Phase 2b study evaluating efficacy, safety and tolerability of study drug called NGM282 (Aldafermin) in Patients with Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis

Phase 1

• Conditions: Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis; MedDRA version: 24.1Level: PTClassification code 10053219Term: Non-alcoholic steatohepatitisSystem Organ Class: 10019805 - Hepatobiliary disorders; MedDRA version: 20.1Level: LLTClassification code 10064844Term: Compensated cirrhosisSystem Organ Class: 10019805 - Hepatobiliary disorders; Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

• Registration Number: EUCTR2019-002341-38-DE
• Lead Sponsor: GM Biopharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-04-09
• Last Update Posted: 8 January 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. Males and females between 18 and 75 years of age, inclusive, who are able to comprehend and willing to sign an Informed Consent Form (ICF).
2. Liver biopsy consistent with a diagnosis of NASH Cirrhosis according to NASH CRN criteria and per the central pathologist evaluation.
a. A historical biopsy is acceptable if tissue slides are available from within 12 months prior to Screening and are acceptable for the central pathologist evaluation.
b. Liver biopsies must be consistent with cirrhosis according to the NASH CRN classification (NASH CRN fibrosis score of 4), as assessed by the central reader (see also Inclusion Criterion 4).
c. NASH must be the etiology of cirrhosis (i.e., no other causes of cirrhosis; see also Inclusion Criterion 4)
d. A limited number of subjects (capped at 10% of planned enrollment) with clinical diagnosis of NASH cirrhosis may be enrolled despite a NASH CRN fibrosis score of 3.(please refer to Protocol)
3. Criterion deleted per Protocol Version 5.0
4.Subjects must have Definitive NASH cirrhosis as defined in Noureddin 2020. (refer to Protocol)
5. AFP = 20 ng/mL at Screening.
6. Negative for hepatic lesions/nodules indicating HCC risk
a. MRI is the preferred imaging modality. There must be no nodules with a Liver Imaging and Reporting Data System (LI-RADS) score of = 2 by central radiologist evaluation.
b. If MRI is not available or not possible to be performed, a multi-phasic CT scan may be used to assess HCC risk. There must be no nodules with
a LI-RADS score = 2 by central radiologist evaluation.
c. If MRI and CT are not available or not possible to be performed for screening a potential subject, then ultrasonography of the liver may be performed:
1) If no hepatic lesions or nodules (local radiologist evaluation) and AFP = 20 ng/mL, the potential subject may be considered further for enrollment.
2) For any findings of hepatic lesions or nodules (local radiologist
evaluation) that are not clearly benign cysts and have not been shown clearly benign by prior CT or MRI, follow up MRI must be performed and meet criteria (no nodules with LI-RADS score of = 2 evaluated centrally) in order for the potential subject to be considered further for enrollment.
7. Subjects with Type 2 Diabetes (T2D) or insulin resistance are permitted as long as diabetic medications are reasonably stable within 3 months prior to Screening, as outlined in Section 6.4.
8. Other concomitant medications/therapies used for the treatment of coexisting conditions (Section 6.4) are acceptable but require a stable regimen for at least 3 months prior to the Screening except for non-statin lipid lowering agents, which can be used until Da1 of
Screening.
9. Statin use is acceptable based on the following criteria, as assessed by the investigator at Screening:
a. Statin-naïve is defined as no administration of statins within 3 months prior to Screening.
b. Statin-Experienced is defined as currently receiving = 50% of the maximal approved dose of statin therapy
i. Requires a reasonably stable statin dosing at least 3 months prior to Screening
10. The following additional laboratory parameters must be met at Screening:
a. Total bilirubin = 1.3 mg/dL
i. If Gilbert's Syndrome, direct bilirubin within ULN.
b. HbA1c = 9.5%.
c. Platelet count = 120,000/mm3. Subjects who meet the Baveno VI criteria with a platelet count >110,000/mm3 and <120,000/mm3 may be enrolled if they meet the expanded Baveno VI criteria (Note: No more than 30% of the remaining p

Exclusion Criteria

1. Other causes of liver disease that are primary, secondary, or otherwise causes of cirrhosis or which may confound the intended patient population according to the investigator, including but not limited to alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders, primary biliary cirrhosis, drug-induced hepatotoxicity, Wilson’s disease, hemochromatosis, and alpha-1-anti-trypsin deficiency based on medical history and/or centralized read of liver histology.
2. Evidence of drug induced steatohepatitis secondary to amiodarone, corticosteroids, estrogens, methotrexate, tetracycline, or other medications known to cause hepatic steatosis.
3. History of hepatic decompensation, including: variceal bleeding, ascites, or hepatic encephalopathy.
4. Prior or pending liver transplantation.
5. Child Pugh class B and C status.
6. Model of end stage liver disease (MELD) score > 12.
7. Evidence of worsening liver disease (defined below) between screening visits (i.e. Day -56 and Day -42) including measures of AST, ALT, alkaline phosphatase (ALP) or total bilirubin (TBL):
8. History of porto-systemic shunt procedure.
9. No evidence of gastroesophageal varices as documented by one of the following assessments:
a. A historical and locally evaluated EGD obtained within 365 days of screening or
b. A locally evaluated EGD conducted during the screening period
10. Clinically significant cardiovascular or cerebrovascular event or new diagnosis within 6 months of Screening, including but not limited to congestive heart failure, myocardial infarction, acute coronary syndrome, revascularization, stroke (hemorrhagic or ischemic), transient ischemic attack (TIA), or implanted defibrillator or pacemaker (for uncomplicated elective, non-biventricular pacemaker procedure, 3 months post procedure will be allowed).
11. Gastric bypass or bariatric surgery in the past 5 years or planned procedure during the study period.
12. History of clinically significant unstable or untreated illness or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol.
13. Documented significant weight change (± 5%) < 3 months prior to Screening.
14. Screening ECG with clinically significant abnormalities that in the investigator's opinion, require evaluation and possible treatment.
15. Positive for HBsAg, antiHIV Ab, or antiHCV Ab plus HCV-RNA. Subjects who are antiHCV Ab- positive but HCV-RNA negative (secondary to treatment or viral clearance) are eligible with at least a 1-year period since documented sustained viral response at Week 12 post-treatment.
16. History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ or breast ductular carcinoma in situ is allowed if appropriately treated within 2 years prior to Screening); subjects under evaluation for suspected malignancy are not eligible. History of hepatocellular carcinoma at any point regardless of treatment or treatment success will be excluded.
17. A positive drug screen (e.g., morphine, heroin, cocaine) will exclude subjects unless it can be clearly explained by a prescribed medication. The diagnosis and prescription must be approved by the Investigator and the Medical Monitor.
18. Significant alcohol intake as measured by a phosphatidylethanol (PEth) level = 200 ng/mL AND significant alcohol use, as determined by the Alcohol Use Disorder

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to evaluate the efficacy and safety of aldafermin compared to placebo.;Secondary Objective: The secondary objectives of this study are to evaluate the efficacy of aldafermin and the effect of aldafermin on pharmacokinetics and on biomarkers of target engagement, fibrogenesis and imaging. ;Primary end point(s): 1. The primary efficacy endpoint is the change in Enhanced Liver Fibrosis (ELF) score from baseline to Week 48 with aldafermin or matched placebo.<br>2. The primary safety endpoint is frequency, severity and timing of adverse events (AEs) and serious adverse events (SAEs). ;Timepoint(s) of evaluation of this end point: end point 1: after 48 weeks of treatment with aldafermin or matched placebo<br>end point 2: throughout the study