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

Official title

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

Overview

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.

Detailed description

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.

Interventions

• Drug HS-10542
  HS-10542 low dose,QD
• Drug HS-10542
  HS-10542 high dose, QD
• Drug HS-10542
  Orally QD ，The recommended dose from Ph1b

Primary outcome measures

• Phase 1b: Incidence and severity of adverse events [Time frame: 12 weeks]
• Phase 2: In the absence of red blood cell infusion the proportion of subjects with at least 3 times of ≥120 g/L of hemoglobin level measured 4 times between weeks 18 and 24 [Time frame: From the 18th to the 24th week]

Secondary outcome measures (12)

• Phase 1b: In the absence of red blood cell infusion the proportion of subjects of ≥120 g/L of hemoglobin level between weeks 3 and 12 [Time frame: From the 3th to the 12th week]
• Phase 1b: the Proportion of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 20g/L in the Absence of Red Blood Cell Transfusions [Time frame: hemoglobin between Day 15 and Day 84 and absence of transfusions]
• Phase 1b: The proportion of subjects who did not receive red blood cell infusion from week 3 to week 12 [Time frame: From the 3th to the 12th week]
• Phase 1b: Change in LDH level from baseline [Time frame: 12 weeks]
• Ph1b:change from baseline in hemoglobin concentration [Time frame: 12 weeks]
• Phase 1b: Change From Baseline in Hgb.LDH.free-Hgb. haptoglobin and ferritin [Time frame: by week 2 and week 4]
• Phase 1b: The number of red blood cell units transfused by the participants who received blood transfusions [Time frame: 12 weeks]
• Phase 1b: The average change of the score of Chronic Disease Treatment Function Assessment (FACIT) compared to the baseline [Time frame: Baseline and week 2, week 4, week 8, week 12]
• Phase 1b: The incidence of breakthrough hemolysis(BTH)from Week 1 to week 12 [Time frame: From the 1th to the 12th week]
• Phase 1b: The incidence of Major Adverse Vascular Events(MAVEs) from Week 1 to week 12 [Time frame: From the 1th to the 12th week]
• Phase 2: the Proportion of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 20 g/L in the Absence of Red Blood Cell Transfusions [Time frame: From the 18th to the 24th week]
• Phase 2: The proportion of subjects who did not receive red blood cell infusion from week 3 to week 24 [Time frame: From the 3th to the 24th week]

Eligibility criteria

Inclusion criteria

• Men or women aged more than or equal to (≥) 18 years, and less than (≤) 75 years.
• 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%
• Stable use of C5 complement inhibitor ikuzumab/covalimab for the first 6 months of random treatment
• 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.
• 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.
• LDH > 1.5 x Upper Limit of Normal (ULN) at the time of screening
• Inoccution of Neisseris meningitis and Streptococcus pneumoniae vaccine at least 2 weeks before the first administration of HS-10542;
• if HS-10542 treatment must begin less than 2 weeks after vaccination, preventive antibiotic treatment must begin at least 2 weeks after vaccination.
• 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,
• 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

• Known or suspected hereditary or acquired complement deficiency
• Currently active primary or secondary immunodeficiency
• History of infection with pod bacteria (such as Neisseris meningitis, Streptococcus pneumoniae, etc.)
• Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L; platelets <30x109/L; neutrophils <0.5x109/L);
• Presence of a bone marrow failure disorder (e.g., aplastic anemia, myelodysplastic syndrome, myelofibrosis)
• Presence of active anemia unrelated to PNH, such as renal anemia or anemia due to blood loss.
• 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)
• During screening, there are advanced heart disease (such as NYHA level IV),
• unstable thrombosis events that may exist for other causes,
• 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.
• Major surgery within 3 months prior to the first dose. \*Note: See Appendix for definitions of Grade 3/4 surgeries.
• Known active infection requiring systemic therapy
• Diagnosed malignant tumors in the past 5 years
• Those who have a history of splenectomy or History of bone marrow/hematopoietic stem cells or solid organ transplantation
• Severe or poorly controlled hypertension
• poorly controlled diabetes
• Those who are suspected of being allergic to experimental drugs or any ingredient in experimental drugs
• 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
• 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
• 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
• During screening, there are serious concurrent diseases, such as severe kidney disease (such as eGFR<30 mL/min/1.73 m2, dialysis),
• ALT/ALP>3×ULN,
• Screening positive blood pregnancy test and breastfeeding women at the time of the visit,

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital，Zhejiang University School of Medicine — Hangzhou

Identifiers

NCT: NCT07470762 · HS-10542-201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗