Safety Study of OA-235i in Subjects With Nonalcoholic Steatohepatitis

Study Overview
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Brief Summary
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This study is a Phase 1, first-in-human single-dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of OA-235i in subjects with nonalcoholic steatohepatitis.

Detailed Description
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The purpose of this study is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single ascending dose (SAD) in participants with suspected or confirmed diagnosis of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) without advanced hepatic fibrosis. This dose-escalating strategy will test the safety of OA-235i when given as a single subcutaneous dosage using up to five successive cohorts. Each cohort will have three non-randomized participants receiving the active medication. One (1) planned multiple dose (MD) expansion dose cohort with 8 NAFLD/NASH subjects will be enrolled for a 7-day dosing regimen at a dose level to be determined from the SAD portion of the study.

Official Title
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A Phase 1a/1b Single Ascending and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of OA-235i, a PAR2 Inhibitor, in Adults With Nonalcoholic Steatohepatitis

Conditions
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Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Liver

Intervention / Treatment
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* Drug: OA-235i (4 mg)
* Drug: OA-235i (8 mg)
* Drug: OA-235i Dose 3
* Drug: OA-235i Escalating Dose 4
* Drug: OA-235i Escalating Dose 5
* Drug: OA-235i Multiple Dose


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Male and female subjects between the ages of 18 and 70 years, inclusive, at Screening. Body mass index (BMI) of ≥25 and <40 kg/m2 with a total body weight 50-150 kg (inclusive) at Screening and Day 1 Pre-dose. Suspected or confirmed diagnosis of noncirrhotic NAFLD/NASH without advanced hepatic fibrosis by one of the following: Histologically with liver biopsy within 2 years prior to Screening (documentation with pathology report); or Radiologically with ≥5% steatosis measured by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF), or controlled attenuation parameter (CAP) >288 dB/m via FibroScan assessment, or presence of hepatic steatosis on abdominal ultrasound within 1 year prior to Screening; or Clinically with a diagnosis of Metabolic Syndrome (MetS) reflecting the presence of at least 3 of 5 factors/criteria (ie, abdominal obesity, elevated triglycerides, reduced HDL-C, elevated blood pressure, and/or elevated fasting glucose [IFG or type 2 diabetes mellitus]) as defined by the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) [Grundy 2005]; and fatty liver on imaging within 1 year prior to Screening. Key Exclusion Criteria: History or presence of cirrhosis as assessed by Investigator following review of diagnostic measures (clinical, imaging, histopathology, or laboratory). Clinical evidence of hepatic decompensation (laboratory or clinical abnormalities- ascites, variceal bleeding, etc.). History or presence of other concomitant liver disease (eg, hepatitis B & C, alcoholic liver disease, autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin (A1AT) deficiency, bile duct obstruction, liver primary or metastatic cancer, drug-induced liver disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Sequential Assignment
Interventional Model Description: Single ascending dose (SAD) sequential group study of a sc dose of OA-235i in five (5) planned dose cohorts with 3 subjects/cohort administering a bolus injection at escalating dose levels from 4 to 40 mg. One (1) planned multiple dose (MD) expansion dose cohort with 8 NAFLD/NASH subjects will be enrolled for a 7-day dosing regimen at a dose level to be determined from the SAD portion of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OA-235i (4-40 mg)<br>Single ascending dose (SAD): OA-235i (4-40 mg) administered subcutaneously (SC) once to adult subjects with suspected or confirmed diagnosis of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) without advanced hepatic fibrosis. Multiple dose (MD): OA-235i (dose level to be determined from SAD) administered subcutaneously (SC) once daily for 7 days to adult subjects with suspected or confirmed diagnosis of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) without advanced hepatic fibrosis. | Drug: OA-235i (4 mg)<br>* 3 participants will receive 4 mg as a single subcutaneous dose<br>* Other names: PAR2 inhibitor;Drug: OA-235i (8 mg)<br>* 3 participants will receive 8 mg as a single subcutaneous dose<br>* Other names: PAR2 inhibitor;Drug: OA-235i Dose 3<br>* 3 participants will receive a single escalating subcutaneous dose<br>* Other names: PAR2 inhibitor;Drug: OA-235i Escalating Dose 4<br>* 3 participants will receive a single escalating subcutaneous dose<br>* Other names: PAR2 inhibitor;Drug: OA-235i Escalating Dose 5<br>* 3 participants will receive a single escalating subcutaneous dose<br>* Other names: PAR2 inhibitor;Drug: OA-235i Multiple Dose<br>* 8 participants will receive a daily subcutaneous dose for 7 consecutive days<br>* Other names: PAR2 inhibitor;|

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) | Number of participants with treatment-emergent with adverse events (incidence and severity) | 30 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the OA-235i Pharmacokinetics (PK) by Cmax | OA-235i PK by peak plasma concentration (Cmax) | 8 Days | 
| To characterize the OA-235i Pharmacokinetics (PK) by t1/2 | OA-235i PK by the terminal elimination half-life (t1/2) | 8 Days | 
| To characterize the OA-235i Pharmacokinetics (PK) by Tmax | OA-235i PK by time to peak plasma concentration (Tmax) | 8 Days | 
| To characterize the OA-235i Pharmacokinetics (PK) by AUC | OA-235i PK by area under the plasma concentration versus time curve (AUC) | 8 Days |