A Study to Evaluate the Safety and Efficacy of Efruxifermin in Subjects with Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH) And Fibrosis

Phase 3

Recruiting

Conditions: Other specified inflammatory liverdiseases,

Registration Number: CTRI/2023/11/060385

Lead Sponsor: Akero Therapeutics, Inc.

Brief Summary: This is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of Efruxifermin (EFX) in subjects with non-cirrhotic NASH and fibrosis stage 2 or 3 (F2 or F3). An additional cohort of subjects with non-cirrhotic NASH and fibrosis stage 1 (F1) will be enrolled and evaluated only for safety and noninvasive efficacy endpoints.

Approximately 1000 patients will be enrolled globally, out of which 100 patients will be enrolled in India with approx. 75 patients with Fibrosis stages F2-F3 while 25 patients with Fibrosis stage F1.

Subjects meeting the studyâ€™s eligibility criteria will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups (Placebo, Efruxifermin (28 mg) and Efruxifermin (50 mg)).

EFX will be provided in a prefilled, single-use, non-pyrogenic LyoJect 3S dual chamber syringe (DCS). Chamber one contains lyophilized dry EFX powder, and chamber two contains a nominal volume of 1.0 mL of water for injection (WFI) diluent. The two chambers are separated by a middle plunger stopper. Efruxifermin is presented as a white to off-white powder and the diluent is presented as a colorless to slightly yellow liquid. Placebo will be provided as a lyophilized powder in chamber one of the LyoJect 3S DCS with a nominal volume of 1.0 mL of diluent contained in chamber two.

Efruxifermin/Placebo will be administered subcutaneously, once a week for 96 weeks.

The primary endpoint analysis will occur after all F2/F3 subjects have completed the Primary Endpoint Treatment duration (i.e., completed 52 weeks of treatment or permanently discontinued from the study prior to Week 52). For evaluation of longer-term safety and efficacy, subjects will continue to receive their assigned treatment for up to a total of 96 weeks. The 30-day Follow-up visit will be completed 30 days following the last dose of study drug.

Study participation may last up to 112 weeks, including a 12-week screening period, 96-week treatment period, and a 30-day Follow-up visit.

Detailed Description: Not available

Recruitment & Eligibility

Status: Open to Recruitment

Sex: All

Target Recruitment: 1000

Inclusion Criteria

Males and non-pregnant, non-lactating females between 18â€“75 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 greater than or equal to 6.5%]) or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose).
Body mass index (BMI) greater than or equal to 25.0 kg/m2.
Subjects who do not have a historical liver biopsy specimen that meets Inclusion Criteria 7 must meet either inclusion criterion 4a OR 4b prior to collection of a liver biopsy specimen during the Screening visit: a.
FibroScanÂ® liver stiffness measurement (LSM) > 7.5 kPa, OR b.
Enhanced Liver Fibrosis (ELF) score greater than or equal to 7.7 5.
Central laboratory tests at screening that meet all of the following criteria: a.
Estimated glomerular filtration rate (eGFR) greater than or equal to 15 mL/min, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); b.
Hemoglobin A1c (HbA1c) less than or equal to 9.5%; c.
International Normalized Ratio (INR) < 1.3, unless due to therapeutic anticoagulation; d.
Total bilirubin < 1.3 mg/dL and direct bilirubin less than or equal to 0.5 mg/dL.
For subjects with Gilbertâ€™s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin less than or equal to ULN; e.
Creatine kinase (CK) < 3 Ã— upper limit of normal (ULN); f.
Platelet count greater than or equal to 100,000/ÂµL; g.
Aspartate aminotransferase (AST) > 17 for females and > 20 for males, AST less than or equal to 5 Ã— ULN; i.
Alanine aminotransferase (ALT) less than or equal to 5 Ã— ULN; j.
Alkaline phosphatase (ALP) < 2 Ã— ULN; k.
25-Hydroxy Vitamin D greater than or equal to 20 ng/mL Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigatorâ€™s discretion 6.
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 less than or equal to 1.5 Ã— ULN, there is no limit to the difference between the values.
If at least 1 of the screening or pre-baseline values of ALT or AST is > 1.5 Ã— ULN and shows worsening at pre-baseline, the percent increase must be less than or equal to 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 Investigatorâ€™s discretion.
Biopsy-proven NASH.
Must have had a liver biopsy obtained less than or equal to 180 days prior to screening with fibrosis stage 1, 2, or 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of more than or equal to 4 with at least 1 point in each of the following components: a.
Steatosis (scored 0 to 3), b.
Ballooning degeneration (scored 0 to 2), and c.
Lobular inflammation (scored 0 to 3) Note: F1 subjects will be limited to approximately 25% of the total study population.
The remaining population will be approximately balanced between F2 and F3 subjects.
8.Subjects on Vitamin E greater than or equal to 800 IU/day, antidiabetic, weight loss, or lipid-modifying medication(s) must be on a stable dose (defined as no significant change in prescription efficacy, initiation of medication, or medication discontinuation) within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility through randomization.
Dose adjustments (but not initiation or discontinuation) of metformin are permitted in the 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
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.
11.Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.

Exclusion Criteria

1.Presence of cirrhosis on liver biopsy (fibrosis stage 4).
2.Weight loss > 10% within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
3.Type 1 diabetes.
4.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.
5.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.
6.Subjects with osteoporosis, defined as a T-score of less than or equal to -2.5 at the femoral neck, total hip, 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.
7.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 Investigatorâ€™s discretion 8.Any current or prior history of decompensated liver disease including ascites requiring medical management, hepatic encephalopathy (HE), or variceal bleeding.
9.Model for End-Stage Liver Disease (MELD) score > 12, unless due to therapeutic anticoagulation or Gilbertâ€™s syndrome.
10.History of pancreatitis.
11.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.
12.Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV RNA positive).
Subjects cured of HCV infection less than 2 years prior to the Screening visit (based on date of RNA PCR negative confirmation following conclusion of treatment) are not eligible.
Surgery failure less than 2 years prior to screening is also exclusionary.
14.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.
15.History of liver transplantation.
16.Current or prior history of hepatocellular carcinoma (HCC).
17.Current diagnosis of Cushingâ€™s syndrome.
18.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.
19.Human immunodeficiency virus (HIV) infection.
20.Uncontrolled cardiac arrhythmia or confirmed QT interval corrected using Fridericiaâ€™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 Investigatorâ€™s opinion, the subjectâ€™s cardiac function is stable.
Note:ECG for eligibility assessment may be repeated one time at the Investigatorâ€™s discretion 21.Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 90 days prior to screening.
22.Life expectancy of less than 2 years.
23.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.
24.Use of any prohibited medication(s) mentioned in protocol including any prior exposure to EFX.
25.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.
27.Presence of any laboratory abnormality or significant systemic or major illnesses (other than liver disease) that, in the opinion of the Investigator, compromises the subjectâ€™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.
28.Unavailable for follow-up assessment or concern for subjectâ€™s compliance with the protocol procedures.
Known hypersensitivity to the study drug, the metabolites, or formulation excipients.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Proportion of subjects with fibrosis stage 2 or 3 who achieve NASH resolution (defined as a NAS of 0â€“1 for inflammation & 0 for ballooning) AND greater than	Week52
or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score)	Week52

Secondary Outcome Measures

Name	Time	Method
Proportion of subjects with fibrosis stage 2 or 3 who achieve NASH resolution (defined as a NAS of 0â€“1 for inflammation & 0 for ballooning) & no worsening of fibrosis (based on NASH CRN fibrosis score)	Proportion of subjects with fibrosis stage 2 or 3 who achieve greater than or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) & no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis)

Trial Locations

Locations (26): All India Institute of Medical Science, Rishikesh
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Dehradun, UTTARANCHAL, India
All India Institution of Medical Sciences (AIIMS)
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Delhi, DELHI, India
BAPS Pramukh Swami Hospital,
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Surat, GUJARAT, India
Gandhi Medical College and Hospital
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Hyderabad, TELANGANA, India
Gleneagles Global Health city,
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Chennai, TAMIL NADU, India
Gleneagles Hospital
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Hyderabad, TELANGANA, India
Government Medical college PO
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Thiruvananthapuram, KERALA, India
IMS, Banaras Hindu University,Varanasi
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Varanasi, UTTAR PRADESH, India
Institute of Liver and Biliary Sciences, Hospital
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West, DELHI, India
IPGME&R and SSKM Hospital
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Kolkata, WEST BENGAL, India
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All India Institute of Medical Science, Rishikesh
🇮🇳Dehradun, UTTARANCHAL, India
Dr Rohit Gupta
Principal investigator
7579067715
docgupta1976@gmail.com