Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Efruxifermin in Compensated Cirrhosis Due to NASH/MASH

Trial ID: 2024-512895-36-00
Protocol: AK-US-001-0106
Sponsor: Akero Therapeutics Inc.

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

diseases

person_search

investigators

handshake

vendors

Diseases & Conditions

Hepatic cirrhosis Metabolic dysfunction-associated steatohepatitis Non-alcoholic steatohepatitis

Objectives

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of **Efruxifermin** (EFX) compared to placebo on all-cause mortality and liver-related clinical outcomes. This is measured by the time to the first occurrence of any pre-defined, adjudicated events in subjects with compensated cirrhosis due to Nonalcoholic Steatohepatitis (NASH) or Metabolic Dysfunction-Associated Steatohepatitis (MASH). Additionally, the study aims to assess the effect of EFX on fibrosis regression without worsening of NASH/MASH in subjects with biopsy-proven compensated cirrhosis due to NASH/MASH at Week 96, specifically in Cohort 1. These objectives are clinically relevant as they address critical outcomes in the management of NASH/MASH-related cirrhosis, potentially impacting patient survival and disease progression.

Secondary objectives include evaluating the effect of EFX compared to placebo on:

Non-invasive markers of fibrosis
Markers of liver injury and function
Lipoproteins
Markers of insulin sensitivity and glycemic control
Weight change
Safety, tolerability, and immunogenicity of EFX
Fibrosis regression in subjects with biopsy-proven compensated cirrhosis due to NASH/MASH at Week 96 (Cohort 1 only)
Achieving NASH/MASH resolution in subjects with biopsy-proven compensated cirrhosis due to NASH/MASH at Week 96 (Cohort 1 only)
Achieving both NASH/MASH resolution and fibrosis regression in subjects with biopsy-proven compensated cirrhosis due to NASH/MASH at Week 96 (Cohort 1 only)

These secondary objectives aim to provide a comprehensive understanding of EFX's impact on various clinical and biochemical parameters associated with NASH/MASH, offering insights into its potential therapeutic benefits beyond primary outcomes.

Participants

The clinical trial involves a total of **1027 participants** diagnosed with **Non-Alcoholic Steatohepatitis (NASH)** or **Metabolic Dysfunction-Associated Steatohepatitis (MASH)**. 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 compensated cirrhosis due to NASH/MASH, and they must meet specific laboratory criteria at screening. The trial includes individuals with a history or presence of type 2 diabetes or metabolic syndrome components, and a body mass index (BMI) of at least 25.0 kg/m². Lifestyle considerations such as diet and physical activity are not explicitly detailed, but participants must adhere to stable medication doses if applicable. The trial population is not limited to a specific gender, and both males and females of childbearing potential are required to use specified contraception methods. The study also includes a vulnerable population, ensuring comprehensive representation within the trial. Key inclusion criteria focus on the stability of liver enzyme levels and the presence of biopsy-proven compensated cirrhosis, ensuring that participants meet the necessary health parameters for the study.

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 compensated cirrhosis due to **Non-Alcoholic Steatohepatitis (NASH)** or **Metabolic Dysfunction-Associated Steatohepatitis (MASH)**. The trial aims to assess the effect of Efruxifermin compared to placebo on all-cause mortality and liver-related clinical outcomes, as well as fibrosis regression without worsening of NASH/MASH. The study is expected to commence recruitment on October 21, 2024, and conclude by September 3, 2029.

Participants will be involved in the study for a maximum treatment period of 260 weeks. The trial includes several key visits: an initial screening visit to determine eligibility based on specific inclusion criteria, including age, laboratory test results, and medical history. Following the screening, eligible participants will be randomized to receive either Efruxifermin or placebo via subcutaneous injection. The study will involve regular follow-up visits to monitor safety, efficacy, and any adverse events. The primary endpoint will be assessed at Week 96, focusing on event-free survival and histological efficacy in Cohort 1. Secondary endpoints include changes in liver stiffness, biochemical markers, and metabolic parameters.

The trial design ensures that participants and investigators remain blinded to the treatment allocation to minimize bias. Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The end-of-study visit will involve a comprehensive assessment to evaluate the overall outcomes and any long-term effects of the treatment. The study's rigorous methodology and structured visit schedule are designed to ensure the collection of high-quality data to support the evaluation of Efruxifermin's therapeutic potential in this patient population.

Treatment

The clinical trial involves the administration of **Efruxifermin**, an experimental medication developed by Akero Therapeutics Inc. Efruxifermin is provided in the form of a **solution for injection** and is classified as a protein of other origin. The medication is administered subcutaneously using a dual chamber syringe, specifically the Lyo-Ject III S DCS, and a K-Pack Surshield Needle. The maximum daily dose of Efruxifermin is 50 mg, with a total maximum dose of 1300 mg over a treatment period of 260 days. The dosing schedule and participant compliance are monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind study. The placebo is designed to match the appearance of the Efruxifermin solution for injection but does not contain any active substance. The placebo is administered in the same manner as the experimental medication, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This approach allows for an unbiased evaluation of the safety and efficacy of Efruxifermin in subjects with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH).

Efficacy

The efficacy of Efruxifermin in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary clinical outcomes analysis will focus on **Event-Free Survival (EFS)**, which will be measured from the time of randomization to the first clinical event, including disease progression, liver decompensation events, liver transplantation, eligibility for liver transplantation, and all-cause mortality. Additionally, for Cohort 1, a primary endpoint at Week 96 will involve a histology efficacy analysis using a Cochran-Mantel-Haenszel (CMH) test to compare the proportions of subjects achieving a ≥1 stage improvement in fibrosis without worsening of steatohepatitis between the Efruxifermin and placebo arms, adjusting for stratification factors.

Secondary endpoints will include changes from baseline in various biomarkers and clinical parameters. These will encompass changes in the Enhanced Liver Fibrosis (ELF) score and its components, liver stiffness assessed by FibroScan, and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additional secondary endpoints will evaluate changes in lipid profiles, including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and low-density lipoprotein cholesterol (LDL-C). Metabolic parameters such as HbA1c, C-peptide, adiponectin, insulin, and HOMA-IR will also be assessed, along with changes in body weight. For Cohort 1, specific secondary endpoints will measure the proportion of subjects achieving ≥1 stage improvement in fibrosis and resolution of NASH/MASH, as defined by the NASH CRN criteria, at Week 96.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Males and non-pregnant, non-lactating females between 18–80 years of age, inclusive, on the day of signing informed consent. Note: The minimum age for participation as an adult will be based on the age of legal consent for clinical research as defined by local regulations in each participating country
Use of any conditionally allowed medications must follow the stable dose and adjustment criteria
Willing and able to give written informed consent prior to any study specific procedures being performed
Female subjects of childbearing potential 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
Previous history or presence of type 2 diabetes (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 at screening
Subjects who require a centrally read biopsy to satisfy Inclusion 5 or Inclusion 6a who do not have a historical liver biopsy specimen (collected ≤ 365 days prior to screening and available for submission to the central readers) must meet either Inclusion criterion prior to collection of a liver biopsy specimen during the screening period: a. FibroScan® liver stiffness measurement (LSM) kilopascals (kPa) b. ELF score
Cohort 1 Subjects only: Biopsy-proven compensated cirrhosis (fibrosis stage 4) due to NASH/MASH based on a centrally read biopsy. Must have had a liver biopsy specimen collected during screening or ≤ 365 days prior to screening with fibrosis stage 4 and meets ONE of the following: a. NAFLD activity score (NAS) of ≥ 3 with at least 1-point each in: — Steatosis (scored 0 to 3), — Ballooning degeneration (scored 0 to 2), and — Lobular inflammation (scored 0 to 3) OR b. Evidence of current or prior steatosis (as defined in Inclusion 7) and 2 current coexisting features of metabolic comorbidities (T2D, obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose) to corroborate a diagnosis of NASH/MASH as the cause of cirrhosis (Noureddin 2020)
Central laboratory tests that meet all of the following criteria at screening: a. Albumin ≥ 3.5 g/dL; b. 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); c. Hemoglobin A1c (HbA1c) ≤ 9.5%; d. International Normalized Ratio (INR) ≤ 1.3, unless due to therapeutic anticoagulation; e. Direct bilirubin ≤ 0.5 mg/dL; f. Creatine kinase (CK) < 3 × upper limit of normal (ULN); g. Triglyceride (TG) level ≤ 500 mg/dL; h. 25-Hydroxy Vitamin D ≥ 13 ng/mL Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion. A subject who fails to meet Inclusion Criterion 8h will be allowed to retest 25-Hydroxy Vitamin D during the same screening period OR rescreen provided that they agree to take supplementation with Vitamin D
Central laboratory tests that meet all of the following criteria at screening and pre-baseline: a. Total bilirubin < 1.3 mg/dL. For subjects with Gilbert’s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin ≤ ULN at screening; b. Platelet count ≥ 75,000/µL; c. Alanine aminotransferase (ALT) ≤ 5 × ULN; d. Aspartate aminotransferase (AST) ≤ 5 x ULN; e. Alkaline phosphatase (ALP) < 1.5 × ULN Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion
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), with a minimum of 28 days between blood draws to confirm either criterion 10a or 10b above. Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion.

cancel

Exclusion Criteria

Where a biopsy is used to assess subject eligibility, weight loss > 10% is not permitted within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility through randomization. For all other subjects, weight loss > 10% is not permitted within 90 days prior to screening through randomization
Child-Pugh score > 6 (Class B or C) at screening, unless due to haemolytic anaemia, therapeutic anticoagulation, or Gilbert’s syndrome
History of significant pancreatic disorders (acute pancreatitis, chronic pancreatitis, hereditary pancreatitis, and pancreatic cancer)
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. Note: Subjects who were previously diagnosed with chronic HCV infection who achieved sustained viral response (SVR) following treatment, or subjects with spontaneous clearance of HCV infection (positive serology for HCV infection, negative for HCV RNA at screening, and no documented history of acute HCV infection within 2 years prior to screening) may be enrolled
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, clinically significant iron overload, or alpha-1-antitryspin deficiency. Additional requirements for Wilson disease and alpha-1-antitryspin deficiency are outlined
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
Type 2 diabetes
Human immunodeficiency virus (HIV) infection
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 ECG assessment. Subjects with cardiac pacemakers or pre-existing right bundle branch block (RBBB) 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. Note: Without written approval from the Sponsor, a historical biopsy cannot be used for screening eligibility if the biopsy was collected prior to or during treatment with an investigational drug
Use of any prohibited medication(s), 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
Cohort 1 only: 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,malignancy, history of substance abuse and/or a serious psychiatric condition, defined as 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
Unstable T2D defined as: a. Insulin dose adjustment > 35% within 30 days prior to screening through randomization b. Any prior history of diabetic ketoacidosis and/or hyperosmolar hyperglycaemic state
Known hypersensitivity to the study drug, its metabolites, or formulation excipients
Hypoglycaemia unawareness, hospitalization due to hypoglycaemia, or history of severe hypoglycaemia (hypoglycaemia requiring outside assistance to regain normal neurologic status) within 90 days prior to screening
Any history of osteoporosis or a T-score of ≤ ─2.5 at the femoral neck or lumbar spine based on a centrally read dual-energy X-ray absorptiometry (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 (average of triplicate systolic blood pressure measurement > 160 mm Hg, or average of triplicate 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
Any current or prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal bleeding
Model for End-Stage Liver Disease 3.0 (MELD-3) score > 12 at screening, unless due to hemolytic anemia, therapeutic anticoagulation, or Gilbert’s syndrome

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Yet Recruiting	21 Oct 2024	10
France	Recruiting	21 Oct 2024	45
Germany	Recruiting	21 Oct 2024	27
Greece	Not Yet Recruiting	21 Oct 2024	10
Italy	Recruiting	21 Oct 2024	34
Poland	Recruiting	21 Oct 2024	47
Spain	Recruiting	21 Oct 2024	26