Leronlimab (PRO 140) in Patients With Nonalcoholic Steatohepatitis

This is a phase II study of of Leronlimab (PRO 140)-Humanized monoclonal antibody to CCR5 in patients with Nonalcoholic Steatohepatitis (NASH).

This is an exploratory phase II, multi-center, two-part study (Part 1: randomized, placebo-controlled, two-arm with 60 patients; Part 2: non-randomized, single-arm, open-label with 30 patients) designed to evaluate the safety and efficacy of leronlimab after subcutaneous (SC) administration in patients with NASH for 13 weeks.

A Follow Up visit was conducted 28 (± 3) days after receiving the last study treatment (i.e., after last dose of Leronlimab (PRO 140) or placebo.

Eligibility Criteria:
Inclusion Criteria: Subjects are required to meet ALL of the following criteria for enrollment into the study:

1. Subject is a male or female between 18 to 75 years of age inclusive.
2. Evidence of nonalcoholic steatohepatitis (NASH) based on one of the following criteria:

   * Criteria 1: Histologically-confirmed diagnosis of NASH on a liver biopsy, or
   * Criteria 2: FibroScan or Shearwave US during screening (or within 6 months before screening) shows kPa ≥7 but \<14 and CAP ≥260.
3. Subject shows presence of hepatic fat fraction as defined by ≥ 8% on MRI-PDFF and cT1 ≥ 800 ms at Screening.
4. Has had a stable body weight (±5%) within 6 months prior to Screening.
5. Body Mass Index (BMI) ≥ 28 kg/m2 at Screening
6. Has clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.
7. Laboratory Screening results as indicated below:

   1. AST:ALT Ratio ≤ 1, if AST or ALT value is \> ULN
   2. Screening Liver enzymes (AST, ALT, and ALK PHOS) \< 5 x ULN.
   3. Total Bilirubin ≤ 1.3 mg/dL (except if Gilbert's Disease)
   4. Platelet count ≥ 150,000/mm3
   5. International normalized ratio (INR) \< 1.3
   6. Estimated Glomerular Filtration Rate (eGFR) ≥ 60/mL/min
   7. Glycosylated hemoglobin (HbA1c) \< 9%.
   8. Thyroid-Stimulating Hormone (TSH) within normal reference range. Note: Any subject with a non-clinically significant TSH value outside of the normal range may be enrolled if their T3 and free T4 values are within the normal range.
8. Subjects with pre-diabetes or type 2 diabetes will be allowed to participate if the following criteria is met:

   * Subjects who are taking anti-diabetic medications should be on a stable dose for a period of at least 3 months prior to Screening and do not anticipate clinically significant dose adjustments during the course of study.
   * Subjects must be on a stable diet/lifestyle regimen for at least 3 months prior to screening and do not anticipate a clinically significant change during the course of study.
9. Subjects who are taking Vitamin E should be on a stable dose of Vitamin E (if ≥ 400 IU) for a period of at least 4 weeks prior to Screening and do not anticipate dose adjustments for the duration of the study.
10. Both male and female patients and their partners of childbearing potential must agree to use two medically accepted methods of contraception (e.g., barrier contraceptives \[male condom, female condom, or diaphragm with a spermicidal gel\], hormonal contraceptives \[implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings\], or one of the following methods of birth control (intrauterine devices, tubal sterilization or vasectomy) or must practice complete abstinence from intercourse of reproductive potential from study entry to 6 months after the last day of treatment (excluding women who are not of childbearing potential and men who have been sterilized).
11. Females of child-bearing potential must have a negative serum pregnancy test at Screening Visit and negative urine pregnancy test prior to receiving the first dose of study drug; and Male participants must agree to use contraception and refrain from donating sperm for at least 90 days after the last dose of study intervention.
12. Subject is willing and able to give informed consent prior to any study specific procedures being performed.
13. Subject is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures and study restrictions

Exclusion Criteria: Subjects meeting ANY of the following criteria will be excluded from enrollment:

1. Any concurrent clinically significant liver disease with an etiology other than NASH including autoimmune hepatitis, alcoholic hepatitis, hypoxic/ischemic hepatopathy, and biliary tract disease.
2. History of alcohol consumption greater than 21/units/week (for males) and 14/units/week (for females) within the last 2 years prior to screening.

   Note: Use of online unit calculator for alcohol consumption is recommended (e.g., https://alcoholchange.org.uk/alcohol-facts/interactive-tools/unit-calculator)
3. Any drug-induced steatohepatitis secondary to amiodarone, corticosteroids, estrogens, methotrexate, tetracycline, or other medications known to cause hepatic steatosis.
4. Undergone major surgery, including liver surgery, within 6 months prior to screening deemed clinically significant by the investigator.
5. Prior or pending liver transplantation.
6. History or presence of cirrhosis or stage 4 fibrosis in historical liver biopsy and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.
7. Active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test), hepatitis C (defined as having a positive Anti-HCV test with detectable reflex HCV RNA; Note: Subject with positive Anti-HCV test and with undetectable HCV RNA would not be excluded), acute hepatitis A (defined as subjects with serum positive for hepatitis A IgM (HAV) antibody) or acute hepatitis E (defined as having anti-HEV IgM antibody).
8. Any active infection requiring systemic therapy at the time of screening, which is considered clinically significant per the Investigator.
9. Positive test for human immunodeficiency virus (HIV) or HIV infection.
10. History of bleeding diathesis within 6 months of screening.
11. Any malignancy within the past 5 years, excluding successfully treated basal cell carcinoma or squamous cell carcinoma without evidence of metastases.
12. Seizure disorder requiring ongoing antiseizure therapy or with any condition that, in the judgment of the investigator, is likely to increase the risk of seizure (e.g. CNS malignancy)
13. Clinically significant active cardiac disease which would interfere with study conduct or study results interpretation per the PI.
14. Any known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. Prior therapy with Leronlimab or any other CCR5 antagonist (e.g. maraviroc) within 6 months prior to screening.
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to humanized monoclonal antibodies.
17. Any condition requiring continuous systemic treatment with immunosuppressive (such as corticosteroids) or immunomodulatory medications.

    Note: Inhaled or topical steroids of up to 5 mg daily prednisone equivalent dose are permitted in the bsence of active autoimmune disease.
18. History of administration of a live, attenuated vaccine within four weeks prior to start of PRO 140 treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study.

    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed. However intranasal influenza vaccines (e.g., Flu-Mist ®) are live attenuated vaccines, and are not allowed.
19. Currently participating in an investigational study or received an investigational drug within 28 days or 5 half-lives (whichever is longer) prior to study drug administration