A Phase 1 Randomised, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INI-822 in Healthy Volunteers and Participants with Non-alcoholic Steatohepatitis (NASH) or Presumed NASH
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, and D and in participants with a history of NASH or presumed NASH in Part C.
• Females must not be pregnant or lactating, and must use acceptable, highly effective double contraception (see Section 7.3.1) from Screening until 90 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 90 days after the last dose of IP or 5 half-lives, whichever is longer.
• 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 (see Section 7.3.1) must be used from Day -1 until study completion. 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 90 days after the last dose of IP or 5 half-lives, whichever is longer.
• Able and willing to attend the necessary visits to the study site.
• 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.
• Normal renal function (estimated glomerular filtration rate \> 60 mL/min using Cockcroft-Gault).
• For Parts A and B only:
• 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 Medical Monitor (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.
• 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.
• Body mass index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2 with a maximum body weight of 120 kg.
• 18 to 55 years of age (inclusive at the time of informed consent).
⁃ 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:
• 18 to 65 years of age (inclusive at the time of informed consent).
‣ 12\. A diagnosis of NASH confirmed by 1 or more of the following:
• Historical liver biopsy consistent with NASH (presence of Grade 1 steatosis, hepatocellular ballooning, and lobular inflammation) according to the non-alcoholic fatty liver disease (NAFLD) activity score.
• F0-3 fibrosis according to the NASH Clinical Research Network classification within 1 year of Screening.
• A clinical diagnosis of NASH, and the presence of any component of the metabolic syndrome (obesity, dyslipidemia, hypertension, elevated fasting glucose, or type 2 diabetes).
• 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 ≥ 18.0 and ≤ 40.0 kg/m2