A Multiple Ascending Dose Study of BIO89-100 in Subjects With Biopsy Confirmed NASH or NAFLD and at High Risk of NASH

Study Overview
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Brief Summary
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Part 1: This is a multi-center evaluation of BIO89-100 (administered weekly or every other week) in a randomized, double-blind, placebo-controlled study administered for 12 weeks in subjects with NASH and NAFLD at high risk of NASH, including a pre-defined number of subjects with biopsy confirmed NASH and fibrosis stages F1-F3 to be enrolled Part 2: This is a multi-center, open label evaluation of BIO89-100 at 27 mg administered weekly for 20 weeks in subjects with biopsy-poven NASH (NAS ≥4, fibrosis stage F2 or F3)

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetic Properties of BIO89-100 Administered Subcutaneously in Subjects With Nonalcoholic Steatohepatitis (NASH) or With Nonalcoholic Fatty Liver Disease (NAFLD) and at High Risk of NASH

Conditions
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NASH

Intervention / Treatment
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* Drug: BIO89-100
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subjects must be 21 to 75 years of age inclusive, at the time of signing the informed consent form (ICF). Evidence of steatosis by Fibroscan and MRI-PDFF NASH or NAFLD at high risk for NASH as reflected by AT LEAST ONE of the following: Diagnosis of NASH with fibrosis (stages F1, F2 or F3), without cirrhosis, by percutaneous liver biopsy within 24 months prior to screening Central obesity WITH T2DM Central obesity WITH either increased ALT and/or Fibroscan VCTE score ≥7 KPa. Part 2 only: Biopsy-proven NASH in a liver biopsy obtained within 24 weeks of baseline with fibrosis stage F2 or F3 and NAS ≥4, with a score of at least 1 in each of steatosis, ballooning degeneration, and lobular inflammation. A small number of high risk F1 allowed. Key Exclusion Criteria: Clinically significant disorder or a history of any illness that, in the opinion of the Investigator, might confound the results of the study, or pose additional risk to the subject by participation in the study. History of type 1 diabetes. Weight loss of more than 5% within 3 months prior to Day -1 or more than 10% within 6 months prior to Day -1 or planning to try to lose weight during conduct of study. History of a liver disorder other than NASH or clinical suspicion of a liver disorder other than NASH History of cirrhosis or evidence of cirrhosis

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose 1<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|
| Experimental: Dose 2<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|
| Experimental: Dose 3<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|
| Experimental: Dose 4<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|
| Experimental: Dose 5<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|
| Experimental: Dose 6<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Subcutaneous injection<br>|
| Experimental: Dose 4 Open Label<br> | Drug: BIO89-100<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Part 1-16 weeks, Part 2-23 weeks | 
| Number of subjects who discontinued due to AEs and due to related AEs |  | Part 1 only-16 weeks | 
| To characterize the BIO89-100 Pharmacokinetics (PK) by Peak Plasma Concentration |  | Part 1 only-13 weeks | 
| To characterize the BIO89-100 PK by Time to Peak Plasma Concentration (Tmax) |  | Part 1 only-13 weeks | 
| To characterize the BIO89-100 PK by Area under the plasma concentration versus time curve (AUC) |  | Part 1 only-13 weeks | 
| To characterize the BIO89-100 PK by the terminal elimination half-life (t1/2) |  | Part 1 only-13 weeks | 
| To characterize effect of BIO89-100 on liver histology by Improvement in NAS score | At least a 2-point improvement in NAFLD Activity Score (NAS) with at least a 1 point improvement in ballooning or lobular inflammation, and no worsening of fibrosis | Part 2 only-20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from baseline in Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) |  | Part 1-13 weeks, Part 2-20 weeks | 
| Percentage change from baseline in triglycerides |  | Part 1-13 weeks, Part 2-20 weeks | 
| Percentage change from baseline in Low Density Lipoprotein (LDL) Cholesterol |  | Part 1-13 weeks, Part 2-20 weeks | 
| Percentage change from baseline in Alanine Transaminase (ALT) |  | Part 1-13 weeks, Part 2-20 weeks | 
| Percentage change from baseline in N-terminal type III collagen propeptide (Pro-C3) |  | Part 1-13 weeks, Part 2-20 weeks | 
| Assessment of the incidence and characteristics of anti drug antibodies (ADA) developed against BIO89-100 after dosing |  | Part 1-16 week, Part 2-24 weeks | 
| To characterize effect of BIO89-100 on liver histology by improvement of fibrosis | Improvement of fibrosis ≥1 stage without worsening of NASH | Part 2 only-20 weeks | 
| To characterize effect of BIO89-100 on liver histology by NASH resolution | NASH resolution without worsening of fibrosis | Part 2 only-20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, NAFLD, Liver diseases, Fatty Liver, Metabolic diseases