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

Phase 1

Terminated

Conditions: Nonalcoholic Steatohepatitis (NASH)
Overweight or Obesity

Interventions: Drug: FT-4101
Drug: FT-4101 placebo
Other: Deuterated Water

Registration Number: NCT04004325

Lead Sponsor: Forma Therapeutics, Inc.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Meets all of the following criteria:
1. CAP ≥ 300 dB/m by FibroScan® OR Liver biopsy within 24 months, consistent with NASH with stage 2-3 fibrosis
2. 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:
1. 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
2. HbA1c < 9% (one retest is permitted with the result of the last test being conclusive)
3. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A	FT-4101	-
Cohort A	FT-4101 placebo	-
Cohort A	Deuterated Water	-
Cohort B	FT-4101	-
Cohort B	FT-4101 placebo	-
Cohort B	Deuterated Water	-

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Liver Fat on Magnetic Resonance Imaging- Proton Density Fat Fraction (MRI-PDFF)	At week 12	Percent change from baseline in liver fat on MRI-PDFF is reported.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From start of study drug administration up to 20 weeks	TEAEs were defined as an adverse events (AEs) with an onset that occurred after receiving the first dose of the study drug (AE start date greater than or equal to \[\>=\] first dose date) and within 30 days after receiving the last dose of the study drug (AE start date - last dose date less than or equal to \[\<=\] 30). Number of participants with TEAEs are reported.
Number of Participants With Clinically Significant Changes in Laboratory Values	Up to 20 weeks	Number of participants with clinically significant changes in laboratory values (hematology, serum chemistry, and urinalysis) are reported.
Number of Participants With Clinically Significant Changes in Physical Examination	Up to 20 weeks	Number of participants with clinically significant changes in physical examination are reported.
Change From Baseline in Vital Signs: Blood Pressure (BP)	Baseline, Day 92	Change from baseline in blood pressure (systolic and diastolic) are reported.
Change From Baseline in Vital Signs: Heart Rate (HR)	Baseline, Day 92	Change from baseline in heart rate is reported.
Change From Baseline in Vital Signs: Respiratory Rate	Baseline, Day 92	Change from baseline in respiratory rate is reported.
Change From Baseline in Vital Signs: Temperature	Baseline, Day 92	Change from baseline in temperature is reported.
Change From Baseline in 12-lead Electrocardiogram (ECG) Parameters: ECG Mean Heart Rate	Baseline, Day 92	Change from baseline in ECG mean heart rate is reported.
Change From Baseline in 12-lead ECG Parameters: QT Interval	Baseline, Day 92	Change from baseline in QT interval is reported.
Change From Baseline in 12-lead ECG Parameters: PR Interval	Baseline, Day 92	Change from baseline in PR interval is reported.
Change From Baseline in 12-lead ECG Parameters: QRS Interval	Baseline, Day 92	Change from baseline in QRS interval is reported.
Change From Baseline in 12-lead ECG Parameters: RR Interval	Baseline, Day 92	Change from baseline in RR interval is reported.
Change From Baseline in 12-lead ECG Parameters: QTc (Corrected) Using the Fridericia Correction (QTcF) Interval	Baseline, Day 92	Change from baseline in QTcF interval is reported.
Change From Baseline in Liver Fat on Magnetic Resonance Imaging- Proton Density Fat Fraction (MRI-PDFF)	At week 12	Change from baseline in percentage of liver fat on MRI-PDFF is reported.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Liver Fat on MRI-PDFF	At week 6	Change from baseline in percentage of liver fat on MRI-PDFF is reported.
Percent Change From Baseline in Liver Fat on MRI-PDFF	At week 6	Percent change from baseline in liver fat on MRI-PDFF is reported.
Percentage of Participants Experiencing a Relative Reduction of 30% or Greater of Liver Fat as Assessed by MRI-PDFF	At week 12	Percentage of participants experiencing a relative reduction of 30% or greater of liver fat as assessed by MRI-PDFF at week 12 are reported.
Change From Baseline in Alanine Aminotransferase (ALT)	Baseline, Day 92	Change from baseline in ALT is reported.
Change From Baseline in Aspartate Aminotransferase (AST)	Baseline, Day 92	Change from baseline in AST is reported.
Change From Baseline in Gamma-glutamyl Transferase (γGT)	Baseline, Day 92	Change from baseline in γGT is reported.
Change From Baseline in Alkaline Phosphatase	Baseline, Day 92	Change from baseline in alkaline phosphatase is reported.
Change From Baseline in Total Bilirubin	Baseline, Day 92	Change from baseline in total bilirubin is reported.
Maximum Plasma Concentration (Cmax) of FT-4101	Cycle 1 (Day 1), Cycle 4 (Day 14); each Cycle length = 21 days	Maximum plasma concentration (Cmax) of FT-4101 is reported
Area Under the Concentration-time Curve for a Dosing Interval (AUCtau) of FT-4101	Cycle 1 (Day 1), Cycle 4 (Day 14); each Cycle length = 21 days
Data for This Endpoint Was Not Collected and Analysed.	Cycle 1 (Day 1), Cycle 4 (Day 14); each Cycle length = 21 days