Non-cirrhotic metabolic dysfunction-associated steatohepatitis
Conditions
Interventions
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. Injection volumes for the 225-mg and 3
Sponsors
Lochhead Paul
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 - 4 confirmed by a central pathologist
Exclusion criteria
Exclusion criteria: 1. Contraindication or ineligibility for percutaneous liver biopsy 2. ALT or AST >- 5 * upper limit of normal (ULN) 3. 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 - 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 - 1.5 mg/dL or creatinine clearance - 20 ng/mL 10. HbA1c >- 9.0% 11. Model for End-Stage Liver Disease (MELD) score >- 12 unless the score is elevated in the absence of liver dysfunction (eg, Gilbert's syndrome) 12. Phosphatidylethanol (PEth) >- 80 ng/mL at Screening 13. Evidence of infection with any of the following: a. Human immunodeficiency virus b. Hepatitis B virus (detectable HBsAg at Screening) c. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| -Achieving improvement in fibrosis by >- 1 stage and no worsening of steatohepatitis (defined as no increase in NAS score for ballooning, inflammation, or steatosis) at Week 52. -Achieving resolution of steatohepatitis reading and no worsening of MASH CRN score at Week 52. -Time from randomization to an adjudicated composite clinical outcome: liver-related outcome will comprise all-cause mortality; transplantation; and occurrence of significant hepatic events (e.g, liver decompensation; progression to cirrhosis histologically, or as defined by non-invasive tests; and increase in MELD score from - 15). | — |
Secondary
| Measure | Time frame |
|---|---|
| - For all participants at Week 52 and Month 48, - Incidence and severity of TEAEs. - Incidence and severity of TEAEs leading to discontinuation. - Incidence of Grade 3 and Grade 4 laboratory abnormalities. - Achieving resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >- 1 stage (MASH CRN fibrosis score) at Week 52 - Achieving improvement in fibrosis by >- 1 stage and no worsening of steatohepatitis (defined as no increase in NAS score for ballooning, inflammation, or steatosis) at Month 48. - Achieving improvement in fibrosis by >- 2 stages and no worsening of steatohepatitis (defined as no increase in NAS score for ballooning, inflammation, or steatosis) at Week 52 and Month 48. - Achieving resolution of steatohepatitis reading and no worsening of MASH CRN score at Month 48. - Absolute and relative change from baseline to Week 52 and Month 48 in VCTE-LSM and CAP scores for all participants. - Achieving a change from baseline in VCTE-LSM >- 30% at Week 52 and Month 48. - Absolute and relative change from baseline to Week 52 and Month 48 in that subset of participants with MRE scores. - Absolute and relative change from baseline to Week 52 and Month 48 in ELF score for all participants. - Achieving improvement in ELF score of >- 0.5. - Absolute and relative change from baseline to Week 52 and Month 48 in HFF by MRI-PDFF for all participants. - Absolute and relative change from baseline to Week 52 and Month 48 in ALT, AST, and ALT/AST ratio for all participants. - Achieving ALT and HFF normalization at Week 52 and Month 48. - Achieving HFF <- 5%. - Change from baseline to Week 52 and Month 48 in HbA1c for participants with T2DM. - Change from baseline to Week 52 and Month 48 in body weight for all participants. - Change from baseline in fasting total cholesterol, LDL-C, HDL-C, and fasting triglycerides at Week 52 and Month 48 for all participants. - Proportion of all participants with ADAs at Week 52 an | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, France, Germany, Greece, Hong Kong, India, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Poland, Saudi Arabia, Singapore, South Korea, Spain, Taiwan, Turkiye, United Kingdom, United States
Contacts
Public ContactPaul Lochhead
GlaxoSmithKline K.K.
Outcome results
None listed