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)
Medical condition: Metabolic Dysfunction-Associated Steatohepatitis (MASH) Medical condition in lay language: Metabolic Fatty Liver Inflamation Therapeutic areas: Diseases [C] - Nutritional and Metabolic Diseases [C18]
Overall Design Summary: This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 48-month study of the safety and efficacy of efimosfermin administered every 4 weeks (Q4W) by subcutaneous (SC) injection in adult MASH participants with fibrosis that is consistent with stage F2 or F3. Patients will be randomized using a computerised system/ program. The total time of participation in the study, inclusive of Screening and safety follow-up, is approximately 52 months. Brief Summary: The purpose of this study is to assess the safety and efficacy of monthly efimosfermin injection 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 following a maximum treatment duration of 48 months. Study Arms and Duration: Participants will be enrolled and randomized 1:1:1 to receive 225 mg efimosfermin, 300 mg efimosfermin, or placebo Q4W by SC injection for a period of 48 months, followed by a final follow-up safety assessment at Week 212 of the study. Total time of participation in the study, inclusive of a screening period of up to 3 months and the final safety assessment, is approximately 52 months. Since injection volumes for the 225-mg and 300-mg efimosfermin arms are 1.5 mL and 2.0 mL, respectively, additional measures will be implemented to preserve the study's blinding.
1. Able and willing to understand and sign a written ICF 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 (Grundy et al, 2005): 3.1. Obesity/overweight (BMI ≥ 25 kg/m2 ; BMI ≥ 23 kg/m2 for Asian regions) or waist circumference of ≥ 40 inches (102 cm) for men and ≥ 35 inches (89 cm) for women 3.2. Increased triglycerides: ≥ 150 mg/dL (1.7 mmol/L) or taking medications to lower triglycerides 3.3. Reduced HDL cholesterol: males, ≤ 1.03 mmol/L (40 mg/dL); females, ≤ 1.29 mmol/L (50 mg/dL) 3.4. Elevated fasting glucose (≥100 mg/dL), or on drug treatment for elevated glucose 3.5. Hypertension 4. Magnetic resonance imaging (MRI)-derived proton density fat fraction (PDFF)≥ 8% for new or historical analysis submitted to the central reader ≤ 3 months before randomization Note: MRI-PDFF assessment will be conducted at Screening if a historical value determined within 3 months prior to randomization is not available. 5. Vibration-controlled transient elastography (VCTE™)-liver stiffness measurement (LSM) ≥ 8.0 kPa and < 20 kPa with a controlled attenuation parameter (CAP™) score of ≥ 285 dB/m ≤ 3 months prior to randomization 6. Stable body weight for the past 6 months (change ≤ 5%) 7. Liver biopsy confirmation of MASH consistent with stage F2 or F3 fibrosis and a NAS score ≥ 4 confirmed by a central pathologist 7.1. If a historical liver biopsy was performed ≤ 6 months before Screening, the individual may proceed with Screening if the following conditions are confirmed: 7.1.1. The biopsy has been reviewed by a central pathologist and is consistent with the inclusion criteria. 7.1.2. No concomitant investigational drugs are being received. Note: All previous investigational drugs used for MASH should have been discontinued ≥ 6 months before the historical liver biopsy and should not be used for the 6 mo
Liver Biopsy 1. Contraindication or ineligibility for percutaneous liver biopsy Laboratory and Imaging Findings 2. Vitamin D ≤ 12 ng/mL. Individuals with values > 12 ng/mL but < 20ng/mL should agree to receive vitamin D supplementation according to the standard of care or local guidelines to ensure rapid repletion. 3. ALT or AST ≥ 5 × upper limit of normal (ULN) 4. Total bilirubin ≥ 1.3 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. 5. Serum albumin ≤ 3.5 g/dL 6. 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 CONFIDENTIAL 301160 Protocol Amendment 1 Final 14 Jan 2026 55 7. Alkaline phosphatase (ALP) ≥ 2 × ULN 8. Hemoglobin (Hb) ≤ 11.0 g/dL for males and ≤ 10.0 g/dL for females 9. Neutrophils ≤ 1500/mm3 (Black participants: ≤ 1200/mm3 ); individuals with documented benign ethnic neutropenia may be enrolled at the discretion of the Study Medical Monitor. 10. Platelet (PLT) count < 140,000/mm3; individuals with a PLT count between 110,000/mm3 and 140,000/mm3 may be enrolled after discussion with the Study Medical Monitor. 11. Serum creatinine ≥ 1.5 mg/dL or creatinine clearance ≤ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation (2021). 12. Alpha-fetoprotein ≥ 20 ng/mL 13. Thyroid-stimulating hormone outside the normal reference range unless free thyroxine value is within the normal range 14. Triglycerides ≥ 500 mg/dL 15. HbA1c ≥ 9.0% 16. Model for End-Stage Liver Disease (MELD) score ≥ 12 unless the score is elevated in the absence of liver dysfunction (eg, Gilbert’s syndrome) 17. Phosphatidylethanol (PEth) ≥ 80 ng/mL at Screening Medical Histo