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

Recruitment Status
RECRUITING
(See Contacts and Locations)Verified June 2026 by GlaxoSmithKline
Sponsor
GlaxoSmithKline
Information Provided by (Responsible Party)
GlaxoSmithKline
Clinicaltrials.gov Identifier
NCT07221227
Other Study ID Numbers:
301160
First Submitted
October 14, 2025
First Posted
October 26, 2025
Last Update Posted
July 26, 2026
Last Verified
June 2026

ClinicalTrials.gov processed this data on July 2026. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

Condition or DiseaseIntervention/Treatment
Non-alcoholic Fatty Liver Disease
Drug: Efimosfermin alfaDrug: Efimosfermin alfaDrug: Placebo

Study Design

Study TypeInterventional
Actual Enrollment1200 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingDouble
Primary PurposeTreatment
Official TitleA 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)
Study Start DateOctober 23, 2025
Actual Primary Completion Date1yr 7mos from now
Actual Study Completion Date5yrs 4mos from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Participants receiving dose level 1 of efimosfermin alfa
Drug: Efimosfermin alfa
Efimosfermin alfa will be administered
Participants receiving dose level 2 of efimosfermin alfa
Drug: Efimosfermin alfa
Efimosfermin alfa will be administered
Participants receiving Placebo
Drug: Placebo
Placebo will be administered

Outcome Measures

Primary Outcome Measures
  1. Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of steatohepatitis at Week 52
    Proportion of participants experiencing improvement in fibrosis of greater than or equal to (\>=) 1 stage by MASH clinical research network (CRN) fibrosis scores and no worsening of steatohepatitis (defined as no increase in nonalcoholic fatty liver disease activity score \[NAS\] for ballooning, inflammation, or steatosis) at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity.
  2. Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN fibrosis score at Week 52
    Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. NAS score ranges from 0 to 8, higher score indicates worse disease activity. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity.
  3. Time from randomization to an adjudicated composite liver-related clinical outcome
    Liver-related outcome will comprised of all-cause mortality; transplantation; occurrence of significant hepatic events.
Secondary Outcome Measures
  1. Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity
  2. Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity
  3. Number of participants with Grade 3 and Grade 4 laboratory abnormalities
  4. Proportion of participants experiencing resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >=1 stage at Week 52
    Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis on overall histopathological reading on liver biopsies. Proportion of participants experiencing improvement in fibrosis of \>=1 stage by MASH CRN fibrosis scores and resolution of steatohepatitis on overall histopathological reading at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity
  5. Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of Steatohepatitis at Month 48
    Proportion of participants experiencing improvement in fibrosis of \>=1 stage by MASH CRN fibrosis scores and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Month 48 will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity.
  6. Proportion of participants experiencing improvement in fibrosis by >=2 stage and no worsening of Steatohepatitis at Week 52 and Month 48
    Proportion of participants experiencing improvement in fibrosis of \>=2 stage by MASH CRN fibrosis scores and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at at Week 52 and Month 48 will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity
  7. Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN score at Month 48
    Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. NAS score ranges from 0 to 8, higher score indicates worse disease activity. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity.
  8. Absolute change from Baseline in vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM)
  9. Percent change from Baseline in VCTE-LSM
  10. Absolute change from Baseline in controlled attenuation parameter (CAP) scores
    The CAP score is measured by FibroScan, will be used to quantify and detect liver fat. CAP less than (\<) 238 decibel-milliwatts (dB/m) indicated no hepatic steatosis, 238 less than or equal to (\<=) CAP \<=259 dB/m denoted mild steatosis, 260 \<=CAP \<=291 dB/m indicated moderate steatosis, and CAP greater than (\>) 291 dB/m denoted severe steatosis.
  11. Percent change from Baseline in CAP scores
    The CAP score is measured by FibroScan, will be used to quantify and detect liver fat. CAP \<238 dB/m indicated no hepatic steatosis, 238 \<=CAP \<=259 dB/m denoted mild steatosis, 260 \<=CAP \<=291 dB/m indicated moderate steatosis, and CAP \>291 dB/m denoted severe steatosis.
  12. Proportion of participants achieving Change from Baseline in VCTE-LSM >=30 percent (%) at Week 52 and Month 48
    VCTE-LSM is a non-invasive test that uses vibration-controlled transient elastography to measure the stiffness of the liver in kilopascal (kPa).
  13. Absolute change from Baseline in magnetic resonance elastography (MRE) scores
    MRE is a non-invasive imaging technique that combine magnetic resonance imaging (MRI) scanning with low-frequency mechanical vibrations to measure the stiffness of liver. MRE scores \<2.5 is normal, 2.5 - 3.0 Normal or inflammation, 3.0 - 3.5 Stage 1-2 fibrosis, 3.5 - 4.0 Stage 2-3 fibrosis, 4.0 - 5.0 Stage 3-4 fibrosis and \> 5.0 Stage 4 fibrosis.
  14. Percent change from Baseline in MRE Score
    MRE is a non-invasive imaging technique that combine MRI scanning with low-frequency mechanical vibrations to measure the stiffness of liver. MRE scores \<2.5 is normal, 2.5 - 3.0 Normal or inflammation, 3.0 - 3.5 Stage 1-2 fibrosis, 3.5 - 4.0 Stage 2-3 fibrosis, 4.0 - 5.0 Stage 3-4 fibrosis and \> 5.0 Stage 4 fibrosis.
  15. Absolute change from Baseline in Enhanced Liver Fibrosis (ELF) Score
    The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers. The ELF score is used as a prognostic marker for disease progression: ELF score \<9.8: Low risk of progression, ELF score 9.8 to \<11.3: Moderate risk of progression and ELF score \>=11.3: High risk of progression.
  16. Percent change from Baseline in ELF Score
    The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers. The ELF score is used as a prognostic marker for disease progression: ELF score \<9.8: Low risk of progression, ELF score 9.8 to \<11.3: Moderate risk of progression and ELF score \>=11.3: High risk of progression.
  17. Proportion of participants experiencing improvement in ELF score of >=0.5
    The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers. The ELF score is used as a prognostic marker for disease progression: ELF score \<9.8: Low risk of progression, ELF score 9.8 to \<11.3: Moderate risk of progression and ELF score \>=11.3: High risk of progression.
  18. Absolute change from Baseline in hepatic fat fraction (HFF) by MRI-derived proton density fat fraction (PDFF)
    HFF is the percentage of fat in the liver measured by MRI proton density fat fraction technique, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver.
  19. Percent change from Baseline in HFF by MRI-PDFF
    HFF is the percentage of fat in the liver measured by MRI proton density fat fraction technique, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver.
  20. Absolute change from Baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (International units per liter)
  21. Percent change from Baseline in ALT and AST (International units per liter)
  22. Absolute change from Baseline in ALT and AST ratio (ALT/AST)
    ALT/AST ratio is calculated as ALT/AST ratio equal to ALT divided by AST.
  23. Percent change from Baseline in ALT and AST ratio (ALT/AST)
    ALT/AST ratio is calculated as ALT/AST ratio equal to ALT divided by AST.
  24. Proportion of participants experiencing ALT and HFF normalization at Week 52 and Month 48
  25. Proportion of participants experiencing HFF <=5% at Week 52 and Month 48
    HFF is the percentage of fat in the liver measured by MRI proton density fat fraction technique, which ranges from 0-75%. Less than or equal to 5% is considered normal (no significant fatty infiltration (steatosis) in the liver.
  26. Change from Baseline in glycated hemoglobin (HbA1c) (Percentage of HbA1c) in participants with Type 2 Diabetes Mellitus (T2DM)
  27. Change from Baseline in body weight (kilograms)
  28. Change from Baseline in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)- cholesterol, and triglycerides (Millimoles per liter)
  29. Proportion of participants with antidrug and antiFGF21 antibody (ADA)
  30. Change from Baseline in Chronic Liver Disease Questionnaire-Nonalcoholic Steatohepatitis (CLDQ-NASH) in domain and total score
    CLDQ-NASH is a NASH-specific health-related quality of life (HRQoL) Patient-Reported Outcomes (PRO) designed to assess 6 health domains over 36 items: abdominal symptoms (3 items), activity/energy (5 items), emotional health (9 items), fatigue (6 items), systemic symptoms (6 items) and worry (7 items). The domain scores range from 1 to 7, higher scores indicating better HRQoL. A score of 1 meaning the symptom being assessed is &quot;present always&quot; while a score of 7 means the symptom is &quot;never present&quot;. The total score can range from 36 to 252, a higher score corresponds to a better quality of life while a lower score corresponds to a worse quality of life.
  31. Change from Baseline in Short Form-36 (SF-36) component and domain scores at Week 52 and Month 48
    SF-36 is a generic HRQoL PRO designed to assess 8 health domains over 36 items: physical functioning (10 items), bodily pain (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), general health (5 items), mental health (5 items), social functioning (2 items), and vitality (4 items). Each domain is scored from 0 (poorer health) to 100 (better health). SF-36 is scored into 8 domains and 2 component scores: physical component summary (PCS) and mental component summary (MCS). The domain and component scores range from 0 to 100, with higher scores indicating better HRQoL.
  32. Serum drug Concentration of efimosfermin alfa

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
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

Contacts and Locations

Sponsors and CollaboratorsGlaxoSmithKline
Locations
GSK Investigational Site | Chandler Arizona, United States, 85224GSK Investigational Site | Tucson Arizona, United States, 85712GSK Investigational Site | Little Rock Arkansas, United States, 72211GSK Investigational Site | Arcadia California, United States, 91006GSK Investigational Site | Covina California, United States, 91723GSK Investigational Site | Folsom California, United States, 95630GSK Investigational Site | Los Angeles California, United States, 90057GSK Investigational Site | Montclair California, United States, 91763GSK Investigational Site | Riverdale California, United States, 30274GSK Investigational Site | San Diego California, United States, 92120GSK Investigational Site | Santa Maria California, United States, 93458GSK Investigational Site | Van Nuys California, United States, 91405GSK Investigational Site | Colorado Springs Colorado, United States, 80907GSK Investigational Site | Boynton Beach Florida, United States, 33435GSK Investigational Site | Cape Coral Florida, United States, 33914GSK Investigational Site | Clermont Florida, United States, 34711GSK Investigational Site | Fort Myers Florida, United States, 33912GSK Investigational Site | Hialeah Florida, United States, 33016GSK Investigational Site | Hialeah Florida, United States, 33016GSK Investigational Site | Homestead Florida, United States, 33033GSK Investigational Site | Inverness Florida, United States, 34452GSK Investigational Site | Jacksonville Florida, United States, 32216GSK Investigational Site | Kissimmee Florida, United States, 34744GSK Investigational Site | Lakeland Florida, United States, 33803GSK Investigational Site | Maitland Florida, United States, 32751GSK Investigational Site | Miami Florida, United States, 33135GSK Investigational Site | Miami Florida, United States, 33144GSK Investigational Site | Miami Florida, United States, 33155GSK Investigational Site | Miami Florida, United States, 33156GSK Investigational Site | Miami Florida, United States, 33173GSK Investigational Site | Miami Florida, United States, 33176GSK Investigational Site | Miami Florida, United States, 33184GSK Investigational Site | Miami Lakes Florida, United States, 33014GSK Investigational Site | Ocala Florida, United States, 34471GSK Investigational Site | Palmetto Bay Florida, United States, 33157GSK Investigational Site | Sarasota Florida, United States, 34201GSK Investigational Site | Marietta Georgia, United States, 30060GSK Investigational Site | Topeka Kansas, United States, 66606GSK Investigational Site | Bastrop Louisiana, United States, 71220GSK Investigational Site | Marrero Louisiana, United States, 70072GSK Investigational Site | Kansas City Missouri, United States, 64131GSK Investigational Site | Springfield Missouri, United States, 62703GSK Investigational Site | St Louis Missouri, United States, 63141GSK Investigational Site | Las Vegas Nevada, United States, 89106GSK Investigational Site | East Syracuse New York, United States, 13057GSK Investigational Site | New York New York, United States, 10036GSK Investigational Site | New York New York, United States, 10036GSK Investigational Site | Fayetteville North Carolina, United States, 28304GSK Investigational Site | Morehead City North Carolina, United States, 28557GSK Investigational Site | Akron Ohio, United States, 44320GSK Investigational Site | Springboro Ohio, United States, 45066GSK Investigational Site | Westlake Ohio, United States, 44145GSK Investigational Site | Chattanooga Tennessee, United States, 37421GSK Investigational Site | Arlington Texas, United States, 76012GSK Investigational Site | Austin Texas, United States, 78704GSK Investigational Site | Austin Texas, United States, 78757GSK Investigational Site | Austin Texas, United States, 78759GSK Investigational Site | Bellaire Texas, United States, 77401GSK Investigational Site | Brownsville Texas, United States, 78526GSK Investigational Site | Dallas Texas, United States, 75243GSK Investigational Site | DeSoto Texas, United States, 75115GSK Investigational Site | Houston Texas, United States, 77004GSK Investigational Site | Irving Texas, United States, 75061GSK Investigational Site | Richmond Texas, United States, 77406GSK Investigational Site | San Antonio Texas, United States, 78209GSK Investigational Site | San Antonio Texas, United States, 78215GSK Investigational Site | San Antonio Texas, United States, 78229GSK Investigational Site | Seabrook Texas, United States, 77586GSK Investigational Site | Sugar Land Texas, United States, 77479GSK Investigational Site | Tomball Texas, United States, 77375GSK Investigational Site | Waco Texas, United States, 76710GSK Investigational Site | Waco Texas, United States, 76712GSK Investigational Site | West Jordan Utah, United States, 84088GSK Investigational Site | Manassas Virginia, United States, 20110GSK Investigational Site | Norfolk Virginia, United States, 23502GSK Investigational Site | Seattle Washington, United States, 98105GSK Investigational Site | Broadmeadow New South Wales, Australia, 2292GSK Investigational Site | Heidelberg Victoria, Australia, 3084GSK Investigational Site | Québec Quebec, Canada, G1N 4V3GSK Investigational Site | Pokfulam , Hong Kong, GSK Investigational Site | Gifu , Japan, 503-8502GSK Investigational Site | Kanagawa , Japan, 215-0026GSK Investigational Site | Kyoto , Japan, 602-8566GSK Investigational Site | Musashino , Japan, 180-8610GSK Investigational Site | Yokohama , Japan, 236-0004GSK Investigational Site | Wellington , New Zealand, 6021GSK Investigational Site | San Juan , Puerto Rico, 00927GSK Investigational Site | Riyadh , Saudi Arabia, 11472GSK Investigational Site | Chiayi City , Taiwan, 600GSK Investigational Site | Kaohsiung City , Taiwan, 80756GSK Investigational Site | Kaohsiung City , Taiwan, 83301
Investigators
Study Director: GSK Clinical Trials, GlaxoSmithKline