNewswire) - "Metacrine, Inc...announced it will host a virtual R&D Day for analysts and investors on Wednesday, September 15, 2021 at 12:00 p.m. ET. The event will showcase Metacrine’s programs in...inflammatory bowel disease (IBD), as well as the introduction of a new discovery program."

Clinical • Immunology • Inflammatory Bowel Disease

Metacrine Updates MET642 Clinical Development Milestone and Reports Second-Quarter 2021 Results (GlobeNewswire) - "'Our team has done a fantastic job achieving enrollment targets for both studies, as we get ready to select the best candidate to move forward into late-stage development in both NASH and our planned expansion into inflammatory bowel disease (IBD) in 2022'...The event will showcase Metacrine’s programs in NASH and IBD, featuring management presentations and discussions by prominent key opinion leaders (KOL)."

Clinical • Immunology • Inflammatory Bowel Disease

Week 4 Liver Fat Reduction on MRI as an Early Predictor of Treatment Response in Participants with Nonalcoholic Steatohepatitis. (PubMed, Radiology) - "Materials and Methods In this secondary analysis of a prospective phase Ib clinical trial evaluating a candidate treatment (MET409, a farnesoid X receptor agonist) for NASH, participants were analyzed at baseline and at 4 and 12 weeks after either active treatment with MET409 or placebo treatment between June 2019 and January 2020...Conclusion In participants with nonalcoholic steatohepatitis enrolled in a phase Ib treatment trial, the relative change in the MRI-based proton-density fat fraction (PDFF) at week 4 was highly predictive of the treatment response estimated by using the week 12 MRI-based PDFF."

Journal • Hepatology • Non-alcoholic Steatohepatitis • MRI

Study to Evaluate MET409 Alone or in Combination With Empagliflozin in Patients With Type 2 Diabetes and NASH (clinicaltrials.gov) - P2a; N=120; Active, not recruiting; Sponsor: Metacrine, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • FGF19

Metacrine Initiates Phase 2a Combination Trial of MET409 with Empagliflozin in Patients with Type 2 Diabetes and NASH - "'NASH is a multifactorial liver disease associated with a number of co-morbidities, including type 2 diabetes,' said Eric J. Lawitz, M.D....primary investigator for the Phase 2a trial. 'Even though patients with T2DM are perceived to have a more aggressive form of NASH and fibrosis, there has been a lack of innovative treatments for these patients. I am encouraged by MET409's monotherapy clinical data in patients with NASH, as well as its potential to combine with a SGLT2 inhibitor. I look forward to evaluating MET409 in this combination, potentially enabling its clinical use in the future.'"

Media quote

[VIRTUAL] DOSE-DEPENDENT CHANGES IN PHARMACOKINETIC AND PHARMACODYNAMIC PROFILES OF MET409, A SUSTAINED FXR AGONIST, AFTER 12 WEEKS OF TREATMENT IN PATIENTS WITH NASH (AASLD 2020) - "Dose-dependent increases in MET409 levels were seen after 12 weeks of dosing in patients with biopsy-confirmed or phenotypic NASH based on non-invasive assessment. MET409 also decreased circulating levels of C4 and was associated with increasing trends of FGF19. These results demonstrate robust, sustained FXR activation by MET409 and correlate with previously-reported benefits of LFC reduction and improvement in liver chemistries."

Clinical • PK/PD data • Addiction (Opioid and Alcohol) • Dermatology • Dyslipidemia • Hepatology • Non-alcoholic Steatohepatitis • Pruritus • FGF • FGF19 • MRI

FXR agonists for NASH: How are they different and what difference do they make? (PubMed, J Hepatol) - No abstract available

Journal • Dermatology • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Pruritus

[VIRTUAL] MET409, an optimized farnesoid X receptor agonist, decreased liver fat and improved liver enzymes in patients with non-alcoholic steatohepatitis: a 12-week, randomized, placebo-controlled study (EASL-ILC-I 2020) - "MET409 significantly decreased LFC and improved liver enzymes after 12 weeks of treatment in patients with biopsy-confirmed or phenotypic NASH based on TE. Additionally, MET409 at 50 mg delivered a differentiated, favorable pruritus and LDL-C profile. These results provide the first clinical evidence that the therapeutic index of FXR agonists can be enhanced through structural optimization."

Clinical • Late-breaking abstract • Dermatology • Dyslipidemia • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Pruritus

The identification of farnesoid X receptor modulators as treatment options for non-alcoholic fatty liver disease. (PubMed, Expert Opin Drug Discov) - "FXR agonists that are currently undergoing phase2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways."

Journal • Cardiovascular • Dermatology • Hepatology • Non-alcoholic Fatty Liver Disease • Pruritus

MET642, FXR AGONIST WITH A UNIQUE CHEMOTYPE, DEMONSTRATES A SAFE, SUSTAINED PROFILE IN A 14-DAY RANDOMIZED STUDY IN HEALTHY SUBJECTS (NASH-TAG 2021) - "MET409 repressed daily trough plasma C4 levels and final day area-under-the-curve (↓~53-95%, Table) relative to PBO, with repression observed throughout 24 hours post-dosing. MET642, a novel FXR agonist, demonstrated sustained target engagement and an encouraging safety and tolerability profile – including a lack of adverse LDL-C effects or pruritus − in healthy subjects after 14 days of daily oral dosing."

Clinical • Addiction (Opioid and Alcohol) • Dermatology • Dyslipidemia • Hepatology • Non-alcoholic Steatohepatitis • Pruritus • FGF19

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis. (PubMed, J Hepatol) - "MET409 lowered LFC in 12 weeks in NASH patients and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization."

Clinical • Journal • Dermatology • Dyslipidemia • Hepatology • Non-alcoholic Steatohepatitis • Pruritus

Study to Evaluate MET409 Alone or in Combination With Empagliflozin in Patients With Type 2 Diabetes and NASH (clinicaltrials.gov) - P2a; N=120; Recruiting; Sponsor: Metacrine, Inc.

Clinical • Combination therapy • New P2a trial • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • FGF

[VIRTUAL] CHANGE IN LIVER FAT CONTENT AT 4 WEEKS ACCURATELY PREDICTS CHANGE IN LIVER FAT CONTENT AT 12 WEEKS IN NON-ALCOHOLIC STEATOHEPATITIS PATIENTS TREATED WITH AN FXR AGONIST: ANALYSIS FROM A 12-WEEK, RANDOMIZED, PLACEBO-CONTROLLED STUDY WITH MET409 (AASLD 2020) - "In a study with a sustained FXR agonist, relative LFC reduction at Week 4 is strongly predictive of LFC reduction at Week 12. Additional investigations with MET409 and other NASH therapeutic agents are warranted to determine whether early LFC assessment can be a useful indicator of long-term treatment response."

Clinical • Hepatology • Non-alcoholic Steatohepatitis • MRI

Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH). (PubMed, Expert Opin Investig Drugs) - "EDP305, tropifexor, cilofexor, nidufexor, TERN.101, Px-104, EYP001, MET409...Efficacy of combining an FXR agonist with statins, CCR2, and ACC inhibitors is currently investigated. Identification of patient subsets would allow development of patients tailored therapy using a combination of drugs acting on different molecular mechanisms."

Journal • Addiction (Opioid and Alcohol) • Dermatology • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Pruritus

[VIRTUAL] MET409, a potent, non-bile acid sustained FXR agonist, improves NAFLD activity score and exerts anti-fibrotic effects in a diet-induced obese mouse model of biopsy-confirmed fibrosing NASH (EASL-ILC-I 2020) - No abstract available

Preclinical • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity

[VIRTUAL] Sustained FXR agonist MET642 shows improved potency and efficacy relative to MET409 in a diet-induced obese biopsy-confirmed mouse model of NASH and in non-human primate pharmacodynamics (EASL-ILC-I 2020) - No abstract available

PK/PD data • Preclinical • Non-alcoholic Steatohepatitis • Obesity

Sustained fxr agonist met642 shows improved potency and efficacy relative to met409 in a diet-induced obese biopsy-confirmed mouse model of nash and in non-human primate pharmacodynamics (EASL-ILC 2020) - No abstract available

PK/PD data • Preclinical

Met409, a potent, non-bile acid sustained fxr agonist, improves nafld activity score and exerts anti-fibrotic effects in a diet-induced obese mouse model of biopsy-confirmed fibrosing nash (EASL-ILC 2020) - No abstract available

Preclinical

Metacrine demonstrates best-in-class FXR drug program with positive clinical results in NASH patients (P&T) - "'The initial clinical results with Metacrine's FXR program are impressive and unprecedented for the FXR class of drugs,' said Stephen A. Harrison, MD...'Based on publicly presented data, MET409 shows at least double the efficacy of liver fat reduction at 12 weeks, as compared to other FXR agonists in development.'"

Media quote

MET409, A SUSTAINED FXR AGONIST, DECREASED HEPATIC FAT AND IMPROVED LIVER FUNCTION WITHOUT RAISING LDL-C AFTER 28 DAYS IN NASH PATIENTS (AASLD 2019) - "MET409, an optimized sustained non-bile acid FXR agonist, reduced hepatic fat, improved liver function, did not raise LDL-C or cause pruritus, and was safe and well-tolerated at 50 mg after 28 days of dosing in NASH patients. These results demonstrate the potential of sustained FXR agonism to deliver a differentiated, best-in-class profile. Higher dose levels of MET409 – those that suppress C4 levels by >99% – are being assessed in a longer-term, placebo-controlled study."

Clinical

Metacrine reports positive interim results with sustained FXR agonist in NASH patients (GlobeNewswire) - P1b, N=10; "'These initial clinical results with Metacrine’s sustained FXR agonist are highly encouraging,' said Stephen Harrison...'The lack of LDL cholesterol increase seems to be a differentiating feature from other FXR agonists in development and the early signs of efficacy as judged by rapid liver fat improvement at four weeks is noteworthy.'"

Media quote • P1 data

MET409, an optimized sustained FXR agonist, was safe and well-tolerated in a 14-day phase 1 study in healthy subjects (EASL-ILC 2019) - "MET409, an optimized FXR agonist, demonstrated sustained FXR engagement and an encouraging safety and tolerability profile-including a lack of adverse impact on LDL cholesterol levels in healthy male subjects.Figure:"

Clinical • P1 data