A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects with Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Akero Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

7 Mar 2024 → ongoing

Decision date (initial)

2023-12-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Akero Therapeutics Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the effect of EFX compared to placebo on achieving NASH/MASH resolution AND fibrosis regression at Week 52 (in Cohort 1 only)
To evaluate the effect of EFX compared to placebo on all-cause mortality and liver-related clinical outcomes as measured by the time to first occurrence of any of the predefined, adjudicated events in subjects with NASH/MASH and fibrosis

Secondary objectives 8

1. For Cohort 1 only:To evaluate the effect of EFX compared to placebo on achieving NASH/MASH resolution with no worsening of fibrosis at Week 52
2. For Cohort 1 only: To evaluate the effect of EFX compared to placebo on fibrosis regression without worsening of NASH/MASH at Week 52
3. To evaluate the effect of EFX compared to placebo on non invasive markers of liver fibrosis
4. To evaluate the effect of EFX compared to placebo on markers of liver injury
5. To evaluate the effect of EFX compared to placebo on lipoproteins
6. To evaluate the effect of EFX compared to placebo on markers of insulin sensitivity and glycemic control
7. To evaluate the effect of EFX compared to placebo on weight change
8. To assess the safety, tolerability, and immunogenicity of EFX

Conditions and MedDRA coding

Fibrosis

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003114-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 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)
3. Body mass index (BMI) ≥ 25.0 kg/m2
4. 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.
5. 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.
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 ≤ 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.
7. 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
8. Use of any conditionally allowed medications must follow the stable dose and adjustment criteria as outlined in Table 3.
9. Willing and able to give written informed consent prior to any study specific procedures being performed.
10. 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.
11. 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 27

1. Presence of cirrhosis on liver biopsy (stage 4 fibrosis).
2. History of pancreatitis.
3. 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.
4. 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.
5. 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.
6. 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.
7. History of liver transplantation.
8. Current or prior history of hepatocellular carcinoma (HCC).
9. Current diagnosis of Cushing’s syndrome.
10. 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.
11. Human immunodeficiency virus (HIV) infection.
12. Weight loss > 10% within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
13. 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
14. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 90 days prior to screening and through randomization.
15. Life expectancy of less than 2 years.
16. 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.
17. Use of any prohibited medication(s) as outlined in Table 2 of the protocol including any prior exposure to EFX.
18. 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.
19. Unable to safely undergo a liver biopsy.
20. 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.
21. Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures.
22. Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
23. Type 1 diabetes.
24. 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.
25. 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.
26. 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.
27. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary histology endpoint will be the proportion of subjects in Cohort 1 who achieve NASH/MASH resolution (defined as a NAS of 0─1 for inflammation and 0 for ballooning) AND ≥ 1 stage improvement in fibrosis (based on NASH Clinical Research Network [CRN] fibrosis score) at Week 52.
2. The primary clinical outcomes endpoint will be Event-Free Survival (EFS). EFS will be assessed by 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 endpoints 9

1. Cohort 1 only: Proportion of subjects who achieve NASH/MASH resolution (defined as a NAS of 0─1 for inflammation and 0 for ballooning) and no worsening of fibrosis (based on NASH CRN fibrosis score) at Week 52.
2. Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Week 52.
3. Change from baseline in ELF score and components (tissue inhibitor of metalloproteinase-1 [TIMP-1], hyaluronic acid [HA], amino terminal pro-peptide of type 3 procollagen [PIIINP]), pro-peptide of type 3 procollagen (Pro-C3), and liver stiffness assessed by FibroScan®.
4. Change from baseline in ALT, AST, gamma-glutamyl transferase (GGT), and uric acid
5. Change from baseline total cholesterol, TG, high density lipoprotein cholesterol (HDL-C), non-HDL—C, and low-density lipoprotein cholesterol (LDL-C)
6. Change from baseline in HbA1c and adiponectin
7. Change from baseline in body weight.
8. Safety and tolerability will be assessed through the reporting of extent of exposure, AEs, and clinical assessments.
9. Immunogenicity will be assessed through the detection and measurement of ADA, including NAb, against EFX.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Akero Therapeutics Inc.

Sponsor organisation

Akero Therapeutics Inc.

Address

601 Gateway Boulevard Suite 350

City

South San Francisco

Postcode

94080-7030

Country

United States

Scientific contact point

Organisation

Akero Therapeutics Inc.

Contact name

Akero Info

Public contact point

Organisation

Akero Therapeutics Inc.

Contact name

Akero Info

Third parties 8

Locations

5 EU/EEA countries · 58 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 52 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications