Evaluating the Efficacy and Safety of of HSK44459 in Patients With Behçet's Disease

A Multi-center, Randomised, Double-blind, Placebo-controlled Phase II Clinical Study Evaluating the Efficacy and Safety of HSK44459 Tablets in Patients With Behçet's Disease

This is a phase 2, multi-center, randomised, double-blind, placebo-controlled study with an equal randomization among the HSK44459 dose 1, dose 2 and placebo treatment groups. The main objective is to evaluate of the efficacy and the secondary objective is to evaluate the safety and pharmacokinetic.

This study is a phase 2, multi-center, randomized, double - blind, placebo - controlled study designed to evaluate the efficacy and safety of HSK44459 in the treatment of patients with Behçet Disease (BD). Approximately 120 subjects will be randomized into this study.

The entire study will consist of 3 phases: a screening phase, a 12-week treatment phase, and a 4-week follow-up phase.

Screening: All subjects will undergo a screening period of up to 6 weeks before the first dose (Visit 3, Day 1).

Treatment phase: Eligible BD patients will be randomly assigned to the HSK44459 dose 1 group, the HSK44459 dose 2 group, or the placebo group. During the treatment period, HSK44459 or placebo will be administered twice daily for 12 weeks.

Follow-up phase: Subjects in the study (including those who withdraw from treatment for any reason) will have an additional 4 - week follow-up after the end of the last administration.

Inclusion Criteria:

1. Male and female subjects aged between 18 and 75 years (inclusive) at the time of signing the informed consent document.
2. Diagnosed with Behçet's disease (BD) meeting the International Criteria for Behçet's Disease (ICBD, ICBD-2013) criteria.
3. Suffered from at least 3 episodes of oral ulcers within 12 months prior to randomization.
4. Had at least 2 oral ulcers present during the Screening Phase.
5. Had received drug treatment for Behçet's disease.
6. Eligible for systemic treatment of oral ulcers.
7. Consented to participate in this trial, and voluntarily signed the informed consent form.

Exclusion Criteria:

1. Active involvement of major organs related to Behçet's disease - pulmonary (eg, pulmonary artery aneurysms), vascular (eg, thrombophlebitis), gastrointestinal (eg, gastrointestinal ulcers), and central nervous system (eg, meningoencephalitis) manifestations, and ocular lesions (eg, uveitis) requiring immunosuppressive treatment.

2. Subjects who have received the following immunomodulatory treatments, including:

   1. Hydroxychloroquine was used within 5 days prior to randomization;
   2. Colchicine was used within 7 days prior to randomization;
   3. Azathioprine, mycophenolate mofetil, baricitinib, or tofacitinib was used within 10 days prior to randomization;
   4. Cyclosporine, methotrexate, cyclophosphamide, thalidomide, or dapsone was used within 4 weeks (28 days) prior to randomization;
   5. Biological agents were used within 5 half-lives prior to randomization;

3. Subjects who have received systemic corticosteroid treatment prior to randomization;

4. Subjects who have used traditional Chinese patent medicines with immunomodulatory effects within 2 weeks prior to randomization; those who have taken traditional Chinese patent medicines that may affect the efficacy within 2 weeks prior to randomization;

5. Patients who have previously received systemic treatment with phosphodiesterase 4 (PDE4) inhibitors;

6. Patients who have used a strong CYP3A4 inhibitor or inducer within 14 days prior to randomization or within 5 pharmacokinetic half-lives (whichever is longer); and patients who insist on taking a strong CYP3A4 inhibitor or inducer during the study period;

7. Subjects who have used any investigational medicinal product within 4 weeks prior to randomization or within 5 pharmacokinetic half-lives (whichever is longer);

8. Laboratory tests during the screening period:

   • Hemoglobin ≤ 90g/L;
   • White blood cell count < 3.0×10⁹/L or white blood cell count > 14×10⁹/L;
   • Platelets < 100×10⁹/L;
   • Estimated Glomerular Filtration Rate (eGFR) ≤ 45 ml/min/1.73 m²;
   • Total bilirubin > 1.5×ULN;
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are both > 1.5×ULN;

9. Subjects with clinically significant abnormalities in chest X-ray or CT examination at the time of screening, and as judged by the investigator, may place the subject at safety risk;

10. Subjects with a history of active or recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis and atypical mycobacteriosis, hepatitis B and C, and herpes zoster, but excluding onychomycosis) at the time of screening, or any episode of severe infection within 4 weeks prior to screening that required hospitalization or treatment with intravenous or oral antibiotics;

11. Subjects with other autoimmune diseases or immune-related chronic inflammatory diseases at the time of screening, such as rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, etc.;

12. Subjects who have undergone or plan to undergo major surgery (evaluated as major surgery by the investigator) within 3 months prior to screening or during the study period;

13. Subjects whose blood pressure was still not controlled after treatment with antihypertensive drugs within 3 months prior to screening, and whose blood pressure was ≥ 160/100 mmHg during the screening period;

14. Subjects who had a thromboembolic event (including stroke and transient ischemic attack) within 6 months prior to screening;

15. Subjects who had any clinically significant heart disease (such as but not limited to unstable ischemic heart disease, NYHA class III/IV left ventricular failure, or myocardial infarction) discovered within 6 months prior to screening or those with clinically significant 12-lead electrocardiogram abnormalities, and as judged by the investigator, may place the subject at safety risk or may interfere with the study evaluation;

16. Subjects with a history of attempted suicide within 2 years prior to screening, or a history of major psychiatric illness requiring hospitalization within 3 years prior to screening;

17. Subjects with a history of malignant tumor within 5 years prior to screening (except for patients with treated basal cell carcinoma of the skin, in situ squamous cell carcinoma of the skin, or in situ cervical cancer);

18. History of gastrointestinal surgery or diseases (excluding appendectomy or simple hernia repair) that may interfere with the pharmacokinetics (PK) of the investigational drug;

19. Subjects with active hepatitis B (positive for hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA (HBV-DNA) higher than the upper limit of the normal range), positive for hepatitis C antibody, syphilis infection (positive for anti-TP test), or human immunodeficiency virus (HIV) infection (positive for anti-HIV) during the screening period;

20. Subjects with a history of drug abuse, drug use, or excessive alcohol consumption within 3 months prior to screening. Excessive alcohol consumption means an average daily alcohol intake of > 2 units of alcohol;

21. Subjects with a history of severe drug allergy or those allergic to the investigational medicinal product specified in the protocol;

22. Pregnant and lactating women, or women who plan to become pregnant or breastfeed during the study period;

23. Subjects whom the investigator deems to have any other factors that make them unsuitable for participating in this clinical study.