NASH - Nonalcoholic Steatohepatitis
Conditions
Brief summary
This is a multi-center evaluation of efruxifermin (EFX) in a randomized, double-blind, placebo-controlled study in cirrhotic subjects with biopsy-proven F4 compensated NASH.
Interventions
DRUGEFX
Investigational drug, Efruxifermin
DRUGPlacebo
Placebo
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Males and non-pregnant, non-lactating females between 18-75 years of age inclusive, based on the date of signing informed consent. * Main Study Only: Previous history or presence of Type 2 diabetes or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose). * Main Study Only: Biopsy-proven compensated cirrhosis due to NASH. * Cohort D Only: Diagnosis of type 2 diabetes * Cohort D Only: Use of GLP-1R agonist for at least 90 days * Cohort D Only: Biopsy-proven liver fibrosis stages 1, 2, or 3
Exclusion criteria
* Main Study Only: Weight loss \> 10% in the 90 days prior to screening until randomization or from the time of collection of the liver biopsy used to assess subject eligibility until randomization, whichever is longer. * Type 1 diabetes or uncontrolled Type 2 diabetes * Cohort D Only: Weight loss \> 5% in the 90 days prior to screening * Cohort D Only: Presence of cirrhosis on liver biopsy Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main: Change From Baseline in Fibrosis With no Worsening Steatohepatitis Assessed by NASH CRN System | Week 36 | Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis at Week 36. No worsening of steatohepatitis was defined as no increase in score for any of the 3 components of NAS. The evaluation of the NAS endpoint was calculated using the following 3 categorical features: steatosis \[0-3\], lobular inflammation \[0-3\], and hepatocellular ballooning \[0-2\]. NAS was derived as the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Main: Resolution of NASH Assessed by the NASH CRN System | Week 36, Week 96 | Proportion of subjects who achieve NASH resolution (defined as a NAS of 0-1 for inflammation and 0 for ballooning) as determined by the NASH CRN criteria at Week 36 and Week 96. |
| Main: Fibrosis Improvement and Resolution of NASH Assessed by the NASH CRN System | Week 36, Week 96 | Proportion of subjects who achieve NASH resolution (defined as a NAS of 0-1 for inflammation and 0 for ballooning) and ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) at Week 36 and Week 96 |
| Main: Change From Baseline in Fibrosis With no Worsening of Steatohepatitis Assessed by the NASH CRN System | Week 96 | Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis at Week 96 |
| Main: Change From Baseline in Fibrosis by NASH CRN System | Week 36, Week 96 | Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) at Week 36 and Week 96 |
| Main: Change From Baseline in S-Pro-C3 | Week 36, Week 48, Week 72, Week 96 | Change from baseline in Serum Pro-C3 (N-terminal type III collagen propeptide), a biomarker of type III collagen formation reflecting fibrogenesis, measured in ug/L. |
| Main: Change From Baseline in Enhanced Liver Fibrosis (ELF) Score | Week 36, Week 48, Week 72, Week 96 | ELF score is a composite serum biomarker score derived from HA, PIIINP, and TIMP-1 concentrations. Scores range approximately from 6 to 16, with higher scores indicating greater liver fibrosis severity. |
| Main: Change From Baseline in Liver Stiffness Assessed by Liver Elastography (kPa) | Week 36, Week 48, Week 72, Week 96 | Change from baseline in liver stiffness assessed by liver elastography (kPa) |
| Main: Change From Baseline in Lipoproteins | Week 36, Week 48, Week 72, Week 96 | Change from baseline in Triglycerides (mg/dL), total cholesterol (mg/dL), high-density lipoprotein (HDL-C) (mg/dL), non-HDL-C (mg/dL), and low-density lipoprotein (LDL-C) (mg/dL) |
| Main: Change From Baseline in HbA1c (%) | Week 36, Week 48, Week 72, Week 96 | Glycated hemoglobin (HbA1c), expressed as a percentage, reflects average blood glucose levels over approximately 2 to 3 months and is used as a measure of glycemic control |
| Main: Change From Baseline in C-peptide (ug/L) | Week 36, Week 48, Week 72, Week 96 | C-peptide reflects endogenous insulin secretion and pancreatic beta-cell function. Change from baseline represents the difference between the post-baseline value and the baseline measurement. |
| Main: Change From Baseline in Adiponectin (mg/L) | Week 36, Week 48, Week 72, Week 96 | Adiponectin is involved in glucose and lipid metabolism and is used as a marker of metabolic status. Change from baseline represents the difference between the post-baseline value and the baseline measurement. |
| Main: Change From Baseline in Insulin (mIU/L) | Week 36, Week 48, Week 72, Week 96 | Insulin reflects endogenous insulin levels measured after a period of fasting. Change from baseline represents the difference between the post-baseline value and the baseline measurement. |
| Main: Change From Baseline in HOMA-IR | Week 36, Week 48, Week 72, Week 96 | HOMA-IR has no fixed upper limit. Values near 1 are typically observed in individuals with normal insulin sensitivity, while progressively higher values indicate increasing insulin resistance. The clinical significance of a given value may vary depending on the population and assay methodology. Change from baseline represents the difference between the post-baseline value and the baseline measurement. |
| Main: Change From Baseline in Body Weight | Week 36, Week 48, Week 96 | Change from baseline in body weight (kg) |
| Main: Number of Participants With ADA Against EFX | Through Week 96 | Detect and measure ADA against EFX |
| Main: To Assess the Safety and Tolerability of EFX | Through Week 96 | Safety and tolerability will be assessed through the reporting of AEs, clinical laboratory tests, ECGs, ultrasounds, vital sign assessments, and concomitant medication usage |
| Cohort D: To Assess the Safety and Tolerability of EFX Compared to Placebo When Added to an Existing GLP-1R Agonist in Subjects With Type 2 Diabetes and Liver Fibrosis Due to NASH | Through Week 12 | Safety and tolerability will be assessed through the reporting of AEs, clinical laboratory assessments, ECGs, ultrasounds, vital sign assessments, and concomitant medication usage |
Countries
Mexico, Puerto Rico, United States
Participant flow
Recruitment details
The Main Study was initiated (first subject screened) on 30 July 2021. The last subject visit occurred on 14 November 2024. Sixty-five sites in North America were activated; 61 sites screened subjects; 182 subjects were enrolled at 47 sites, of which 181 started study drug. Cohort D was a 12-week separate assessment of 32 separate subjects, of which 31 started study drug. Participant flow and key secondary endpoint details related to Cohort D only are presented.
Pre-assignment details
Participants with any of the following were not eligible: weight loss \>10% within 90 days of the eligibility liver biopsy; type 1 diabetes; poorly controlled T2D; significant hypoglycemia; osteoporosis; uncontrolled hypertension; current/history of decompensated liver disease; history of pancreatitis; other causes of liver disease, alcoholic liver disease, or autoimmune disorders; or any medical conditions such that inclusion in the study may not have been in the participant's best interest.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 68 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants |
| Age, Continuous | 60.7 years STANDARD_DEVIATION 8.21 |
| Diagnosis of Cryptogenic Cirrhosis Presumed Secondary to NASH No | 45 Participants |
| Diagnosis of Cryptogenic Cirrhosis Presumed Secondary to NASH Yes | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 66 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaskan Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Other | 9 Participants |
| Race/Ethnicity, Customized Race White | 56 Participants |
| Region of Enrollment Mexico | 4 Participants |
| Region of Enrollment Puerto Rico | 3 Participants |
| Region of Enrollment United States | 55 Participants |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 23 Participants |
| Total NAFLD Activity Score (NAS) Category ≤3 | 66 Participants |
| Total NAFLD Activity Score (NAS) Category >3 | 34 Participants |
| Type 2 Diabetes Status No | 37 Participants |
| Type 2 Diabetes Status Yes | 46 Participants |
| Weight | 100.70 kg STANDARD_DEVIATION 18.893 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 61 | 0 / 57 | 0 / 63 | 0 / 10 | 0 / 21 |
| other Total, other adverse events | 59 / 61 | 56 / 57 | 63 / 63 | 7 / 10 | 18 / 21 |
| serious Total, serious adverse events | 11 / 61 | 15 / 57 | 15 / 63 | 0 / 10 | 2 / 21 |
Outcome results
None listed