A Pivotal Clinical Study to Investigate Efimosfermin Alfa in Participants With Biopsy-confirmed F2- or F3-stage MASH (ZENITH-1)

GlaxoSmithKline (GSK)

Status and phase: Enrolling; Phase 3

Conditions: Non-alcoholic Fatty Liver Disease

Treatments: Drug: Efimosfermin alfa; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT07221227

301160

2025-523675-39 (Other Identifier)

Details and patient eligibility

About

The purpose of this study is to assess the safety and efficacy of efimosfermin alfa in the resolution of steatohepatitis and improvement of liver-related clinical outcome compared to placebo in individuals with MASH and biopsy-confirmed F2- or F3-stage fibrosis.

Enrollment: 1,200 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Able and willing to understand and sign a written informed consent form that must be obtained prior to the initiation of study procedures
2. Age >=18 and <=75 years at enrollment
3. History or presence of 2 or more of the 5 components of metabolic syndrome per American Heart Association definition:
4. Liver biopsy confirmation of MASH consistent with stage F2 or F3 fibrosis and a NAS score >=4 confirmed by a central pathologist

Exclusion criteria

1. Contraindication or ineligibility for percutaneous liver biopsy

2. ALT or AST >=5*upper limit of normal (ULN)

3. Total bilirubin (BILI) >=1.3 milligram per deciliter (mg/dL). Individuals with documented Gilbert's syndrome may be enrolled if they experienced an isolated increase in total BILI of >=1.3 mg/dL and direct BILI is <=20% of total BILI; otherwise, the individual will be excluded.

4. Serum albumin <=3.5 grams per deciliter (g/dL)

5. International normalized ratio (INR) >=1.3 not due to therapeutic anticoagulation. Individuals receiving chronic anticoagulant treatment with higher INR values may be enrolled at the discretion of the Investigator and Study Medical Monitor.

6. Alkaline phosphatase (ALP) >=2*ULN

7. Platelet (PLT) count <140,000 per (/) cubic millimeter (mm^3); individuals with a PLT count between 110,000/mm^3 and 140,000/mm^3 may be enrolled after discussion with the Study Medical Monitor.

8. Serum creatinine >=1.5 mg/dL or creatinine clearance <=60 milliliter (mL)/minute (min)/1.73 square meter by Chronic Kidney Disease Epidemiology Collaboration equation

9. Alpha-fetoprotein >=20 nanogram per milliliter (ng/mL)

10. Glycated hemoglobin >=9.0%

11. Model for End-Stage Liver Disease score >=12 unless the score is elevated in the absence of liver dysfunction (e.g., Gilbert's syndrome)

12. Phosphatidyl ethanol (PEth) >=80 ng/mL at Screening

13. Known co-infection with any of the following:

    1. Human immunodeficiency virus;
    2. Hepatitis B virus;
    3. Hepatitis C virus (HCV);
    4. Hepatitis D virus; or
    5. Hepatitis E virus.

14. Chronic liver disease from any other cause including, but not limited to, alcoholic liver disease; evidence of portal hypertension; viral hepatitis or any history or evidence of cirrhosis on screening liver biopsy; or decompensated liver disease such as clinical ascites, bleeding gastroesophageal varices, hepatorenal syndrome, or hepatic encephalopathy prior to Screening or Day 1.

15. Current or history of excessive alcohol intake for >=3 months within the 12-month period prior to Screening

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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1,200 participants in 3 patient groups, including a placebo group

Participants receiving dose level 1 of efimosfermin alfa

Experimental group

Treatment:

Drug: Efimosfermin alfa

Drug: Efimosfermin alfa

Participants receiving dose level 2 of efimosfermin alfa

Experimental group

Treatment:

Drug: Efimosfermin alfa

Drug: Efimosfermin alfa

Participants receiving Placebo

Placebo Comparator group

Treatment:

Drug: Placebo