Study of Safety and Efficacy of HS-10542 in Patients With Paroxysmal Nocturnal Hemoglobinuria

A Phase IB/II,Open Label Study to Assess Efficacy, and Safety, of HS-10542 in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis

This was a phase 1b/2,open label, multi-center study to assess efficacy and safety of HS-10542 in adulte patients with paroxysmal nocturnal hemoglobinuria (PNH) with signs of active hemolysis.

HS-10542 is a novel oral small molecular weight compound that inhibits factor B (FB) of the alternative pathway (AP). Blockade of the AP with oral HS-10542 has the potential to prevent both intra - and extravascular hemolysis. This study consists of a dose exporation(Ph1b) and a dose expansion(Ph 2):

Phase Ib:In participants with paroxysmal nocturnal hemoglobinuria (PNH), two dose levels of HS-10542 will be explored (low dose; high dose randomized 1:1), stratified by whether the patient is currently receiving C5 complement inhibitor therapy. Based on an integrated assessment of interim data on the safety, efficacy, and PK/PD profile of HS-10542 in the target population, the recommended Phase II dose (RP2D) will be determined.

Phase II:Based on the safe and effective dose identified in Phase Ib, the efficacy and safety of HS-10542 will be evaluated in participants with PNH who have an inadequate response to C5 complement inhibitor therapy.

Inclusion Criteria:

1. Men or women aged more than or equal to (≥) 18 years, and less than (≤) 75 years.
2. It was confirmed to be PNH during screening, and the clone size of red blood cells or/and granulocytes or/and monocytes was detected by flow cytopy ≥10%
3. Stable use of C5 complement inhibitor ikuzumab/covalimab for the first 6 months of random treatment
4. Have at least one blood transfusion record within the last 4 months, or sustain a hemoglobin level below 100g/L the last 4 months prior to screening.
5. The average hemoglobin level from two tests conducted by the laboratory at the time of screening is less than 100 g/L, or hemoglobin level <100g/L before transfusion.
6. LDH > 1.5 x Upper Limit of Normal (ULN) at the time of screening
7. Inoccution of Neisseris meningitis and Streptococcus pneumoniae vaccine at least 2 weeks before the first administration of HS-10542;
8. if HS-10542 treatment must begin less than 2 weeks after vaccination, preventive antibiotic treatment must begin at least 2 weeks after vaccination.
9. Male and female subjects with fertility must agree to adopt efficient contraceptive measures with their partners within 60/120 days from the signing of the informed consent form to the last administration,
10. Male subjects who are infertile (such as those who have undergone effective sterilization surgery) must take additional efficient contraceptive measures when it is uncertain whether they have sperm，

Exclusion Criteria:

1. Known or suspected hereditary or acquired complement deficiency
2. Currently active primary or secondary immunodeficiency
3. History of infection with pod bacteria (such as Neisseris meningitis, Streptococcus pneumoniae, etc.)
4. Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L; platelets <30x109/L; neutrophils <0.5x109/L);
5. Presence of a bone marrow failure disorder (e.g., aplastic anemia, myelodysplastic syndrome, myelofibrosis)
6. Presence of active anemia unrelated to PNH, such as renal anemia or anemia due to blood loss.
7. There is or is suspected of systemic active bacteria, virus or fungal infection 2 weeks before the first administration of HS-10542 (according to the researcher's judgment)
8. During screening, there are advanced heart disease (such as NYHA level IV),
9. unstable thrombosis events that may exist for other causes,
10. Abnormal ECG: The absolute value of QTcF (QT interval corrected by Fridericia 's formula > 450 msec for males and > 470 msec for females; or other clinically significant abnormalities as judged by the investigator.
11. Major surgery within 3 months prior to the first dose. *Note: See Appendix for definitions of Grade 3/4 surgeries.
12. Known active infection requiring systemic therapy
13. Diagnosed malignant tumors in the past 5 years
14. Those who have a history of splenectomy or History of bone marrow/hematopoietic stem cells or solid organ transplantation
15. Severe or poorly controlled hypertension
16. poorly controlled diabetes
17. Those who are suspected of being allergic to experimental drugs or any ingredient in experimental drugs
18. Use any of the following drugs, unless there is a stable treatment plan before screening: a) erythropoietin (ESA), hypoxic-inducing factor proaminoyl hydroxylase inhibitor (HIF-PHI) or immunosuppressant for at least 8 weeks b) Systemic use of glucocorticoids (≤15 mg/day Prednisone or equivalent doses of glucocorticoids) at least 4 weeks c) Vitamin K antagonists (such as warfarin) have a stable international standardized ratio (INR) at least 4 weeks d) Low molecular weight heparin, oral anticoagulants such as aspirin, rvaroxaban, apifloxaban, etc. at least 4 weeks e) Iron supplements , vitamin B12, folic acid or androgen for at least 4 weeks
19. Except for C5 complement inhibitors (including but not limited to ecucizumab and covalizumab), the situation of participating in other clinical trials or using other study drugs or approved therapies for experimental use before screening, and the trial drug is still within 5 half-lives or 2 weeks
20. Participants who have previously received B-factor inhibitor treatment, with a treatment duration of no more than one week and having stopped taking the drug for more than five half-lives before screening, may not be excluded
21. During screening, there are serious concurrent diseases, such as severe kidney disease (such as eGFR<30 mL/min/1.73 m2, dialysis),
22. ALT/ALP>3×ULN,
23. Screening positive blood pregnancy test and breastfeeding women at the time of the visit,