A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HW243040 in Healthy Participants

This is a first-in-human, Phase I, randomized, double-blind, placebo-controlled, single-center, dose-escalation clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HW243040, a novel angiotensin II type 2 receptor (AT2R) antagonist, in healthy participants. Preclinical data have demonstrated that HW243040 exhibits good analgesic efficacy in neuropathic pain models with a favorable safety profile, supporting its further clinical development. This study does not aim to explore the maximum tolerated dose (MTD) but focuses on characterizing the safety and PK profile across a range of doses.

The study is divided into two main parts: Part A (Single Ascending Dose, SAD, combined with a Food Effect evaluation) and Part B (Multiple Ascending Dose, MAD) . A total of approximately 98 healthy participants are planned for enrollment across both parts.

Part A: SAD and Food Effect Study Part A consists of 6 dose cohorts: 50 mg, 150 mg, 300 mg, 600 mg, 900 mg, and 1200 mg. Except for the 600 mg cohort, each cohort enrolls 10 participants (8 receiving active HW243040 and 2 receiving placebo) under fasting conditions. The 600 mg cohort enrolls 18 participants (16 active, 2 placebo) and utilizes a two-period, two-sequence crossover design to evaluate the effect of a high-fat, high-calorie meal on the PK of HW243040. In this cohort, participants receive the study drug under fasting conditions in one period and under fed conditions in the other, with a 7-day washout between periods. Dose escalation proceeds sequentially from the lowest to the highest dose, with dose progression decisions made by a Safety Review Committee (SRC) based on review of safety and available PK data from the preceding cohort. Dose escalation will be halted if predefined stopping criteria are met (e.g., ≥1/2 participants with moderate related AEs, ≥1/3 with severe related AEs, or any related SAE).

Part B: MAD Study Based on the safety and PK results from Part A, Part B evaluates three dose levels of HW243040 administered twice daily (BID). The planned dose levels are 150 mg, 300 mg, and 600 mg BID. Each cohort enrolls 10 participants (8 active, 2 placebo). Participants receive the study drug for 5 consecutive days (morning and evening, approximately 12 hours apart, for a total of 9 administrations, with only the morning dose given on Day 5). The final dosing regimen, duration, and sampling schedule for Part B may be adjusted based on emerging data from Part A.

Study Population:

Healthy male and female participants aged 18 to 55 years, with a body mass index (BMI) between 19 and 26 kg/m², and body weight ≥50 kg for males and ≥45 kg for females. Participants must be willing to undergo pain testing procedures and comply with the study requirements.

Intervention and Blinding:

HW243040 is formulated as oral tablets in 50 mg and 200 mg strengths. Matching placebo tablets are provided. The study is double-blinded; participants, investigators, site staff, and outcome assessors will be blinded to treatment allocation. Randomization is performed using a block randomization method with a 8:2 (active:placebo) ratio for most cohorts (and 8:1 for the 600 mg SAD cohort).

Study Procedures and Assessments:

The study comprises a screening period (Day -7 to Day -1), a treatment/observation period, and a follow-up period (for unresolved AEs).

Safety Assessments: Include monitoring of adverse events (AEs), serious adverse events (SAEs), vital signs, physical examinations, 12-lead electrocardiograms (ECGs), clinical laboratory tests (hematology, biochemistry, urinalysis, coagulation, and thyroid function), and pregnancy tests for females of childbearing potential. A C-QTc sub-study is planned for cohorts at doses ≥300 mg (including the 600 mg cohort, Sequence A only) to explore the relationship between HW243040 plasma concentrations and changes in QTcF interval.

Pharmacokinetic Assessments:

SAD/FE (non-600mg cohorts): Blood samples are collected at 13 time points from pre-dose to 72 hours post-dose.

SAD/FE (600mg cohort): Blood samples are collected at 26 time points across two periods (up to 72 hours post-dose per period).

MAD: Blood samples are collected on Day 1 (pre-dose to 12 hours), pre-dose on Days 3, 4, and 5, and intensively on Day 5 up to 72 hours post final dose (25 time points total).

Urine and Feces (Exploratory): Full urine and fecal samples are collected from participants in Sequence A of the 600 mg cohort during the first period for metabolite profiling and excretion mass balance exploration.

Pharmacodynamic Assessments:

PD evaluations are performed using standardized pain tests, including Pressure Pain Threshold (PPT) measured by a pressure algometer and Pain Tolerance Time (PTT) measured by the cold pressor test (immersion of hand in ice water, maximum 120 seconds). PD assessments are conducted at pre-dose and at 1, 2, 4, 6, 8, and 12 hours post-dose.

Pharmacokinetic Parameters:

Key PK parameters calculated using non-compartmental analysis include: C~max~, T~max~, AUC~0-t~, AUC~0-inf~, t~1/2~, CL/F, and Vz/F (SAD); and additionally C~trough,ss~, AUC~tau,ss~, and accumulation ratios (R~ac~) for MAD.

Statistical Analysis:

Analyses will be performed using SAS (Version 9.4 or higher). The Safety Analysis Set (SS) will be used for all safety summaries. PK parameters will be summarized descriptively by dose group. For the food effect evaluation, a linear mixed-effects model (with sequence, period, and treatment as fixed effects and participant as random effect) will be applied to log-transformed exposure parameters (AUC~0-t~, AUC~0-inf~, C~max~) to calculate geometric mean ratios and 90% confidence intervals. PD endpoints, C-QTc relationship, and dose proportionality will be explored descriptively or via appropriate modeling approaches (e.g., power model, linear mixed-effects model).

Study Duration and Follow-up:

Participants will be confined to the clinical unit from Day -1 through the end of the observation period (Day 4 for most SAD cohorts; Day 11 for the 600 mg cohort; Day 8 for MAD cohorts). All participants with ongoing AEs at discharge will be followed until resolution, return to baseline, stabilization, or loss to follow-up.

The study is being conducted at a single center, The Third Xiangya Hospital of Central South University, Changsha, China, under the sponsorship of Hubei Bio-Pharmaceutical Industrial Technology Research Institute Co., Ltd.

Inclusion criteria

• Signed informed consent form prior to any study-related procedures, with full understanding of the study content, procedures, and potential adverse reactions, and ability to complete the study as per protocol requirements.
• Healthy male or female, aged ≥ 18 and ≤ 55 years on the day of signing the informed consent form.
• Body weight: males ≥ 50 kg, females ≥ 45 kg; body mass index (BMI) between 19 and 26 kg/m² inclusive (BMI = weight (kg) / height² (m²)).
• Vital signs, physical examination, laboratory tests (hematology, blood biochemistry, urinalysis, coagulation function, and thyroid function), and 12-lead electrocardiogram (ECG) findings are normal or clinically insignificant at screening and baseline.
• Abdominal ultrasound, thyroid ultrasound, and chest X-ray findings are normal or clinically insignificant at screening.
• Willing and able to undergo pain testing procedures and trained qualified.
• Female participants of childbearing potential and male participants with partners of childbearing potential must have adopted contraceptive measures within 2 weeks prior to signing the informed consent form, and must agree to remain abstinent or use highly effective contraceptive methods from the signing of the informed consent form through the end of the follow-up period.
• Female participants of childbearing potential must agree to use highly effective contraceptive methods during the study and for 3 months after the last dose; serum pregnancy test must be negative at screening and baseline, and must not be breastfeeding. Male participants must agree to use highly effective contraceptive methods and refrain from sperm donation during the study and for 3 months after the last dose.

Exclusion criteria

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• Presence of any of the following diseases or treatment history:

• Current or previous history of any clinically significant disease involving the urinary, cardiovascular, endocrine, neurological, digestive, respiratory, hematopoietic, immune, psychiatric, or metabolic systems, or any other condition that, in the investigator's judgment, may interfere with the study results, such as intestinal diseases (including irritable bowel syndrome) and urinary tract infections.
• History of malignancy (except for cancers that have been cured or in remission for ≥ 5 years, radically resected basal cell or squamous cell skin carcinoma, in situ cervical carcinoma, and resected colon polyps).
• Any condition or disease that, in the investigator's judgment, may affect the absorption, metabolism, and/or excretion of the study drug.
• Severe infection, severe trauma, or major surgery within 3 months prior to screening or baseline, or planned surgery during the study period.
• Use of any medication (including prescription drugs, over-the-counter drugs, herbal medicines, dietary supplements, vitamin A and its derivatives, etc., except for routine vitamins and occasional use of acetaminophen) within 2 weeks prior to screening or baseline, or still within 5 half-lives of the drug at screening or baseline (whichever is longer); or planned use of non-study medications during the study period.
• Participation in any other drug or medical device clinical trial within 3 months prior to screening or baseline, or planned participation during the study period, or still within 5 half-lives of the investigational drug at screening or baseline (whichever is longer).

• Any of the following laboratory findings at screening:

• Sitting systolic blood pressure < 90 mmHg or sitting diastolic blood pressure < 50 mmHg at screening or baseline.
• Orthostatic hypotension confirmed by repeat measurement within 15 minutes at screening or baseline.
• Clinically significant 12-lead ECG abnormalities at screening or baseline; QTcF > 450 ms for males or QTcF > 460 ms for females.
• Positive for hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV) antibody, syphilis antibody, or hepatitis C virus (HCV) antibody at screening.

• General conditions:

• Blood donation or significant blood loss (≥ 400 mL) within 8 weeks prior to screening or baseline, or blood transfusion within 4 weeks prior to screening or baseline; or intention to donate blood during the study period.
• Vaccination within 2 weeks prior to screening or baseline, or planned vaccination during the study period.
• Smoking history (average > 5 cigarettes per day) within 4 weeks prior to screening or baseline, or inability to refrain from using any tobacco products during the study period.
• Average daily alcohol intake > 15 g within 4 weeks prior to screening or baseline (15 g alcohol is equivalent to approximately 450 mL beer, 150 mL wine, or 50 mL liquor), or inability to abstain from alcohol during the study period; or positive breath alcohol test at baseline.
• History of drug abuse or dependence prior to screening or baseline; or positive urine drug screen at baseline.
• Excessive consumption of tea, coffee, or caffeinated beverages (average > 8 cups per day, 250 mL per cup) within 6 months prior to screening or baseline.
• Consumption of special foods (such as grapefruit, grapefruit juice, or foods/beverages containing grapefruit juice, chocolate, tobacco, alcohol, caffeinated foods or beverages, etc.) within 48 hours prior to baseline.
• Special dietary requirements or inability to comply with the standardized diet provided by the study center.
• Dysphagia, difficulty in venous blood collection, or physical condition unable to tolerate intensive blood sampling.
• Known allergy to any component of the investigational medicinal product; history of allergic diseases or allergic constitution.
• Use of strong or moderate inhibitors/inducers of CYP2C9, or any inhibitors of P-gp, OATP1B1, OATP1B3, or OAT3 within 30 days prior to screening or planned during the study period.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in this study, including but not limited to any physiological or psychological condition that may increase the risk of the study, affect the participant's compliance with the protocol, or affect the participant's ability to complete the study.