Willing to participate in the study and provide written informed consent (or assent, as appropriate).
Male or female aged ≥18 to ≤75 years of age at the time of screening.
Patients who are ≥12 months post-liver transplant at the time of screening:
Cohort 1: Patients who have undergone liver transplant for MASH cirrhosis and present a recurrence of liver fat content ≥ 8% as measured by MRI-PDFF.
Cohort 2: Patients who have undergone a liver transplant for etiologies other than MASH cirrhosis and present with de novo liver fat content ≥ 8% measured with MRI-PDFF.
Must meet at least one of the following metabolic factors:
BMI ≥25 kg/m2
Fasting serum glucose ≥5.6 mmol/L (100 mg/dL) OR 2 hr post-load glucose levels ≥7.8 mmol/L (≥140 mg dL) OR glycated hemoglobin (HbA1c) ≥5.7% (39 mmol/L) OR T2DM or treatment for T2DM
Blood pressure ≥130/85 mmHg OR specific antihypertensive drug treatment
Plasma triglycerides (TGs) ≥1.70 mmol/L (150 mg/dL) OR lipid lowering treatment
Plasma high density lipoprotein-cholesterol (HDL-C) ≤1.0 mmol/L (40 mg/dL) (male) and ≤1.3 mmol/L (50 mg/dL) (female) OR lipid lowering treatment.
MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis) as defined by meeting both a and b of the criteria below:
FibroScan VCTE ≥8.5 and <20 kPa and/or magnetic resonance elastography (MRE) ≥3 and <5 kPa
A liver biopsy performed within 6 months of screening or during the Screening Period that, based on the interpretation of the pathologist who is associated with the investigative site, is consistent with Stage F2/F3 MASH and no evidence of other liver pathology, including cirrhosis or acute or chronic graft rejection. NOTE: A patient who meets the liver biopsy criterion but does not meet the noninvasive test criteria may be eligible for participation. Please contact the CRO or Sponsor Medical Monitor.
Stable renal function, ie, estimated glomerular filtration (eGFR) ≥30 mL/min/1.73m2 ≥90 days prior to screening, based on local historical labs. 7. eGFR ≥30 mL/min/1.73m² during the Screening Period calculated by the Modification of Diet in Renal Disease (MDRD-6) equation.
Stable immunosuppression regimen ≥4 weeks prior to Screening.
Female patients are eligible if they are of reproductive potential and have a negative 8. Urine protein to creatinine ratio < 3 g/day (or random urine albumin to creatinine ratio < 300 mg/g) at screening.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) stability as defined by:
Screening ALT and AST are within normal limits or show no worsening greater than 50% for both values, compared to historic ALT and AST obtained within 6 months of start of Screening
If greater than 50% worsening with at least one value above the upper limit of normal (ULN), laboratory tests may be repeated once per principal investigator (PI) discretion, with second draw at least 2 weeks after initial screening labs. Re-draw results for each test must be less than a 50% worsening as compared to screening values or all values below the ULN.
If no historic labs are available, 2 measurements must be obtained during the Screening period at least 2 weeks apart. These must show no worsening of greater than 50% for both ALT and AST. If greater than 50% worsening and at least one value above the ULN, labs may be repeated once per PI discretion, with third draw at least 2 weeks after the second set of labs. The average of the first 2 labs should be compared to third laboratory draw for ALT and AST to confirm that there is no worsening of greater than 50% for either ALT or AST or all values below the ULN.
Participation in another clinical study with intake of an investigational product during the last 30 days or 5 half-lives, whichever is longer, prior to initiation of the Screening Period.
Phosphatidylethanol (PEth) value of ≥20 ng/mL measured at screening OR alcohol consumption of any type, frequency or amount for a period of more than 3 consecutive months within 1 year prior to screening. A repeat test within the Screening Period, per PI discretion, is allowed. NOTE: Alcohol consumption is not allowed during the Screening and Double-blind Periods of the study.
Patients with FibroScan VCTE >20 kPa, a baseline biopsy demonstrating fibrosis consistent with F4, or MRE > 5kPa.
Patients on thyroxine must be on a stable dose for ≥ 2 weeks with screening thyroid stimulating hormone (TSH) between 1 IU/L and 5 IU/L.
Thyroid disease:
Active hyperthyroidism NOTE: Patients with a history of hyperthyroidism are eligible to participate.
Untreated clinical hypothyroidism defined by:
TSH ≥7 IU/L with symptoms of hypothyroidism, or
TSH ≥10 IU/L without symptoms
NOTE: TSH may be repeated once during Screening, and if still does not meet entry criteria, patients will be considered screen failures. Patients with clinical hypothyroidism newly treated with thyroxine may be rescreened once thyroxine dose is stabilized.
Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 μg per day are allowed (patients with partial thyroidectomy and on appropriate dose of thyroxine may be eligible based on discussion with Sponsor).
Evidence of another form of active liver disease including but not limited to viral hepatitis, autoimmune hepatitis, alcohol-associated liver disease, cholestatic liver disease, Wilson’s disease, Alpha-1-antitypsin deficiency, hemochromatosis or DILI.
History of liver transplantation for indication of an inborn error of metabolism.
Evidence of hepatic impairment during Screening Period as defined by any of the following parameters:
Total bilirubin (TBL) ≥ 1.3 mg/dL unless diagnosis of Gilbert’s disease
AST and/or ALT > 150 IU/L
ALP > 250 IU/L
Model of End-Stage Liver Disease (MELD)-Na ≥12
Serum albumin < 3.5 g/dL
International Normalized Ratio (INR) ≥1.3, except for patients under anticoagulant treatment
Platelets < 70 (x103/μL)
Evidence of active portal hypertension (eg ascites, esophageal varices); NOTE: In the post-transplant setting, residual clinical findings suggestive of portal hypertension may be present despite lack of actual ongoing portal hypertension physiology. In such situations, the patient may be eligible for enrolment if the Investigator and Sponsor agree that active ongoing portal hypertension is not present.
Positive serologic evidence of current infectious liver disease including hepatitis B surface antigen (HBsAg), and/or hepatitis C virus antibody (anti-HCV) with detected circulating ribonucleic acid (RNA) during Screening Period (patients who have received an HCV positive organ should have a negative HCV polymerase chain reaction (PCR) at least 3 months after the cessation of HCV therapy).
Steroid resistant rejection of the transplanted liver or kidney, or a history of a rejection treated with high dose steroid within 3 months of screening.
Chronic rejection or chronic plasma-cell hepatitis.
History of hepatic artery thrombosis.
Ischemic or post-transplant cholangiopathy.
Untreated clinically significant anastomotic biliary stricture or biliary leak.
Any of the following within 6 months prior to the Randomization visit:
Myocardial infarction
Cardiac revascularization procedure (coronary artery bypass graft / percutaneous transluminal coronary angioplasty)
Unstable angina
Transient ischemic attack, stroke or cerebrovascular disease
New York Heat Association class III or IV heart failure or known left ventricular ejection fraction <30%.
Unstable or undiagnosed arrhythmias, long QT syndrome, short QT syndrome, history of drug-induced Torsade de Pointe.
Uncontrolled high blood pressure (BP): diastolic BP ≥ 100 mmHg or systolic BP ≥160 mmHg with or without antihypertensive treatment during Screening Period and/or at randomization. NOTE: BP measurement is the mean of 3 measurements performed in the seated position using the same arm. It can be repeated once. If currently treated for hypertension a patient must be on stable therapy (i.e. same dose(s) and same drug(s) for the last 1 month prior to randomization.
Active malignancy or malignancy with a complete remission date within 2 years prior to randomization (except for treated basal cell carcinoma or treated squamous cell carcinoma of the skin, or pre-transplant hepatocellular carcinoma (HCC) with no evidence of recurrence post-transplant).
Currently diagnosed with HCC (diagnosis of HCC prior to liver transplant is not exclusionary).
Diabetes other than T2DM.
Immunocompromised patients diagnosed with human immunodeficiency virus (HIV).
Any other known serious disease with a likely life expectancy <5 years.
Current drug addiction or substance abuse.
Developmental/intellectual disability, limited capacity of recognition, any history of clinically important emotional and/or psychiatric illness, inability to follow the study procedures, or any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.
Known hypersensitivity to any of the constituents or excipients of the study drug, or history of significant drug and/or food allergies (eg anaphylactic, anaphylactoid reactions).
Use of prohibited concomitant medication within 24 weeks prior to the Randomization Visit (NOTE: A transient intake < 2 weeks may be allowed with the approval of the Sponsor):
Chronic use (>2 consecutive weeks) of corticosteroids with a systemic effect at doses ≥10 mg/day of oral prednisone (or equivalent)
Topiramate, amiodarone, bile salt chelators, methotrexate, equal or more than 800 U of vitamin E per day, orlistat, obeticholic acid or any other medications (including vitamins, herbal and dietary supplements) known to affect liver function/steatosis
Glucagon-like peptide 1 receptor agonist (GLP1-RA) therapy should be a stable dose for 24 weeks prior to randomization. A dose modification or a switch within class from a GLP1-RA to a different GLP1-RA at a dose assessed as equivalent by the Investigator would be allowed within 24 weeks prior to randomization as well as during the study for tolerability issues or HbA1c control.
Use of pioglitazone > 15 mg/day. NOTE: Pioglitazone is allowed at doses ≤ 15 mg/day if the patient has been on pioglitazone for ≥12 weeks prior to randomization and a stable dose for ≥4 weeks prior to randomization.
Use of statin therapy for the treatment of dyslipidemia exceeding the following doses:
Rosuvastatin >20 mg/day
Simvastatin >20 mg/day
Pravastatin >40 mg/day
Atorvastatin >40 mg/day
Pitavastatin >2 mg/day
Lovastatin >40 mg/day
Dyslipidemia therapy must be stable for ≥4 weeks prior to randomization
The Randomization visit may occur one week following the discontinuation of a lipid lowering medication.
Statins are recommended to be taken in the evening for ≥2 weeks prior to randomization and continue to be taken in the evening for the duration of the study
Patients recommended for dyslipidemia therapy but those who are intolerant of statins or other dyslipidemia therapy are allowed
NOTE. Other stable dyslipidemia therapies not specifically listed as excluded or dose-restricted, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, are allowed.
Contraindications to MRI such as patients with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field, a history of extreme claustrophobia or the patient cannot fit inside the magnetic resonance scanner cavity.