A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study to Investigate the Safety and Tolerability of Efimosfermin Alfa in Participants With Known or Suspected F2- or F3-Stage Metabolic Dysfunction-Associated Steatohepatitis (MASH) (ZENITH-2)

Official Summary

This study will evaluate the safety and tolerability of Efimosfermin Alfa for participants with known or suspected MASH with fibrosis consistent with stage F2 or F3.

Eligibility Requirements

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

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 1,250 participants

Study Arms

• Efimosfermin Alfa Dose Level 1 (EXPERIMENTAL)
  Participants randomized to this group will receive Efimosfermin Alfa at dose level 1
• Efimosfermin Alfa Dose Level 2 (EXPERIMENTAL)
  Participants randomized to this group will receive Efimosfermin Alfa at dose level 2
• Placebo (PLACEBO_COMPARATOR)
  Participants randomized to this group will receive Placebo

Interventions

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

Primary Outcomes

• Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity (At Week 52)
• Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity (At Week 52)
• Number of participants with Grade 3 and Grade 4 laboratory abnormalities (At Week 52)

Secondary Outcomes

• Absolute Change from Baseline in enhanced liver fibrosis (ELF) score (Baseline (Day 1) and up to Week 52)
• Percent Change from Baseline in ELF score (Baseline (Day 1) and up to Week 52)
• Number of participants achieving an improvement in ELF score greater than equal to 0.5 (At Week 52)
• Absolute Change from Baseline in vibration-controlled transient elastography (VCTE)- liver stiffness measurement (LSM) scores (Baseline (Day 1) and up to Week 52)
• Percent Change from Baseline in VCTE- LSM scores (Baseline (Day 1) and up to Week 52)

Eligibility Criteria

Inclusion Criteria:

* Able and willing to understand and sign a written informed consent form (ICF) that must be obtained prior to the initiation of study procedures
* Age \>=18 through \<=75 years at enrolment
* History or presence of 2 or more of the 5 components of metabolic syndrome per American Heart Association definition
* History or presence of known or suspected MASH with evidence of fibrosis

Exclusion Criteria:

* ALT or AST \>=5 × upper limit of normal (ULN)
* 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.
* Serum albumin \<=3.5 grams per deciliter (g/dL)
* 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.
* Alkaline phosphatase (ALP) \>=2 × ULN
* 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
* 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.
* Alpha-fetoprotein \>=20 nanogram per milliliter (ng/mL)
* HbA1c \>=9.0%
* Model for End-Stage Liver Disease (MELD) 3.0 score \>=12 unless the score is elevated in the absence of liver dysfunction (eg, Gilbert's syndrome)
* Phosphatidylethanol (PEth) \>=80 nanogram per milliliter (ng/mL) at Screening
* Known co-infection with any of the following: a. Human immunodeficiency virus; b. Hepatitis B virus; c. Hepatitis C virus (HCV); d. Hepatitis D virus; or e. Hepatitis E virus.
* 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; or decompensated liver disease such as clinical ascites, bleeding gastroesophageal varices, hepatorenal syndrome, or hepatic encephalopathy prior to Screening or Day 1.
* 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, Cape Coral, Florida, United States
• GSK Investigational Site, Doral, Florida, United States
• GSK Investigational Site, Hialeah, Florida, United States
• GSK Investigational Site, Inverness, Florida, United States
• GSK Investigational Site, Jacksonville, Florida, United States
• GSK Investigational Site, Kissimmee, 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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