A Study of HL40626S Tablets in Healthy Adults

In Part 1 (Single Ascending Dose, SAD), healthy participants are randomized 3:1 to receive a single fasting oral dose of HL40626S tablets or matching placebo across five sequential ascending dose cohorts (25 mg, 100 mg, 200 mg, 400 mg, 800 mg). Each cohort enrolls 8 participants. Participants stay confined at the clinical research unit (CRU) from Day -1 to Day 5 after dosing, with safety, PK and PD assessments conducted through 96 hours post-dose, and a follow-up end-of-study (EOS) visit scheduled on Day 15 ± 1. Sentinel dosing is implemented for every cohort to monitor initial safety before full cohort enrolment.

In Part 2 (Multiple Ascending Dose, MAD), healthy participants are randomized 3:1 to receive once-daily fasting oral doses of HL40626S tablets or matching placebo for 14 consecutive days across three sequential ascending dose cohorts (100 mg, 200 mg, 400 mg). Each cohort enrolls 8 participants. Participants remain as inpatients at the CRU from Day -1 through Day 18 after the final dose, with serial safety, PK, PD and anti-drug antibody (ADA) testing collected throughout dosing and for 96 hours after the last administration. A follow-up EOS visit takes place on Day 29 ± 1. All decisions to escalate to the next dose cohort were reviewed and approved by an independent Safety Review Committee (SRC) following complete data review of the preceding cohort.

Inclusion criteria

• Capable of understanding the written informed consent document; willingly provides valid, signed written informed consent; willing and able to comply with the schedule, requirements and restrictions of the study.
• Between the ages of 18.0 and 55.0 years (inclusive) at the time of Screening.
• BMI between 18.0 and 32.0 kg/m2 (inclusive) at the time of Screening, with a body weight ≥ 50 kg.
• In good general health, as determined by the Investigator.
• Female participants must be non-pregnant and non-lactating.
• Female participants must be of non-childbearing potential, or agree to use dual contraception methods (female participants exclusively in same-sex relationships are exempt from the above contraception requirements), and abstain from ova (egg) donation throughout the entire duration of the study and for at least 90 days after the last dose, and have negative pregnancy test results at Screening (serum) and Day -1 (urine). (Note: As this is a first-in-human [FIH] study, the applicable t₁/₂ and corresponding restriction period may be adjusted based on emerging PK data).
• Male participants with female partners of reproductive potential must agree to practice complete abstinence or to use a condom (male participant) plus an additional highly effective method (female partner) of contraception for the duration of the study and for at least 90 days after last dosing (Male participants exclusively in same-sex relationships are exempt from the above contraception requirements); all male participants must also agree to refrain from sperm donation for at least 90 days after the last dose. (Note: As this is a FIH study, the applicable t₁/₂ and corresponding restriction period will be adjusted based on real-time PK data).
• Supine blood pressure (BP) between 90/40 mmHg and 140/90 mmHg at Screening.
• Normal renal function as determined by Investigator following review of clinical laboratory test results, including eGFR ≥ 80 mL/min/1.73 m2, as estimated using the CKD EPI Creatinine Equation (2021).
• Less or equal to 5 cigarettes per week within 6 months prior to Day 1.
• Willing to comply with CRU's COVID 19 policy.

Exclusion criteria

• Clinically significant abnormal medical history, such as gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, drug hypersensitivity, as determined by the Investigator, any abnormal findings on physical examination, VS measurements, ECG or laboratory tests at Screening, Admission or pre dose on Day 1 that, in the opinion of the Investigator, could jeopardize achieving the study objectives and/or compromise the participant's safety.
• Any of the following ECG findings at Screening, Admission and/or pre dose on Day 1:

• Any out-of-range ECG parameter(s) or abnormal finding(s) considered clinically significant by the Investigator.
• Any ECG finding that, in the opinion of the Investigator, may compromise interpretation of ECG for cardiac safety assessments and/or complicate interpretation of events that may occur post dose (e.g., QT not accurately measurable, conduction abnormalities).
• Participants with QTcF >450 msec (if male) or >470 msec (if female) will be excluded.
• Resting HR < 40 bpm or >100 bpm when vital signs are measured at Screening
• SARS-CoV-2 positive by PCR at Admission regardless of symptoms.
• Unstable cardiovascular disease, including recent (within 6 months of screening) myocardial infarction or cardiac arrhythmia.
• Ongoing liver disease or unexplained liver function test (LFT) elevations, defined as ALT, AST, gamma glutamyltransferase (GGT), alkaline phosphatase (ALP) or total/direct bilirubin > upper limit of the reference range (ULRR) at Screening or Admission. Participants with confirmed Gilbert's syndrome will not be permitted to enroll in the study.
• Indications of pre-metabolic syndrome and/or systemic inflammation, as suggested by high-sensitivity C-reactive protein (hsCRP) of > 3 mg/L, elevated erythrocyte sedimentation rate (Male ≥ 15 mm/hr, Female ≥ 20 mm/hr) or Hemoglobin A1c (HbA1c) >5.3% at Screening.
• History of cancer (malignancy) with the exception of basal or squamous cell carcinoma of the skin.
• Respiratory tract infection (upper and/or lower) treated with antibiotics within 12 weeks of Screening.
• Clinically significant infection or known inflammatory condition or history of clinically significant infection within 28 days prior to study drug administration on Day 1 that, in the opinion of the Investigator, would affect the participant's ability to participate in the trial.
• History of drug or alcohol abuse (as defined by DSM-V) within 12 months prior to Screening.
• Positive test result for alcohol (breath) or drugs of abuse (urine) at Screening or Admission.
• Positive serology result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab) or human immunodeficiency virus antibody (HIV Ab) at Screening.
• Active or recent herpes simplex or herpes zoster infection, if considered clinically relevant as per investigator discretion.
• Venous access considered inadequate for PK sample collection; history of evidence of adverse symptoms associated with phlebotomy or blood donation.
• Participation in a study of any investigational drug, device, biologic or other agent within 30 days (or 5 half-lives, whichever is longer [as applicable]) prior to Day 1.
• Loss or donation of blood >500 mL (within 30 days prior to Screening); donation of bone marrow or peripheral stem cells (within 90 days prior to Day 1); or donation of plasma (within 7 days prior to Screening).
• No more than 10 standard drinks per week per NHMRC alcohol guidelines within 90 days prior to screening.
• Use of alcohol within 72 hours prior to study drug administration on Day 1.
• Use of prescription drugs within 14 days (or 5 half-lives, whichever is longer), or non-prescription drugs and/or herbal supplements within 7 days (or 5 half-lives, whichever is longer) prior to study drug administration on Day 1. Exception: hormonal contraceptives, acetaminophen ≤ 1 gram/day or ibuprofen ≤ 800 mg/day may be administered at Investigator's discretion.
• Use of any drugs known to be significant inhibitors or inducers of cytochrome P450 (CYP) enzymes and/or P-glycoprotein (P-gp), including St. John's Wort, for 28 days prior to the first dose of study drug and throughout the study.
• Receipt of any vaccine within 30 days prior to study drug administration on Day 1.
• Previous exposure to HL40626S.
• Known hypersensitivity to HL40626S or any of its constituents.
• Employee or family member of the Investigator, study site personnel or sponsor.
• Any other reason that, in the opinion of the Investigator, would render the participant unsuitable for study enrollment.
• Individuals with a history of tuberculosis (TB) or a positive TB- gold QuantiFERON test result at Screening.
• Unwilling to follow study restrictions and requirements.