Study of ADI-PEG 20 Versus Placebo in Subjects With NASH

A Phase 2A, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial of ADI-PEG 20 or Placebo in Subjects With Nonalcoholic Steatohepatitis (NASH)

Evaluate efficacy and safety of ADI-PEG 20 in patients with NASH

Study Overview

• Status: Recruiting
• Conditions: Nonalcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Drug: ADI-PEG20; Other: Placebo

Detailed Description

The safety of ADI-PEG 20 will be assessed during the study through the reporting of adverse events (AEs), clinical laboratory tests, electrocardiogram (ECG), vital sign assessments, body weight, and concomitant medication usage.

An external Data Safety and Monitoring Committee (DSMB) that consists of two hepatologists and a statistician will review the safety of the study. The DSMB will convene after 10 subjects (approximately 5 per treatment group) have completed the Week 4 assessments. The DSMB will receive all reports of serious adverse events (SAEs) and convene as needed to monitor for safety.

The primary efficacy will be assessed via the absolute change from baseline in hepatic fat fraction measured by MRI-PDFF at Week 24.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Silvia Lee; Phone Number: 142 02-2656-2727; Email: silvialee@polarispharma.com

Study Locations

• Taiwan
  • Taiwan
    • Chiayi City, Taiwan, Taiwan, 600566
      • Recruiting
      • Ditmanson Medical Foundation Chiayi Christian Hospital；Chiayi Christian Hospital (CYCH)
      • Contact: Perry Weng; Phone Number: 2535 886-5-276-5041; Email: cych06629@gmail.com
    • Kaohsiung, Taiwan, Taiwan, 807
      • Recruiting
      • Kaohsiung Medical University Chung-Ho Memorial Hospital(KMUH)
      • Contact: Feng Yufeng; Phone Number: 6770 886-7-312-1101; Email: fatfat0520@gmail.com
    • Kaohsiung, Taiwan, Taiwan, 824
      • Recruiting
      • E-Da Hospital (EDH)
      • Contact: Chih-Wen Lin; Phone Number: 251179 886-7-6150011; Email: lincw66@gmail.com
    • Kaohsiung, Taiwan, Taiwan, 833
      • Recruiting
      • Chang Gung Medical Foundation-Kaohsiung (CGMF-KS)
      • Contact: Sheng-Nan Lu; Phone Number: 6161 886-7-7317123; Email: juten@ms17.hinet.net
    • Keelung, Taiwan, Taiwan, 204
      • Recruiting
      • Chang Gung Medical Foundation-Keelung (CGMF-KL)
      • Contact: Li-Wen Chen; Phone Number: 6203 886-2-24313131; Email: leiwei@cgmh.org.tw
    • Tainan City, Taiwan, Taiwan, 704
      • Recruiting
      • National Cheng Kung University Hospital (NCKUH)
      • Contact: Ying Ru Lu; Phone Number: 4220 886-6-2353535; Email: ruby10808076@gmail.com
    • Taipei, Taiwan, Taiwan, 100229
      • Recruiting
      • National Taiwan University Hospital (NTUH)
      • Contact: Chun-Hui Fu; Phone Number: 66384 +886-2-23123456; Email: jiun0924@gmail.com
    • Taipei, Taiwan, Taiwan, 112201
      • Recruiting
      • Taipei Veterans General Hospital (TPVGH)
      • Contact: Ying-Luan Wang; Phone Number: 886-958661767; Email: ine0213@yahoo.com.tw
    • Taipei, Taiwan, Taiwan, 243
      • Recruiting
      • Fu Jen Catholic University Hospital (FJCUH)
      • Contact: Chi-Yang Chang; Phone Number: 28880 886-2-85128888; Email: chiyang1112@gmail.com
    • Taoyuan District, Taiwan, Taiwan, 333
      • Recruiting
      • Chang Gung Medical Foundation-Linkou (CGMF-LK)
      • Contact: Chau-Ting Yeh; Phone Number: 8121 886-3-3281200; Email: chauting@cgmh.org.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males and non-lactating, pregnancy test negative females between 18 - 80 years of age with biopsy proven F1 - F4 (compensated cirrhosis, Child-Pugh A, score ≤6) NASH. Limit F1 fibrosis to ≤ 20% of total subject population.
2. Willingness to use appropriate contraceptive measures throughout study treatment and for 90 days thereafter (see Appendix A).
3. Body mass index (BMI) > 23 kg/m2
4. Must have confirmation of ≥ 5 % liver fat content on MRI-PDFF at screening.

5. Biopsy-proven NASH confirmed by a central pathologist. Must have had a liver biopsy either during the screening period or a historical biopsy conducted within the last 6 months prior to pre-screening with fibrosis stage 1 to 4 (F score, F1-F4) and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least a score of 1 in each of the following NAS components:

   1. Steatosis (scored 0 to 3),
   2. Ballooning degeneration (scored 0 to 2), and
   3. Lobular inflammation (scored 0 to 3).
6. Must have no evidence of worsening of ALT and AST (within 50%) measurements within 2 months prior to screening (-8 weeks) visits.

7. Screening laboratory parameters, as determined by the central laboratory:

   1. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft- Gault equation;
   2. HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 μmol if HbA1c is unable to be resulted);
   3. Hemoglobin ≥ 11 g/dL;
   4. INR ≤ 1.3, unless due to therapeutic anticoagulation;
   5. Direct bilirubin ≤ 0.5 mg/dL;
   6. Total bilirubin ≤ 1.3 x upper limit of normal (ULN), unless due to an alternate etiology such as Gilbert's syndrome or hemolytic anemia;
   7. Creatinine kinase < 3 x ULN;
   8. Platelet count ≥ 150,000/μL;
   9. Serum triglyceride level ≤ 500 mg/dL;
   10. ALT < 6 x ULN;
   11. AST < 6 x ULN;
   12. ALP < 2 x ULN.
8. FibroScan® measurement > 7.0 kPa and < 20.0 kPa.
9. Subjects on non-insulin dependent diabetic, weight loss, or lipid-modifying medication(s) must be on stable dose(s) for at least 3 months prior to the diagnostic liver biopsy through randomization.
10. Subjects on vitamin E and pioglitazone must maintain a stable dosage before the diagnostic liver biopsy and during the study period.

Exclusion Criteria:

1. Weight gain or loss > 5% in the 3 months prior to randomization or > 10% in the 6 months prior to screening.
2. Type 1 and insulin-dependent Type 2 diabetes.
3. Poorly controlled hypertension (blood pressure [BP] > 160/100 mmHg).
4. Prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal bleeding.
5. Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive.
6. Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic acid [RNA] positive). Subjects cured of HCV infection less than 1 year prior (based on date of RNA polymerase chain reaction [PCR] negative confirmation following conclusion of treatment) to the screening visit are not eligible.
7. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y gastric bypass), surgery reversal or removal of intragastric balloon > 2 years prior to enrollment would be eligible.
8. Other causes of liver disease based on medical history and/or centralized review of liver histology, including but not limited to alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment.
9. History of liver transplantation.
10. Subjects with primary cancer, including co-existent second malignancy, with the exception of primary solid tumor with no known active disease present in the opinion of the Investigator which will not affect subject outcome in the setting of current diagnosis.
11. Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per day for men. An alcoholic drink is defined as 12 ounces of regular beer, which is usually about 5% alcohol, 5 ounces of wine, which is typically about 12% alcohol, and 1.5 ounces of distilled spirits, which is about 40% alcohol.
12. Human immunodeficiency virus (HIV) infection.
13. Unstable cardiovascular disease in the 6 months prior to screening.
14. Life expectancy less than 2 years.
15. Use of any investigational medication within 30 days or within 5 half-lives of the investigational medication, whichever is longer, prior to screening and throughout the study is prohibited.
16. Subjects with a history of (12 months prior to baseline) or current use of prescription drugs associated with liver steatosis (e.g., methotrexate, amiodarone, high-dose estrogen, tamoxifen, systemic steroids, anabolic steroids, valproic acid) should be excluded. However, subjects currently using silymarin should maintain their current dosage throughout the trial period.
17. Contraindication of magnetic resonance imaging. These include but are not limited to devices or metal foreign bodies, such as Pacemaker, defibrillator or wires other than sternal wires, metallic foreign body in the eye, "triggerfish" contact lens, gastric reflux device, and insulin pumps.
18. MELD score >12
19. Subjects with esophageal or gastric varices with recent bleeding episodes (within 1 year).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug: ADI-PEG 20; Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM)	Drug: ADI-PEG20; Treatment for NASH; Other Names: Pegargiminase
Placebo Comparator: Drug: Placebo; Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM)	Other: Placebo; Treatment for NASH

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine Efficacy of ADI-PEG 20 vs Placebo in the treatment of fatty liver as assessed by change in hepatic fat fraction	Evaluate absolute change from baseline in hepatic fat fraction assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 24	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the Efficacy of ADI-PEG 20 vs Placebo reflected in the percent change from baseline in hepatic fat fraction at week 24	Evaluate percent change from baseline in hepatic fat fraction assessed by MRI-PDFF at Week 24	24 Weeks
Assess the safety of ADI-PEG 20 in subjects with NASH	Evaluate the change from baseline in ALT at Weeks 12 and 24.	24 Weeks
Assess the safety and tolerability of ADI-PEG 20 in subjects with NASH	Laboratory tests and clinical adverse events	24 Weeks

Collaborators and Investigators

• Sponsor: Polaris Group
• Investigators: Study Director: John S Bomalaski, Polaris Group

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: January 20, 2023
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Estimated): September 23, 2025
• Last Update Submitted That Met QC Criteria: September 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Arginine; Nonalcoholic Steatohepatitis (NASH); ADI-PEG 20; Arginine Deiminase; Pegargiminase
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; ADI PEG20
• Other Study ID Numbers: POLARIS2023-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No