KN057 Multiple Dose Study in Patients with Hemophilia a or Hemophilia B with or Without Inhibitors

Inclusion criteria

• Male, 18-70 years old (including thresholds), body weight ≥40 kg and BMI <30 kg/m^2.
• Severe Hemophilia A or moderate-to-severe Hemophilia B (coagulation factor FVIII activity <1% or FIX activity ≤2%).
• Have ≥ 6 treated bleeding episodes within 24 weeks prior to screening (spontaneous and/or traumatic, excluding bleeding episodes related to surgery or traumatic operation).
• Patients without inhibitors must meet the following criteria: FVIII or FIX inhibitor test is negative during the screening period. Use coagulation factor replacement therapy for no less than 100 exposure days before screening.
• Patients with inhibitors must meet the following criteria: FVIII or FIX inhibitor test is positive during the screening period. Inhibitors level with high titer positive (≥5 BU/ml) or current low titer positive (<5 BU/ml) refractory to FVIII or FIX replacement and with FVIII or FIX recovery < 60% of expected within previous 12 months prior to screening.

Exclusion criteria

• Those with serious or poorly controlled chronic diseases or obvious systemic diseases: such as cardiovascular system, respiratory system, endocrine and metabolic system, urinary system, digestive system, autoimmune diseases, neurological diseases or psychiatric diseases, bacterial or viral infection, etc.; have previously received lipid-lowering therapy for hypertriglyceridemia or are currently receiving lipid-lowering therapy for hypertriglyceridemia.
• Have a history of other hereditary or acquired bleeding disorders other than Hemophilia A and Hemophilia B.
• Have symptoms and signs related to thromboembolic disease or are receiving thrombolytic/antithrombotic treatment; have a history of coronary atherosclerotic disease, arterial or venous thrombosis, or ischemic disease of important organs.
• Have high risk factors for thrombosis, including reduced activity of antithrombin III, protein S or protein C.
• When bleeding occurred in the past, rFVIIa was ineffective and (activated) prothrombin complex concentrate (PCC/aPCC) treatment must be used.
• Are undergoing or planning to undergo immune tolerance induction therapy.
• Regular use of immunomodulatory therapy, such as regular infusion of immune globulin or regular use of hormones, is required.
• Those with allergies; those who are allergic to test drugs/similar drugs or excipients; those with a history of multiple allergies (two categories or more); those with a history of specific reactions, such as being allergic to heparin or having experienced heparin-induced thrombocytopenia.
• Hematological abnormalities: platelet count ≤ 100 × 10^9 /L; hemoglobin < 100g/L; fibrinogen level < lower limit of normal (LLN); prothrombin time > 1.5 times upper limit of normal (ULN).
• Abnormal liver and kidney function: alanine aminotransferase and/or aspartate aminotransferase >3 times ULN; lactate dehydrogenase >1.5 times ULN; total bilirubin >1.5 times ULN; serum creatinine, triglyceride > ULN; albumin <0.8 times LLN.
• Chronic active hepatitis B/C virus (HBV/HCV, HBV-DNA or HCV-RNA quantitative detection indicates viral activity); Human immunodeficiency virus (HIV) antibody positive; syphilis antibody positive; Have received antiviral treatment (only for HBV, HCV, and HIV) in the past 3 month, or have plans to undergo antiviral treatment within 28 weeks after the first dose.
• Have had major surgery within the past 3 months (determined by the investigator), or have elective surgery planned within 28 weeks after the first dose.
• Due to treatment needs, anti-fibrinolytic or platelet function-affecting drugs need to be used within 5 days before administration or within 28 weeks after the first administration, including medicines, such as aspirin, COX-1 and non-selective non-steroidal anti-inflammatory drugs (NSAIDs, except for acetaminophen), traditional herbal medicine or health supplements at investigator's discretion.
• Participated in clinical trials related to coagulation factors and received investigational drug treatment within the past 1 month; participated in any other drug clinical trials and received investigational drug treatment within the past 3 months.
• Have been vaccinated in the past month, or have a vaccination plan within 28 weeks after the first dose, including inactivated vaccine, live attenuated vaccine, recombinant protein vaccine, recombinant adenovirus vaccine, RNA vaccine, DNA vaccine, etc.
• Subjects with fertile mates are unable to use effective contraception during the study period and within 3 months after the last dose; effective contraceptive methods include: vasectomy, scientific use of male condoms, etc.
• Have had treatment of Emicizumab within 6 months prior to screening;
• Have had any prior treatment of genetic therapy for hemophilia.
• Those participants who drink heavily or are alcoholic within 24 weeks prior to screening or can't avoid heavy drinking during the trial. Heavy drinking means more than 7 units of alcohol per week, 1 unit=360ml of beer, or 45ml of liquor with 40% alc/vol, or 150ml of wine.
• Other factors that the investigator considers inappropriate for participation in this trial.