A Study of FT 4101 in Overweight/Obese Participants With Non-alcoholic Steatohepatitis

Study Overview
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Brief Summary
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This Phase 1/2 study will evaluate safety, efficacy, PK, and PD of FT-4101 as a single agent in overweight/obese subjects with NASH. The study may be conducted in up to 2 dosing cohorts.

Official Title
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A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability and Efficacy of FT-4101 in Overweight/Obese Subjects With NASH

Conditions
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Nonalcoholic Steatohepatitis (NASH), Overweight or Obesity

Intervention / Treatment
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* Drug: FT-4101
* Drug: FT-4101 placebo
* Other: Deuterated Water


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Meets all of the following criteria: CAP ≥ 300 dB/m by FibroScan® OR Liver biopsy within 24 months, consistent with NASH with stage 2-3 fibrosis Screening MRI-PDFF with ≥ 10% steatosis. Body mass index (BMI) > 25.0 to < 45.0 kg/m2 Stable body weight Subjects with T2DM may also be included, if: Subject with T2DM is on stable doses of metformin monotherapy (subjects on combination therapy of metformin and sulfonylurea (SU) need to undergo washout period prior to dosing) with no changes in medication within the previous 6 months HbA1c < 9% (one retest is permitted with the result of the last test being conclusive) Fasting plasma glucose (FPG) < 240 mg/dL (<13.3 mmol/L) Waist circumference ≤ 57 inches Female subjects must be non-pregnant and non-lactating Key Exclusion Criteria: Type 1 diabetes and type 2 diabetic subjects on insulin therapy Diabetic complications, such as acute proliferative retinopathy Recurrent severe hypoglycemia or hypoglycemic unawareness or recent severe ketoacidosis History of, or active, chronic liver disease due to alcohol, auto-immune, primary biliary cholangitis, HIV, HBV or active HCV-infection, Wilson's, α-1-antitrypsin deficiency, hemochromatosis, etc., and not due to NASH disease History of clinically significant or decompensated chronic liver disease including esophageal varices, ascites, encephalopathy or any hospitalization for treatment of chronic liver disease; or MELD score ≥ 10. History of significant cirrhosis of the liver Alcohol consumption greater than 14 drinks per week for men or greater than 7 drinks per week for women and/or positive alcohol breath test Introduction of an anti-obesity drug in the past 6 months prior to screening History of gastrointestinal malabsorptive bariatric surgery, any other gastrointestinal surgery that may induce malabsorption, history of bowel resection > 20 cm, any malabsorption disorder, severe gastroparesis, any GI procedure for weight loss, as well as clinically significant gastrointestinal disorders within less than 5 years Ingestion of drugs known to produce hepatic steatosis including corticosteroids, high- dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease events, including congestive heart failure, unstable coronary artery disease, myocardial infarction Significant systemic or major illnesses other than liver disease, including cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator, would preclude treatment with FT-4101 and/or adequate follow up History of chronic skin conditions such as psoriasis, eczema or any recurring rash/dermatitis requiring oral or topical corticosteroids or other topical applications within 12 months Hair loss or unexplained alopecia within 12 months History of chronic eye conditions, Sjögren syndrome or any history of dry eyes or allergic conjunctivitis requiring artificial tears or medicated eye drops or previous refractive surgery within 12 months (Subjects with dry eyes due to wearing contact lenses are eligible) History of major depression, anxiety, suicidal behavior or attempts, or other unstable psychiatric disorders (within 2 years of screening), requiring medical treatment Uncontrolled hypertension Any device or other contraindication with the MRI examination Ingestion of deuterated water within the previous 6 months Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) antibody Participation in any other clinical interventional study receiving active treatment within the previous 30 days or 5 half-lives, whichever is longer Unable to abstain from smoking during confinement periods History of illicit drug abuse Clinically under the effect of marijuana at screening Unwillingness to abstain from grapefruit (grapefruit containing food and beverages), star fruit (carambola), pomegranate, Seville orange and other food components that may interact with CYP3A4 from check-in throughout the entire course of the study Donation or loss of > 500 mL of blood or blood product within 56 days of dosing

Ages Eligible for Study
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Minimum Age: 18 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: Cohort A<br> | Drug: FT-4101<br>* FT-4101 will be supplied as active capsules and will be administered per the protocol defined frequency and dose level.<br>Drug: FT-4101 placebo<br>* FT-4101 placebo will be supplied as placebo capsule matching in size and color to all the active capsules and will be administered per the protocol defined frequency and dose level.<br>Other: Deuterated Water<br>* Deuterated water will be provided as individual ready-to-use, single dose bottles each containing 50 mL of deuterated water (70%).<br>|
| Experimental: Cohort B<br> | Drug: FT-4101<br>* FT-4101 will be supplied as active capsules and will be administered per the protocol defined frequency and dose level.<br>Drug: FT-4101 placebo<br>* FT-4101 placebo will be supplied as placebo capsule matching in size and color to all the active capsules and will be administered per the protocol defined frequency and dose level.<br>Other: Deuterated Water<br>* Deuterated water will be provided as individual ready-to-use, single dose bottles each containing 50 mL of deuterated water (70%).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Incidence of clinical lab abnormalities |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in vital signs (blood pressure [BP]: mmHg) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in vital signs (heart rate [HR]: beats/min) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in vital signs (respiratory rate [RR]: breaths/min) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in vital signs (temperature [aural]: degrees Celsius) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in 12-lead electrocardiogram (ECG) parameters (heart rate [HR]: beats/min) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in 12-lead electrocardiogram (ECG) parameters (QT interval: milliseconds) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in 12-lead electrocardiogram (ECG) parameters (PR interval: milliseconds) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in 12-lead electrocardiogram (ECG) parameters (QRS interval: milliseconds) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in 12-lead electrocardiogram (ECG) parameters (RR interval: milliseconds) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Change from baseline in 12-lead electrocardiogram (ECG) parameters (QTcF interval: milliseconds) |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Reduction (absolute and relative) of % liver fat on MRI-PDFF |  | Assessed at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction (absolute and relative) of % liver fat on MRI-PDFF |  | Assessed for up to approximately 20 weeks | 
| Proportion of patients experiencing a relative reduction of 30% or greater of liver fat as assessed by MRI-PDFF |  | Assessed for up to approximately 20 weeks | 
| Assess the PD effect of FT-4101 on circulation biomarkers of liver inflammation after administration of multiple doses by assessment of the reduction of the following liver biochemistry markers: ALT, AST, γGT, Alkaline phosphatase, Total bilirubin |  | Participants to be followed for duration of participation, which is approximately 20 weeks | 
| Maximum concentration (Cmax) |  | Blood samples for PK analysis collected at up to 9 study visits over the course of approximately 20 weeks | 
| Time to maximum concentration (Tmax) |  | Blood samples for PK analysis collected at up to 9 study visits over the course of approximately 20 weeks | 
| Area under the concentration-time curve for a dosing interval (AUCtau) |  | Blood samples for PK analysis collected at up to 9 study visits over the course of approximately 20 weeks | 
| Trough plasma concentrations (Ctrough) at steady state |  | Blood samples for PK analysis collected at up to 9 study visits over the course of approximately 20 weeks |