LR769 in Congenital Hemophilia Patients With Inhibitors Undergoing Elective Surgery or Invasive Procedures

Phase 3 Study of Safety and Efficacy of Coagulation Factor VIIa (Recombinant) for Prevention of Excessive Bleeding in Congenital Hemophilia A/B Patients With Inhibitors to Factor VIII/IX Undergoing Elective Surgery/Other Invasive Procedures

The purpose of this study, PerSept 3, is to evaluate LR769 for the prevention of excessive bleeding and achievement of hemostasis in congenital hemophilia A or B patients who have inhibitors to Factor VIII or Factor IX , are aged 6 months to 75 years, inclusive; and who are undergoing elective surgical or other invasive procedures. Administration of LR769 will be performed just prior to surgery/procedure and will be repeated during and after the surgery/procedure to achieve and maintain adequate hemostasis as determined by the investigator's judgment.

This study is an international, multicenter, single-arm, Phase 3 study. Patients aged 6 months to 75 years, inclusive, who have congenital hemophilia A or B with inhibitors to Factor VIII or Factor IX and who are scheduled for an elective surgical or other invasive procedure will be enrolled. Both major and minor surgical or other invasive procedures are allowed in the study.

Initial Treatment: Regardless of procedure, patients who meet all eligibility criteria will receive an initial intravenous (IV) bolus dose of LR769 within ≤2 minutes before the surgical incision or start of the invasive procedure. For a minor elective surgery or other minor invasive procedure, a dose of 75 μg/kg will be used as the initial dose; for a major elective surgery or other major invasive procedure, a dose of 200 μg/kg of LR769 will be used as the initial dose. For both minor and major procedures, administration will be repeated no more frequently than every 2 hours (±5 minutes) at a dose of 75 μg/kg during and after surgery or invasive procedure.

Treatment for Major Surgical Procedures: The initial dose of LR769 will be followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours after completion of the procedure. The minimum duration of LR769 treatment for major procedures will be 5 days and dosing frequency will be followed according to the guidelines specified in the protocol.

Treatment for Minor Surgical or Other Invasive Procedures: The initial dose of LR769 will be followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours. The minimum duration of LR769 infusion for minor procedures will be 2 days, except for certain procedures that may not require this duration of treatment to achieve hemostasis as noted in the protocol. Dosing frequency will be according to the guidelines specified in protocol for minor surgical or other invasive procedures.

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study:

1. be male with a diagnosis of congenital hemophilia A or B of any severity

2. have one of the following:

   1. a positive inhibitor test Bethesda Unit (BU) ≥5 (as confirmed at screening by the institutional lab), OR
   2. a BU <5 but expected to have a high anamnestic response to FVIII or FIX, as demonstrated from the patient's medical history, precluding the use of FVIII or FIX products to treat or prevent bleeding, OR
   3. a BU <5 but expected to be refractory to increased dosing of FVIII or FIX, as demonstrated from the patient's medical history, precluding the use of FVIII or FIX products to treat or prevent bleeding episodes

3. be ≥6 months to ≤75 years of age; different age restrictions may apply per local regulation and ethical considerations (enrollment of children <12 years of age will not begin until after review of data from the PERSEPT 2 study by the DMC)

4. be scheduled for an elective surgical or other invasive procedure

5. be capable of understanding and willing to comply with the conditions of the protocol OR in the case of a patient <18 years of age, parent(s)/legal guardian(s) must be capable of understanding and willing to comply with the conditions of the protocol

6. have read, understood, and provided written Informed Consent (patient and/or parent(s)/legal guardian(s) if the patient is <18 years of age) or Assent, if applicable

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study:

1. have any coagulation disorder other than hemophilia A or B
2. be immunosuppressed (ie, the patient should not be receiving systemic immunosuppressive medication; cluster of differentiation 4 (CD4) counts at screening should be >200/µL)
3. known intolerance to LR769 or any of its excipients
4. currently receiving immune tolerance induction (ITI) therapy
5. have a known allergy or hypersensitivity to rabbits
6. have a platelet count<100,000/µL
7. have received an investigational drug within 30 days of the planned first LR769 administration , or is expected to receive such drug during participation in this study (with the exception of patients who are or were participating in another LR769 study, eg, a study assessing the treatment of bleeding episodes with LR769)
8. have a clinically relevant hepatic (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN)) and/or renal impairment (creatinine >2 times the ULN)
9. have a history of arterial and/or venous thromboembolic events (such as myocardial infarction, ischemic strokes, transient ischemic attacks, deep venous thrombosis (DVT) or pulmonary embolism (PE)) within 2 years prior to the planned first dose of LR769, uncontrolled arrhythmia, or current New York Heart Association (NYHA) functional classification score of stages II - IV
10. have an active malignancy (those with non-melanoma skin cancer are allowed)
11. have any life-threatening disease or other disease or condition which, according to the investigator's judgment, could imply a potential hazard to the patient, or interfere with the trial participation or trial outcome (eg, a history of non-responsiveness to bypassing products)
12. be using aspirin, NSAIDS, herbs, natural medications, or other drugs with platelet inhibitory properties within one week prior to surgery and for the duration of treatment with LR769
13. have active gastric or duodenal ulcer disease