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

Phase 3RecruitingNCT07221227

GlaxoSmithKline1,200 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

1,200

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Efimosfermin alfaDRUG

Efimosfermin alfa will be administered

Efimosfermin alfaDRUG

Efimosfermin alfa will be administered

PlaceboDRUG

Placebo will be administered

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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

Locations (1)

GSK Investigational Site

Miami, Florida, United States

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: At Week 52

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.

Time frame: At Week 52

Time from randomization to an adjudicated composite liver-related clinical outcome

Liver-related outcome will be comprised of all-cause mortality; transplantation; occurrence of significant hepatic events..

Time frame: From Randomization (Day 1) to 48 months

Secondary Outcomes

Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity

Time frame: At Week 52 and at Month 48

Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity

Time frame: At Week 52 and at Month 48

Central Contacts

US GSK Clinical Trials Call Center

CONTACT

877-379-3718 GSKClinicalSupportHD@gsk.com

EU GSK Clinical Trials Call Center

CONTACT

+44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Number of participants with Grade 3 and Grade 4 laboratory abnormalities

Time frame: 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

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

Time frame: At Week 52

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.

Time frame: At Month 48

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

Time frame: At Week 52 and Month 48

Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN score at Month 48

Time frame: At Month 48

Absolute change from Baseline in vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM)

Time frame: Baseline (Day 1), Week 52 and Month 48

Percent Change from Baseline in VCTE-LSM

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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).

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

Percent Change from Baseline in ELF Score

Time frame: Baseline (Day 1), Week 52 and Month 48

Proportion of participants experiencing improvement in ELF score of >=0.5

Time frame: At Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

Absolute change from Baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (International units per liter)

Time frame: Baseline (Day 1), Week 52 and Month 48

Percent Change from Baseline in ALT and AST (International units per liter)

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

Proportion of participants experiencing ALT and HFF normalization at Week 52 and Month 48

Time frame: At Week 52 and Month 48

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.

Time frame: At Week 52 and Month 48

Change from Baseline in glycated hemoglobin (HbA1c) (Percentage of HbA1c) in participants with Type 2 Diabetes Mellitus (T2DM)

Time frame: Baseline (Day 1), Week 52 and Month 48

Change from Baseline in body weight (kilograms)

Time frame: Baseline (Day 1), Week 52 and Month 48

Change from Baseline in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)- cholesterol, and triglycerides (Millimoles per liter)

Time frame: Baseline (Day 1), Week 52 and Month 48

Proportion of participants with antidrug and antiFGF21 antibody (ADA)

Time frame: At Week 52 and Month 48

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 "present always" while a score of 7 means the symptom is "never present". 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.

Time frame: Baseline (Day 1), Week 52 and Month 48

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.

Time frame: Baseline (Day 1), Week 52 and Month 48

Serum drug Concentration of efimosfermin alfa

Time frame: Up to Month 48

Maximum serum drug concentration (Cmax) of efimosfermin alfa

Time frame: Up to Month 48

Area under the serum concentration-time curve (AUC) of efimosfermin alfa

Time frame: Up to Month 48

Average serum drug concentration (Cavg) of efimosfermin alfa

Time frame: Up to Month 48

Serum concentration of study drug at the end of the dosing interval (Ctrough) of efimosfermin alfa

Time frame: Up to Month 48

Exposure-response relationship for efimosfermin alfa

To evaluate the correlation between pharmacokinetics (PK) derived from plasma concentrations, and biomarker responses, safety, and efficacy.

Time frame: Baseline (Day 1), Week 52 and Month 48