Study to Evaluate MET409 Alone or in Combination With Empagliflozin in Patients With Type 2 Diabetes and NASH

Study Overview
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Brief Summary
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A randomized, multi-center study evaluating MET409 (50 mg) alone or in combination with empagliflozin (10 mg) for 12 weeks. Assignment to MET409 will be double-blind and placebo-controlled. Empagliflozin will be incorporated into two of the treatment arms in an open-label manner.

Detailed Description
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Subjects assigned to receive empagliflozin will be dosed at 10 mg per day for the duration of the study. Approximately 30 subjects will be enrolled per treatment arm.

Official Title
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A Phase 2A Study to Evaluate MET409 Alone or in Combination With Empagliflozin in Patients With Type 2 Diabetes Mellitus (T2DM) and Nonalcoholic Steatohepatitis (NASH)

Conditions
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NASH, NASH - Nonalcoholic Steatohepatitis, Type 2 Diabetes, Diabetes Type 2, Diabetes, Fatty Liver, Fatty Liver, Nonalcoholic, NAFLD

Intervention / Treatment
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* Drug: MET409 Active
* Drug: MET409 Placebo
* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males and females 18 through 75 years of age. Diagnosis of NASH based on NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each of steatosis, inflammation, and ballooning; Magnetic Resonance Elastography (MRE) showing kPa ≥ 2.61 or a multiparametric MRI (ie, LiverMultiScan) showing iron-corrected T1(cT1) > 830 ms within 6 months of enrollment; or Transient elastography (TE, FibroScan) with liver stiffness ≥ 8.5 kPa and controlled attenuation parameter (CAP) > 300 dB/m obtained within 3 months of enrollment. Liver fat content ≥ 8% measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) during screening. Diagnosis of T2DM for ≤ 10 years, with hemoglobin A1c ≤ 10.0% during screening, stable and controlled with diet or treatment for at least 3 months. Key Exclusion Criteria: History of significant liver disease (eg, alcoholic liver disease, viral hepatitis, etc.) or liver transplant. Presence of cirrhosis on any prior liver biopsy (stage 4 fibrosis). Excessive consumption of alcohol. Use of any insulin (injectable or inhaled), SGLT-2 inhibitor or glucagon-like peptide 1 (GLP-1, injectable or oral) products for > 7 days within 3 months of screening. Weight loss > 10% in the 6 months prior to screening or > 5% during screening. Use of drugs historically associated with causing NAFLD for more than 4 consecutive weeks within 12 months prior to screening. Concomitant use of drugs that are strong or moderate CYP3A4 inhibitors. Concomitant consumption of grapefruit juice with the study drug. History of diabetic ketoacidosis (DKA) within 1 month prior to the Screening Visit, or more than 2 episodes within 6 months prior to the Screening Visit. History of > 2 episodes of urosepsis or pyelonephritis within 5 years of screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MET409 A<br>MET409 Active (50mg) | Drug: MET409 Active<br>* MET409 Active (50mg)<br>|
| Placebo Comparator: MET409 P<br>MET409 Placebo (50mg) | Drug: MET409 Placebo<br>* MET409 Placebo (50mg)<br>|
| Experimental: MET409A +Open-Label Empagliflozin<br>MET409 Active (50mg) + Empagliflozin (10mg) | Drug: MET409 Active<br>* MET409 Active (50mg)<br>Drug: Empagliflozin<br>* Empagliflozin (10mg)<br>|
| Placebo Comparator: MET409P +Open-Label Empagliflozin<br>MET409 Placebo (50mg) + Empagliflozin (10mg) | Drug: MET409 Placebo<br>* MET409 Placebo (50mg)<br>Drug: Empagliflozin<br>* Empagliflozin (10mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of MET409 with or without empagliflozin (incidence of adverse events) | Incidence of Treatment-emergent adverse events, incidence of clinically significant changes in vital signs, abnormal laboratory safety tests, and abnormal ECGs. | Up to 28 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacological activity of MET409 alone or in combination with empagliflozin | Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) | 16 weeks | 
| Pharmacokinetic profile of MET409 alone or in combination with empagliflozin | Cmax | 12 weeks | 
| Pharmacokinetic profile of MET409 alone or in combination with empagliflozin | tmax | 12 weeks | 
| Pharmacokinetic profile of MET409 alone or in combination with empagliflozin | AUClast | 12 weeks | 
| Pharmacodynamic profile of MET409 alone or in combination with empagliflozin | Bile acid precursor : C4 (7αhydroxy-4-cholesten-3-one) | 16 weeks | 
| Pharmacodynamic profile of MET409 alone or in combination with empagliflozin | Bile acid precursor : Fibroblast growth factor 19 (FGF19) | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, FXR, Fatty Liver, Diabetes