Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Efruxifermin in Non-Cirrhotic NASH/MASH with Fibrosis
- Trial ID
- 2023-505141-48-00
- Protocol
- AK-US-001-0105
- Sponsor
- Akero Therapeutics Inc.
Trial statistics
Objectives
The primary objective of this study is to evaluate the effect of **Efruxifermin** (EFX) compared to placebo on achieving resolution of Non-Alcoholic Steatohepatitis (NASH) or Metabolic Dysfunction-Associated Steatohepatitis (MASH) and regression of fibrosis at Week 52 in Cohort 1. Additionally, the study aims to assess the impact of EFX on all-cause mortality and liver-related clinical outcomes by measuring the time to the first occurrence of predefined, adjudicated events in subjects with NASH/MASH and fibrosis. This is clinically relevant as it addresses the potential of EFX to improve liver health and reduce mortality in patients with these conditions.
Secondary objectives include: - For Cohort 1 only: Evaluating the effect of EFX compared to placebo on achieving NASH/MASH resolution without worsening of fibrosis at Week 52, and on fibrosis regression without worsening of NASH/MASH at Week 52. - Evaluating the effect of EFX compared to placebo on non-invasive markers of liver fibrosis, markers of liver injury, lipoproteins, markers of insulin sensitivity and glycemic control, and weight change. - Assessing the safety, tolerability, and immunogenicity of EFX.
Participants
The clinical trial involves a total of **1406 participants** diagnosed with **Metabolic Dysfunction-Associated Steatohepatitis (MASH)**, **Fibrosis**, or **Non-Alcoholic Steatohepatitis (NASH)**. The study population includes both male and female subjects, aged between 18 and 80 years, with a specific age range of 19 to 80 years for participants from the Republic of Korea. Participants were selected based on their health status, which includes a history or presence of type 2 diabetes or components of metabolic syndrome such as obesity, dyslipidemia, elevated blood pressure, or elevated fasting glucose. The trial population is characterized by a body mass index (BMI) of 25.0 kg/m² or higher. Lifestyle considerations include the requirement for participants to adhere to specified methods of contraception if of childbearing potential. The trial also includes a vulnerable population, ensuring that all participants are willing and able to provide informed consent. The selection criteria ensure that participants have stable liver enzyme levels and meet specific laboratory test thresholds, such as an estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73m² or higher, and hemoglobin A1c (HbA1c) levels of 9.5% or lower. The trial does not provide additional information on specific lifestyle habits such as diet or physical activity.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of **Efruxifermin** in subjects with non-cirrhotic **Non-Alcoholic Steatohepatitis (NASH)**, **Metabolic Dysfunction-Associated Steatohepatitis (MASH)**, and fibrosis. The primary objective is to assess the effect of Efruxifermin compared to placebo on achieving NASH/MASH resolution and fibrosis regression at Week 52. The trial will also evaluate the effect on all-cause mortality and liver-related clinical outcomes. The study is expected to commence recruitment on January 24, 2024, and conclude by February 23, 2032.
Participants will be involved in the study for a maximum treatment period of 240 weeks. The trial includes several key visits: an initial screening visit to determine eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be males or non-pregnant, non-lactating females aged 18-80 years, with a body mass index (BMI) of at least 25.0 kg/m², and a history or presence of type 2 diabetes or components of metabolic syndrome. Participants must also meet specific laboratory criteria and have a biopsy-proven diagnosis of NASH/MASH with fibrosis.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The study will utilize a subcutaneous route of administration for Efruxifermin, provided as a solution for injection. The trial will employ devices such as the K-Pack Surshield Needle and the Lyo-Ject III S DCS for administration. The primary endpoints include the proportion of subjects achieving NASH/MASH resolution and fibrosis improvement, as well as event-free survival. Secondary endpoints will assess changes in liver function tests, lipid profiles, and other metabolic parameters.
Treatment
The clinical trial involves the administration of **Efruxifermin**, a **solution for injection** developed by Akero Therapeutics Inc. Efruxifermin is a protein-based therapeutic agent, specifically classified under "Protein - Other." The pharmaceutical form of Efruxifermin is a solution intended for subcutaneous administration. The dosing regimen for Efruxifermin includes a maximum daily dose of 4 mg to 7.14 mg, with a total maximum dose of 6720 mg to 12000 mg over a treatment period of up to 240 days. The administration of Efruxifermin is facilitated by devices such as the K-Pack Surshield Needle and the Lyo-Ject III S DCS Dual Chamber Syringe, neither of which possess a CE mark.
The study also includes a **placebo** group, where participants receive an **Efruxifermin (EFX) Placebo**. The placebo is designed to mimic the administration of Efruxifermin without containing the active substance. The placebo is utilized to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in a manner consistent with the experimental treatment to ensure comparability between the groups.
Efficacy
The efficacy of **Efruxifermin** in the treatment of Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) with fibrosis will be assessed through a series of primary and secondary endpoints. The primary histology endpoint is the proportion of subjects in Cohort 1 who achieve NASH/MASH resolution, defined as a Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) of 0-1 for inflammation and 0 for ballooning, along with at least a one-stage improvement in fibrosis based on the NASH Clinical Research Network (CRN) fibrosis score at Week 52. The primary clinical outcomes endpoint is Event-Free Survival (EFS), which will be evaluated by the time from randomization to the first clinical event, including disease progression, liver decompensation events, liver transplantation or eligibility for liver transplantation, and all-cause mortality.
Secondary endpoints include the proportion of subjects achieving NASH/MASH resolution without worsening of fibrosis, and those achieving at least a one-stage improvement in fibrosis without worsening of steatohepatitis at Week 52. Additional secondary measures involve changes from baseline in Enhanced Liver Fibrosis (ELF) score and its components, liver stiffness assessed by FibroScan®, and various biochemical markers such as ALT, AST, gamma-glutamyl transferase (GGT), uric acid, cholesterol levels, HbA1c, adiponectin, and body weight. Safety and tolerability will be monitored through adverse events (AEs) and clinical assessments, while immunogenicity will be evaluated by detecting and measuring anti-drug antibodies (ADA), including neutralizing antibodies (NAb) against Efruxifermin.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males and non-pregnant, non-lactating females between 18–80 (between 19–80 in the Republic of Korea) years of age, inclusive, on the day of signing informed consent.
- Previous history or presence of T2D (as determined by medical history or based on screening lab values if previously undiagnosed [i.e., HbA1c ≥ 6.5%]) or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose)
- Body mass index (BMI) ≥ 25.0 kg/m2
- Cohort 1 Subjects who do not have a historical liver biopsy specimen that meets Inclusion Criteria 7 must meet either inclusion criterion 4a OR 4b OR 4c prior to collection of a liver biopsy specimen during the Screening visit:REDACTED. Cohort 2 Subjects who do not have a historical liver biopsy specimen that meets Inclusion Criteria 7 must meet either inclusion criterion 4d OR 4e OR 4f prior to collection of a liver biopsy specimen during the Screening visit: REDACTEDNote for both Cohort 1 and Cohort 2: If a historical value for FibroScan® is available within 12 weeks prior to randomization, then the screening FibroScan® does not need to be repeated.
- Central laboratory tests at screening or pre-baseline that meet all of the following criteria: a. Estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73m2 (> 30 mL/min/1.73m2 in the Republic of Korea), as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at Screening; b. Hemoglobin A1c (HbA1c) ≤ 9.5% at Screening; International Normalized Ratio (INR) < 1.3 at Screening, unless due to therapeutic anticoagulation; d. Total bilirubin < 1.3 mg/dL at Screening and Pre-baseline and direct bilirubin ≤ 0.5 mg/dL at Screening. For subjects with Gilbert’s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin ≤ ULN; e. Creatine kinase (CK) < 3 × upper limit of normal (ULN) at Screening; f. Platelet count ≥ 100,000/μL at Screening; g. Triglyceride (TG) level ≤ 500 mg/dL at Screening; h. Aspartate aminotransferase (AST) > 17 for females and > 20 for males at Screening and Pre-baseline; Note: The AST inclusion criteria does not apply to subjects with an eligible historical liver biopsy performed ≤ 180 days prior to screening in either Cohort 1 or Cohort 2 as defined in Inclusion Criteria 7. i. AST ≤ 5 × ULN at Screening and Pre-baseline; j. Alanine aminotransferase (ALT) ≤ 5 × ULN at Screening and Pre-baseline; k. Alkaline phosphatase (ALP) < 2 × ULN at Screening and Prebaseline; l. 25-Hydroxy Vitamin D ≥ 13 ng/mL at Screening. Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion. A subject who fails to meet Inclusion Criterion 5l will be allowed to retest 25-Hydroxy Vitamin D during the same screening period OR rescreen provided they agree to take supplementation with Vitamin D. See Section 5.3 for details.
- Documented stability of ALT and AST levels, as evidenced by no significant worsening of ALT and AST values at pre-baseline relative to screening values and the following parameters: a. If the screening and pre-baseline ALT and AST values are both ≤ 1.5 × ULN, there is no limit to the difference between the values. b. If at least 1 of the screening or pre-baseline ALT or AST values is > 1.5 × ULN and shows worsening at pre-baseline, the percent increase must be ≤ 50%. Note: Subjects must have ALT and AST repeated during the screening period (Pre-Baseline visit) at minimum 28 days between blood draws to confirm either criterion 6a or 6b above. Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion.
- a. 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 1 point in each of the following components: 1. Steatosis (scored 0 to 3), 2. Ballooning degeneration (scored 0 to 2), and 3. Lobular inflammation (scored 0 to 3) b. Cohort 2: REDACTED Note: For subjects with weight loss ≥ 5% in the 180 days prior to randomization, the historical liver biopsy must have been collected within 90 days prior to screening. Note: REDACTED
- Use of any conditionally allowed medications must follow the stable dose and adjustment criteria as outlined in Table 3.
- Willing and able to give written informed consent prior to any study specific procedures being performed.
- Female subjects of childbearing potential (see definition in Appendix C) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at baseline/Day 1.
- Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix C.
Exclusion Criteria
- Presence of cirrhosis on liver biopsy (stage 4 fibrosis).
- History of pancreatitis.
- Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive) or acute hepatitis A infection (hepatitis A immunoglobulin M [IgM] antibody positive). For subjects with positive hepatitis B core antibody (HBcAb), HBV DNA by quantitative polymerase chain reaction (PCR) will be required.
- Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV RNA positive). Subjects cured of HCV infection < 2 years prior to the Screening visit (based on date of RNA PCR negative confirmation following conclusion of treatment) are not eligible.
- Prior (< 2 years prior to screening) or planned (during the study period) bariatric surgery (e.g., gastroplasty, Roux-en-Y gastric bypass) or reversal or removal of intragastric balloon. Surgery failure < 2 years prior to screening is also exclusionary.
- Other causes of liver disease based on medical history and/or centralized review of liver histology and/or central laboratory results, including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug induced hepatotoxicity, Wilson disease, or clinically significant iron overload.
- History of liver transplantation.
- Current or prior history of hepatocellular carcinoma (HCC).
- Current diagnosis of Cushing’s syndrome.
- History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening; Note: Significant alcohol consumption is defined as an average exceeding 1 ethanol containing drink/day in female subjects and 2 ethanol containing drinks/day in male subjects.
- Human immunodeficiency virus (HIV) infection.
- Weight loss > 10% within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
- Uncontrolled cardiac arrhythmia or confirmed QT interval corrected using Fridericia’s formula (QTcF) > 450 msec for males and > 470 msec for females at the screening electrocardiogram (ECG) assessment. Subjects with cardiac pacemakers and elevated QTcF (> 450 msec for males and > 470 msec for females) may be allowed to participate if, in the Investigator’s opinion, the subject’s cardiac function is stable. Note: ECG for eligibility assessment may be repeated one time at the Investigator’s discretion
- Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 90 days prior to screening and through randomization.
- Life expectancy of less than 2 years.
- Use of any investigational medication within 30 days or 5 half lives, whichever is longer, prior to screening or concurrent participation in another therapeutic clinical study.
- Use of any prohibited medication(s) as outlined in Table 2 of the protocol including any prior exposure to EFX.
- Positive urine drug screen for amphetamines, cocaine, or opiates (e.g., heroin, morphine) at screening. Subjects with a positive urine drug screen due to prescription medication (e.g., opiates, methylphenidate) are eligible if the prescription and diagnosis are reviewed and approved by the Investigator. Subjects on stable methadone or buprenorphine maintenance treatment for at least 180 days prior to screening may be included in the study.
- Unable to safely undergo a liver biopsy.
- Presence of any laboratory abnormality or significant systemic or major illnesses (other than liver disease) that, in the opinion of the Investigator, compromises the subject’s ability to safely participate in and complete the study including, but not limited to: a. Pulmonary disease, heart failure, renal failure, organ transplantation, serious psychiatric disease, malignancy, history of substance abuse and/or a psychiatric condition requiring hospitalization and/or emergency room visit within 180 days of screening.
- Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures.
- Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
- Type 1 diabetes.
- Unstable Type 2 diabetes defined as: a. Insulin dose adjustment > 35% within 30 days prior to screening through randomization, b. Any prior history of diabetic ketoacidosis and/or hyperglycemic, hyperosmolar state.
- Hypoglycemia unawareness, hospitalization due to hypoglycemia, or history of severe hypoglycemia (hypoglycemia requiring outside assistance to regain normal neurologic status) within 90 days prior to screening.
- Subjects with a T-score of ≤ ─1.75 at the femoral neck or lumbar spine based on a centrally read DXA scan performed during screening. Note: A historical DXA scan performed within 90 days prior to screening may be accepted as the screening DXA scan. The historical scan must have been performed on a scanner previously qualified by the central imaging vendor that is available for use at post-baseline visits.
- Poorly controlled hypertension (systolic blood pressure > 160 mm Hg, or diastolic blood pressure > 100 mm Hg) at the Screening visit or Pre Baseline visit. Note: Vital signs for eligibility assessment may be repeated one time at the Investigator’s discretion
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 24 Jan 2024 | 55 |
 Germany | Recruiting | 24 Jan 2024 | 40 |
 Italy | Recruiting | 24 Jan 2024 | 52 |
 Poland | Recruiting | 24 Jan 2024 | 56 |
 Spain | Recruiting | 24 Jan 2024 | 41 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Efruxifermin | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 7.14 | 240 | PRD10471644 |
Efruxifermin | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 4 | 240 | PRD10471602 |
Efruxifermin (EFX) Placebo | Placebo | N/A | — | — | — | N/A |