CM-101 in NASH Patients - The SPLASH Study

This study will consist of screening period, treatment period and follow-up period. Adults with NASH will be included. Each subject will undergo screening procedures within up to 42 days prior to Randomization, to assess eligibility to participate in the study. After randomization patients will receive a dose of investigational product once every 2 weeks for a total of 8 administrations. This will result in a total coverage of 16 weeks. Study participation will last for up to approximately 26 weeks (up to 6 weeks for screening followed by 14 weeks treatment and 6 weeks follow-up).

Inclusion criteria

• Histological confirmation of steatohepatitis and fibrosis without cirrhosis on a diagnostic liver biopsy obtained within the 18 months prior to the start of treatment, and/or during the screening period with:

a. NAS ≥ 4 with a score of at least 1 for each component (steatosis, ballooning degeneration and lobular inflammation) and b. Hepatic fibrosis stage F1c, 2 or 3 as defined by the NASH CRN scoring scale. F1c subjectspatients must have either: PRO-C3 >14 ng/ml or Liver stiffness value of >8.0 kPa measured by transient elastography

• Patients with presence of greater than or equals to (≥) 10 percent (%) steatosis on MRI-derived proton-density fat-fraction (PDFF) performed as part of the screening procedure or within 12 weeks prior to randomization
• Confirmation of disease status from time of biopsy by Transient Elastography performed during the screening period with liver stiffness value of 7-12 kPa.
• Patients with presence of ≥1 of the following risk factors:

• Obesity (BMI ≥30 kg/m2),
• Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria,
• HTN per 2017 AHA Guidelines for Hypertension,
• ALT >1.5× upper limit of normal (ULN)
• Patients with a stable body mass index (BMI) between 25- 45 kg/m², both inclusive. Body weight is required to be stable (i.e., not varying by > 5% for at least 12 weeks) prior to study entry;
• Patients on chronic medication must be on a stable regimen for ≥ 12 weeks prior to Randomization and should attempt to maintain a stable dosing regimen during the study period;
• Patients must have the following laboratory parameters at screening:

• Total bilirubin < 1.5 mg/dL (26 micromol/L)
• AST < 5 x ULN
• INR < 1.3
• Creatinine clearance ≥60 mL/min as calculated by Cockcroft Gault equation;
• Alpha-fetoprotein in normal range (i.e. <20 ng/mL). If greater than normal, the patient requires a negative ultrasound for hepatocellular carcinoma within 12 weeks prior to randomization
• Women of childbearing potential must agree to use an approved form of contraception (e.g. oral, transdermal patch, implanted contraceptives, intrauterine device, diaphragm, condom, abstinence or surgical sterility) prior to randomization and for the duration of study participation through to 60 days after the last dose of the study medication. Confirmation that female patients are not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for documented postmenopausal or surgically sterilized women;
• Male patients must agree to use a barrier method of contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide) or abstinence for the duration of study participation through 60 days after the last dose of the study medication.
• Patients able to understand and sign a written informed consent form (ICF), communicate with the investigator, and understand and comply with protocol requirements.

Exclusion criteria

• Patients with medical/surgical history of bariatric surgery procedures or bariatric device insertion or patients that are planned for such interventions;
• Patients taking weight loss medications;
• Evidence of drug induced steatohepatitis secondary to amiodarone, corticosteroids, estrogens, methotrexate, tetracycline, or other medications known to cause hepatic steatosis;
• History or presence of cirrhosis (compensated or decompensated) determined by histology or relevant medical complications and laboratory parameters;
• Model for End-stage Liver Disease (MELD) score >12;
• History of liver transplant, or current evaluation for or placement on a liver transplant waiting list;
• Abnormal laboratory screening values:

• Hemoglobin < 12.0 g/dL in males and < 11.0 g/dL in females
• Platelet count < 140,000/mm3
• Total white blood cells (WBC) < 3,000 cells/mm3
• Absolute neutrophil count (ANC) < 1,500 cells/mm3
• Serum albumin < 3.5 g/dL
• Screening ECG demonstrating prolongation of QT interval corrected by Fredericia Correction Formula (QTcF) of > 500 msec, or a history of clinically significant arrythmias
• History of other chronic liver diseases including:

• Alcoholic liver disease
• Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)
• Hepatitis C as defined by presence of hepatitis C virus antibody (HCV-Ab) even if successfully treated with an antiviral regimen or positive HCV RNA (if necessary)
• History or evidence of well documented autoimmune hepatitis (i.e. specific autoantibodies, hypergammaglobulinemia, consistent histologic changes)
• History or evidence of primary biliary cholangitis (PBC)
• History or evidence of primary sclerosing cholangitis (PSC)
• History or evidence of Wilson's disease
• History or evidence of alpha-1-antitrypsin deficiency
• History or evidence of hemochromatosis
• History or evidence of drug-induced liver disease, as defined on the basis of typical exposure and history
• Known bile duct obstruction or a history of prior biliary tract diversion
• Suspected or proven liver cancer;
• History of human immunodeficiency virus (HIV) infection (positive HIV Ab);
• Patients with diabetes mellitus type 1;
• Patients with decompensated diabetes mellitus type 2 defined as either a HbA1c ≥ 9.5% at the time of screening or patients who are insulin dependent;
• Patients under evaluation for a suspected malignancy, with any history of hepatocellular carcinoma (HCC), or a history of other malignancy diagnosed or treated within 2 years prior to Randomization (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening);
• Patients showing deleterious effects of alcohol abuse (as assessed by the investigator) or that consume excessive amounts of alcohol (>14 units/week for both females and males; for the purposes of this study one unit of alcohol is considered to be equal to 8 gr);
• Patients treated with chronic medication including but not limited to anti-retrovirals, tamoxifen, methotrexate, cyclophosphamide, isotretinoin, bile acid binding resins, obeticholic acid, ursodeoxycholic acid or pharmacologic doses of oral glucocorticoids (≥ 10 mg of prednisone per day or equivalent) within 12 weeks of Randomization
• Significant systemic or major illness other than liver disease including:

• Acute coronary syndrome, unstable angina, congestive heart failure, or cerebrovascular event within 24 weeks prior to Randomization
• Major surgery within 12 weeks prior to Randomization
• CNS disorders including Alzheimer's disease or other forms of dementia, seizure disorders and Parkinson's disease
• Autoimmune disease that has required systemic treatment in the 2 years preceding the study screening (i.e., with the use of disease-modifying agents, corticosteroids or immunosuppressive drugs)
• Uncontrolled thyroid disease
• Clinically significant renal dysfunction (estimated GFR < 60 ml/min (CKD equation))
• A history of any clinically significant medical disorder that, in the judgement of the investigator, would interfere with patient treatment, assessment, or compliance with the protocol;
• Known severe allergic or anaphylactic reactions to recombinant therapeutic proteins, fusion proteins, or chimeric, human, or humanized antibodies;
• Patients with any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements.
• Participation in a study of another investigational agent within 28 days or five half-lives of the drug (whichever is longer) prior to screening;
• Prior treatment with CM-101 antibody