Metabolic Dysfunction-Associated Steatohepatitis
Conditions
Keywords
Metabolic Dysfunction-Associated Steatohepatitis (MASH) or Presumed MASH
Brief summary
This Phase 1 trial will explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses of INI-822 in healthy volunteers in Parts A, B, D and F and in participants with a history of MASH or presumed MASH in Part C and in participants with MASH in E.
Detailed description
The study will consist of 6 parts: Approximately 168 participants are planned to be enroled into the study. * In Part A (SAD), approximately 48 healthy adult participants are planned to be enroled in 5 cohorts of 8 participants each (Cohorts A1 to A5, including one fasted:fed crossover cohort to assess food effect). * In Part B (MAD), approximately 24 healthy adult participants are planned to be enroled in 3 cohorts of 8 participants each (Cohorts B1 to B3). * In Part C (Pharmacodynamics), approximately 24 participants with Metabolic Dysfunction-Associated Steatohepatitis (MASH) or Presumed Metabolic Dysfunction-Associated Steatohepatitis (MASH) are planned to be enrolled in 2 cohorts of 12 participants each (Cohorts C1 to C2). * In Part D (SAD Tablet Formulation Crossover), approximately 8 healthy adult participants are planned to be enrolled in 1 Cohort of 8 participants. * In Part E (POC), approximately 48 participants with Metabolic Dysfunction-Associated Steatohepatitis (MASH) are planned to be enrolled in 2 cohorts of approximately 24 participants each (Cohorts E1 to E2). * In Part F (TMD), approximately 24 healthy adult participants are planned to be enrolled in 3 cohorts of 8 participants each (Cohorts F1 to F3). Note: The total number of participants planned is 168 as Cohort A6 has been removed based on SRC review. Estimated overall study duration: 18 months Estimated study duration for each participant: * Part A: up to 5 weeks including Screening for 5 fasted cohorts and at least 7 weeks for the fasted:fed crossover cohort, dependent on Safety Review Committee (SRC) decision on timing of the fed dosing (healthy volunteers) * Part B: up to 7 weeks including Screening (healthy volunteers) * Part C: up to 9 weeks including Screening (participants with MASH or presumed MASH) * Part D: up to 6 weeks including Screening (healthy volunteers) * Part E: up to 18 weeks including Screening (participants with MASH) * Part F: up to 7 weeks including Screening (healthy volunteers)
Interventions
OTHERPlacebo (B)
Matching placebo to INI-822
DRUGINI-822 (A)
Different dose levels of INI-822
Sponsors
Inipharm Australia Pty Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
1. Females must not be pregnant or lactating, and must use acceptable, highly effective double contraception from Screening until 30 days after their last dose of IP or 5 half-lives, whichever is longer. Females with same-sex partners (abstinent from penile-vaginal intercourse) or who are abstinent from heterosexual intercourse are not required to use contraception when this is their preferred and usual lifestyle. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Day -1. Women not of childbearing potential must be postmenopausal for ≥ 12 months (postmenopausal status is to be confirmed through testing of follicle stimulating hormone \[FSH\] levels ≥ 40 IU/L at Screening for amenorrhoeic female participants). Females must not donate ova from the first dose of IP until at least 30 days after the last dose of IP. 2. Males must be surgically sterile (\> 30 days since vasectomy \[documented evidence\] with no viable sperm), or, if engaged in sexual relations with a WOCBP, they must use a condom and either his partner must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or an acceptable, highly effective contraceptive method must be used from Day -1 until at least 30 days after the last dose of IP. Males with same-sex partners (abstinent from penile-vaginal intercourse) or abstinent from heterosexual intercourse are not required to use contraception when this is their preferred and usual lifestyle. Males must not donate sperm from the first dose of IP until at least 30 days after the last dose of IP. 3. Able and willing to attend the necessary visits to the study site. 4. Able and willing to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures. 5. Normal renal function (estimated glomerular filtration rate \> 60 mL/min using Cockcroft-Gault) at Screening and Day -1 Visits. For Parts A and B, D, and F only: 6. Clinical laboratory values within normal range at Screening and Day -1 and Day 7 (Part D), as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or designee. Any laboratory values \> upper limit of normal (ULN) at Screening should be discussed with the Sponsor, independent MM, or Investigator for approval prior to inclusion. Repeat testing at Screening is acceptable for out-of-range values following approval by the Investigator or designee. Inclusion of participants with laboratory values \> ULN at Day -1 and Day 7 (Part D) will be at the Investigator's discretion. 7. In good general health, with no significant medical history, and no clinically significant abnormalities on physical examination at Screening and/or before the first administration of IP, at the discretion of the Investigator or designee. 8. Body mass index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2 with a maximum body weight of 120 kg. 9. 18 to 55 years of age (inclusive at the time of informed consent). 10. Able and willing to refrain from use of tobacco and other nicotine-containing products while at the study site and through the study treatment period. For Part C only: 11.18 to 65 years of age (inclusive at the time of informed consent). 12\. A diagnosis of MASH confirmed by 1 or more of the following: 1. Historical liver biopsy consistent with MASH (presence of Grade 1 steatosis, hepatocellular ballooning, and lobular inflammation) according to the non-alcoholic fatty liver disease (MAFLD) activity score. 2. F0-3 fibrosis according to the MASH Clinical Research Network classification within 1 year of Screening. 3. A clinical diagnosis of MASH, and the presence of any component of the metabolic syndrome (obesity, dyslipidemia, hypertension, elevated fasting glucose, or type 2 diabetes). 4. FibroScan-aspartate aminotransferase (FAST) score more than equal to 0.35. 13\. Alanine aminotransferase (ALT) \> 1.00 × ULN at 2 separate time points in the past 6 months. At least 1 time point must be at Screening and the values must be at least 2 weeks apart. Patients with ALT values \<1.00 × ULN may be included in the study on a case-by-case basis after approval by the Sponsor. 14\. Fibrosis-4 (FIB-4) score ≤ 2.67, controlled attenuation parameter (CAP) score by FibroScan® ≥ 280 Db/m, and liver stiffness measurement (LSM) by FibroScan® ≤ 14 kPa. 15\. No documented weight loss \> 5% in the 6 months preceding Screening. 16\. If on glucagon-like peptide 1 (GLP1) agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors, or vitamin E (dose \> 400 IU/day), then should have been on a stable dose for at least 3 months. 17\. Platelet count \> 150,000 and albumin ≥ 35 g/L. 18\. BMI Greater than equals to 18.0 and ≤ 40.0 kg/m2 For Part E only: 19\. 18 to 70 years of age (inclusive at the time of informed consent). 20\. A diagnosis of MASH confirmed by 1 or more of the following: 1. Historical liver biopsy within 1 year of Screening, consistent with MASH (presence of Grade 1 steatosis, hepatocellular ballooning, and lobular inflammation) according to the non-alcoholic fatty liver disease (MAFLD) activity score. 2. F0-3 fibrosis according to the MASH Clinical Research Network classification within 1 year of Screening. 3. FibroScan-aspartate aminotransferase (FAST) score ≥ 0.36 and AST ≥ 24. 21\. FIB-4 score ≤ 3.25, CAP score by FibroScan® ≥ 280 Db/m, and LSM by FibroScan® ≤ 15 kPa. 22\. No documented weight loss \> 5% in the 6 months prior to first IP administration. 23\. If on GLP1 agonists, SGLT2 inhibitors, or vitamin E (dose ≥ 400 IU/day), then should have been on a stable dose for at least 3 months prior to first IP administration. 24\. Platelet count ≥ 150,000 and albumin ≥ 35 g/L at Screening and Day -1 Visits. 25\. BMI ≥ 18.0 and ≤ 45.0 kg/m2.
Exclusion criteria
A participant who meets any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs). | Part A: Up to 5 Weeks | AEs will be graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Number of participants with clinical laboratory abnormalities | Part A: Up to 5 Weeks | Abnormal laboratory findings (e.g., haematology, biochemistry, coagulation, and urinalysis) or other abnormal assessments (e.g., ECG and vital signs) per se are not reported as AEs. |
| Incidence of adverse events (AEs) | Part E: Up to 12 weeks | AEs will be graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma area under the curve (AUC) from time 0 to t (AUC0-t) | Part A: Up to 5 Weeks, Part A fasted fed crossover cohort: Up to 8 weeks, Part B: Up to 7 weeks, Part C: Up to 9 weeks, Part E: Up to 12 Week | The results of the outcome are collectively measured. |
| AUC from time 0 to infinity (AUC0-inf) | Part A: Up to 5 Weeks, Part A fasted fed crossover cohort: Up to 8 weeks, Part B: Up to 7 weeks, Part C: Up to 9 weeks | The results of the outcome are collectively measured. |
| Maximum concentration (Cmax) | Part A: Up to 5 Weeks, Part A fasted fed crossover cohort: Up to 8 weeks, Part B: Up to 7 weeks, Part C: Up to 9 weeks | The results of the outcome are collectively measured. |
Countries
Australia
Contacts
CONTACTKatelyn Patterson
Outcome results
None listed