MASH With Fibrosis, NASH With Fibrosis
Conditions
Brief summary
This is a multi-center evaluation of efruxifermin (EFX) in a randomized, double-blind, placebo-controlled study in subjects with non-cirrhotic NASH/MASH and fibrosis stage 2 or 3 (F2 or F3). The study will enroll subjects in two cohorts for a total samples size of 1650 subjects.
Detailed description
This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of efruxifermin (EFX) in subjects with non-cirrhotic nonalcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 2 or 3 (F2 or F3). Approximately 1,650 subjects will be enrolled into 2 cohorts. Cohort 1 will enroll approximately 750 subjects with biopsy-confirmed NASH/MASH and fibrosis stage F2 or F3. Subjects in Cohort 1 will undergo evaluation of histologic efficacy endpoints at Week 52. Cohort 2 will enroll approximately 900 subjects with biopsy-confirmed fibrosis stage F3. Subjects in Cohort 2 may enroll regardless of NAFLD Activity Score (NAS). Subjects in Cohort 2 will undergo liver biopsy assessment at Week 96. Eligible subjects will be randomized in a 1:1:1 ratio to receive: * EFX 28 mg administered subcutaneously once weekly * EFX 50 mg administered subcutaneously once weekly * Placebo administered subcutaneously once weekly Subjects will participate in: * a screening period of up to 12 weeks, * a 52-week primary histology endpoint treatment period (Cohort 1), * a 96-week secondary histology endpoint period (Cohort 2), * long-term treatment and clinical outcomes follow-up for up to approximately -240 weeks total treatment duration, and * a follow-up visit approximately 30 days after the last dose of study drug. The study will evaluate the effects of EFX compared with placebo on histologic improvement in NASH/MASH, fibrosis regression, noninvasive markers of liver fibrosis, biochemistry markers of lipidic and glycemic metabolism, liver-related clinical outcomes, and long-term safety. Clinical outcomes assessments include evaluation of liver-related events and all-cause mortality. Key secondary and long-term outcome assessments include evaluation of fibrosis progression, liver stiffness by FibroScan, and Enhanced Liver Fibrosis (ELF) score at prespecified time points including Weeks 96 and 240. Subjects who discontinue study drug may continue study assessments according to the protocol schedule to support long-term efficacy and safety evaluations.
Interventions
DRUGEfruxifermin
Administered by subcutaneous injection
DRUGPlacebo
Administered by subcutaneous injection
Sponsors
Akero Therapeutics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Males and non-pregnant, non-lactating females between 18 - 80 years of age inclusive, based on the date of the screening visit. * Previous history or presence of 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose) or type 2 diabetes. * Cohort 1: Biopsy-proven NASH/MASH. Must have had a liver biopsy obtained ≤ 180 days prior to screening with fibrosis stage 2 or 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least a score of 1 in each of the following NAS components: * Steatosis (scored 0 to 3), * Ballooning degeneration (scored 0 to 2), and * Lobular inflammation (scored 0 to 3). * Cohort 2: Biopsy-proven fibrosis stage 3. Must have had a liver biopsy obtained ≤ 180 days prior to screening. Subjects with NAS \<4 may be enrolled and are not required to meet 1 point in each of the components of NAS.
Exclusion criteria
* Other causes of liver disease based on medical history and/or liver histology and/or central laboratory results. * Presence of cirrhosis on liver biopsy (fibrosis stage 4). * Type 1 or uncontrolled Type 2 diabetes. Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1 Only: Resolution of NASH/MASH and a ≥ 1 stage improvement in fibrosis | 52 Weeks | Based on NAS (scored by 0-3 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = perisinusoidal or periportal fibrosis, 2 = perisinusoidal and portal/periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis) |
| Event-free survival | 240 Weeks | Based on time from randomization to the first clinical event including evidence of disease progression, liver decompensation events, liver transplantation or eligibility for liver transplantation, and all-cause mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1 Only: Resolution of NASH/MASH and no worsening of fibrosis | 52 Weeks | Based on NAS (scored by 0-3 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = perisinusoidal or periportal fibrosis, 2 = perisinusoidal and portal/periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis) |
| Cohort 1 Only: ≥ 1 stage improvement in fibrosis and no worsening of steatohepatitis | 52 Weeks | Based on NAS (scored by 0-3 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = perisinusoidal or periportal fibrosis, 2 = perisinusoidal and portal/periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis) |
| Change from baseline of non-invasive markers of liver fibrosis: ELF score | 52 Weeks | The ELF score measures the severity of liver fibrosis and estimates the risk of disease progression to cirrhosis or liver-related events, with higher scores indicating higher liver fibrosis level and higher risk of disease progression. |
| Change from baseline of non-invasive markers of liver fibrosis: ELF score components (TIMP-1, HA, PIIINP, Pro-C3) | 52 Weeks | Tissue inhibitor of metalloproteinase-1 \[TIMP-1\], hyaluronic acid \[HA\], amino terminal pro-peptide of type 3 procollagen \[PIIINP\]), and propeptide of type 3 procollagen (Pro-C3) |
| Change from baseline in non-invasive markers of liver fibrosis: ELF score | 96 Weeks, 240 Weeks | The ELF score measures the severity of liver fibrosis and estimates the risk of disease progression to cirrhosis or liver-related events, with higher scores indicating higher liver fibrosis level and higher risk of disease progression. |
| Change from baseline in non-invasive markers of liver fibrosis: ELF score components: TIMP-1, HA, PIIINP, Pro-C3 | Week 240 | The ELF score measures the severity of liver fibrosis and estimates the risk of disease progression to cirrhosis or liver-related events, with higher scores indicating higher liver fibrosis level and higher risk of disease progression. |
| Change from baseline of non-invasive markers of liver fibrosis: Fibroscan | 52 Weeks | Liver stiffness assessed by transient elastography (FibroScan) |
| Change from baseline of markers of liver injury: ALT, AST, GGT | 52 Weeks, 240 Weeks | ALT (U/L), AST (U/L), GGT (U/L) |
| Change from baseline of markers of liver injury: Uric Acid | 52 Weeks, 240 Weeks | Uric acid (mg/dL) |
| Change from baseline of lipoproteins: Total cholesterol, TG, Non-HDL-C, HDL-C, and LDL-C | 52 Weeks, 240 Weeks | Total cholesterol (mg/dL), TG (mg/dL), Non-HDL-C (mg/dL), HDL-C (mg/dL), and LDL-C (mg/dL) |
| Change from baseline of markers of insulin sensitivity and glycemic control: HbA1c | 52 Weeks, 240 Weeks | HbA1c (%) |
| Change from baseline of markers of insulin sensitivity and glycemic control: Adiponectin | 52 Weeks, 240 Weeks | Adiponectin (mg/L) |
| Change from baseline of body weight (kg) | 52 Weeks, 240 Weeks | — |
| To assess the safety and tolerability of EFX through the reporting of extent of exposure (weeks) | 52 Weeks, 240 Weeks | — |
| To assess the safety and tolerability of EFX through the reporting of adverse events (severity of events) | 52 Weeks, 240 Weeks | — |
| To assess the safety and tolerability of EFX through the reporting of adverse events (frequency of events) | 52 Weeks, 240 Weeks | — |
| To assess the safety and tolerability of EFX through the reporting of abnormal clinical laboratory tests, ECGs, ultrasounds, vital sign assessments (number of patients) | 52 Weeks, 240 Weeks | — |
| To assess the immunogenicity of EFX through the reporting of antidrug antibodies (number of patients) | 52 Weeks, 240 Weeks | — |
Countries
Argentina, Australia, Canada, France, Germany, India, Israel, Italy, Mexico, Poland, Puerto Rico, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTAkero Study Director
Outcome results
None listed