A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study to Investigate the Safety and Efficacy of Efimosfermin Alfa in Participants With Biopsy-Confirmed F2- or F3-Stage Metabolic Dysfunction-Associated Steatohepatitis (MASH) (ZENITH-1)

Official Summary

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.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 75 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 1,200 participants

Study Arms

• Participants receiving dose level 1 of efimosfermin alfa (EXPERIMENTAL)
• Participants receiving dose level 2 of efimosfermin alfa (EXPERIMENTAL)
• Participants receiving Placebo (PLACEBO_COMPARATOR)

Interventions

• DRUG: Efimosfermin alfa — Efimosfermin alfa will be administered
• DRUG: Efimosfermin alfa — Efimosfermin alfa will be administered
• DRUG: Placebo — Placebo will be administered

Primary Outcomes

• Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of steatohepatitis at Week 52 (At Week 52)
• Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN fibrosis score at Week 52 (At Week 52)
• Time from randomization to an adjudicated composite liver-related clinical outcome (From Randomization (Day 1) to 48 months)

Secondary Outcomes

• Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity (At Week 52 and at Month 48)
• Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity (At Week 52 and at Month 48)
• Number of participants with Grade 3 and Grade 4 laboratory abnormalities (At Week 52 and at Month 48)
• Proportion of participants experiencing resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >=1 stage at Week 52 (At Week 52)
• Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of Steatohepatitis at Month 48 (At Month 48)

Eligibility Criteria

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 x upper limit of normal (ULN)
3. Total bilirubin \>=1.3 milligram per deciliter (mg/dL). Individuals with documented Gilbert's syndrome may be enrolled if they experienced an isolated increase in total bilirubin of \>=1.3 mg/dL and direct bilirubin is \<=20% of total bilirubin; 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. Evidence of infection with any of the following:

    1. Human immunodeficiency virus;
    2. Hepatitis B virus (detectable HBsAg at Screening);
    3. Hepatitis C virus (HCV);
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 Locations

• GSK Investigational Site, Arcadia, California, United States
• GSK Investigational Site, Covina, California, United States
• GSK Investigational Site, Los Angeles, California, United States
• GSK Investigational Site, Santa Maria, California, United States
• GSK Investigational Site, Van Nuys, California, United States
• GSK Investigational Site, Boynton Beach, Florida, United States
• GSK Investigational Site, Cape Coral, Florida, United States
• GSK Investigational Site, Hialeah, Florida, United States
• GSK Investigational Site, Hialeah, Florida, United States
• GSK Investigational Site, Inverness, Florida, United States
• ...and 10 more locations

Contact Information

• US GSK Clinical Trials Call Center — CONTACT
  Phone: 877-379-3718
  Email: GSKClinicalSupportHD@gsk.com
• EU GSK Clinical Trials Call Center — CONTACT
  Phone: +44 (0) 20 89904466
  Email: GSKClinicalSupportHD@gsk.com

Study Officials

• GSK Clinical Trials — STUDY_DIRECTOR
  GlaxoSmithKline

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