A Study of NST-6179 in Adult Subjects With Intestinal Failure-Associated Liver Disease (IFALD).

Study Overview
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Brief Summary
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This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NST-6179 in adult subjects with intestinal failure-associated liver disease (IFALD) receiving parenteral nutrition (PN). The study will be conducted in 2 sequential parts. Up to 36 adult subjects diagnosed with IFALD will be enrolled in the study, of which 18 subjects will be enrolled in each of the 2 parts and randomized (2:1) to receive NST-6179 (N=12/part) or matched placebo (N=6/part). Subjects in Part A will receive once daily (QD) oral administration of 800 mg (32 mL solution) NST-6179 or placebo for 4 weeks. The NST-6179 dose for Part B is planned to be 1200 mg QD for 12 weeks. Actual dose, however, will be determined during the safety review meeting.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NST-6179 in Adult Subjects With Intestinal Failure-Associated Liver Disease (IFALD)

Conditions
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Intestinal Failure Associated Liver Disease

Intervention / Treatment
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* Drug: NST-6179 Part A
* Drug: NST-6179 Part B
* Other: Matched Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adult persons aged 18 years or older at the time of informed consent. Minimum of 6 months on Parenteral supplementation. Established clinical diagnosis of IFALD based on a persistent elevation of liver enzymes (ALP, AST, ALT, or GGT ≥1.5 × upper limit of normal [ULN]) for ≥6 months and/or total bilirubin > ULN for ≥6 months. Laboratory parameters consistent with stable liver disease without cirrhosis as defined by: ALT and AST <5 × ULN; Total bilirubin ≤2.0 mg/dL in the absence of Gilbert's Syndrome. Serum albumin ≥3 g/dL; International normalized ratio (INR) ≤1.3 in the absence of anticoagulant therapy; Platelet count ≥120,000/mm3. Key Exclusion Criteria: Clinical, laboratory, imaging, or histopathologic evidence of other causes of acute or chronic liver disease, including autoimmune, viral, metabolic, or alcoholic liver disease. Clinical evidence of compensated or decompensated hepatic cirrhosis as assessed by historical liver histology, ultrasound-based and/or signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy). Presence of hepatic impairment, end-stage liver disease, and/or a model for end-stage liver disease (MELD) score >12. Transient elastography read >20.0 kPA within 3 months prior to or during the Screening Period. Estimated glomerular filtration rate <45 mL/min based on the 2021 CKD-EPI creatinine equation. Poor nutritional status defined as body mass index (BMI) <17 kg/m2.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A-800 mg NST-6179<br>up to 12 subjects | Drug: NST-6179 Part A<br>* Once daily (QD) oral administration of 800mg (32 mL solution) of NST-6179 for 4 weeks<br>|
| Experimental: Part A matched NST-6179 placebo<br>up to 6 subjects | Other: Matched Placebo<br>* Matched placebo for administration in Part A or Part B<br>|
| Experimental: Part B- 1200mg NST-6179<br>up to 12 subjects | Drug: NST-6179 Part B<br>* Once daily (QD) oral administration of 1200mg of NST-6179 for 12 weeks<br>|
| Experimental: Part B matched NST-6179 placebo<br>up to 6 subjects | Other: Matched Placebo<br>* Matched placebo for administration in Part A or Part B<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and tolerability of NST-6179 | Incidences of treatment-emergent adverse events, clinically significant chances in laboratory tests, vital signs and ECGs | Up to 14 Weeks | 
| To assess the pharmacokinetics of NST-6179 | area under the concentration-time curve from time 0 to last measurable concentration (AUC0-last) | Day 1 and Day 14 | 
| To assess the pharmacodynamic effects of NST-6179 on hepatic steatosis | Relative change from baseline to week 12 in biomarkers for hepatic steatosis as measured by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) and controlled attenuation parameter (CAP) | 12 weeks | 
| To assess the pharmacodynamic effects of NST-6179 on hepatic inflammation | Absolute and relative change from baseline to week 12 in hepatic inflammation (aspartate transaminase [AST], alanine transaminase [ALT], and high sensitivity C-reactive protein [hsCRP]) | 12 weeks | 
| To assess the pharmacodynamic effects of NST-6179 on hepatic cholestasis (bilirubin, ALP, GGT) | Absolute and relative change from baseline to week 12 in hepatic cholestasis (total bilirubin, direct bilirubin, alkaline phosphatase [ALP], and gamma-glutamyl transferase [GGT]) | 12 weeks | 
| To assess the pharmacodynamic effects of NST-6179 on hepatic fibrosis (ELF, Pro-C3, FIB-4) | Absolute and relative change from baseline to week 12 in hepatic fibrosis as measured non-invasively by FibroScan VCTE kPa, enhanced liver fibrosis (ELF) score (and individual components), propeptide of type III collagen (PRO-C3), and fibrosis-4 (FIB-4) | 12 weeks |