Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B

Phase 3/4, single arm, open-label study to evaluate PK, safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects \< 12 years of age.

Study APVO101-903 is a Phase 3/4, single arm, open-label clinical trial. The purpose of the study is to evaluate pharmacokinetics (PK), safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects \< 12 years of age. The study is designed to gather information in two age groups of previously treated (with a minimum of 50 previous ED to factor IX replacement therapy) pediatric patients, specifically those \< 6 years of age and 6 to \<12 years of age.

Study APVO101-903 consists of three distinct phases:

* PK Phase - PK evaluation will consist of administration of a single 75 ± 5 IU/kg dose, followed by factor IX activity and safety assessments up to 50 hours post-infusion.
* Treatment Phase - subjects will receive APVO101 prophylaxis (starting prophylaxis dose to be determined based on APVO101 recovery; ideally within the recommended dose range: 35 - 75 IU/kg; twice weekly) for 50 ED (approximately 6 months).
* Continuation Phase - subjects may continue to receive APVO101 prophylaxis (recommended dose range: 35 - 75 IU/kg; twice weekly) for an additional ≥ 50 ED.

Eligibility Criteria:
Inclusion Criteria:

1. Age: \< 11.5 years of age at the time of the first dose and \< 12 years throughout the Treatment Phase of the study (for at least 50 ED).
2. Informed consent: subject's parent or legal guardian written Institutional Review Board (IRB)/Ethics Committee (EC)-approved informed consent. An assent form (IRB/EC-approved) will be obtained, when required by local regulations/guidelines.
3. Willingness and ability to make the required study visits, and follow instructions while enrolled in the study (for at least 50 ED; approximately 6 months).
4. Documented severe or moderately severe hemophilia B diagnosis (factor IX activity ≤ 2 IU/dL); in addition, severity may be indicated by the occurrence of one or more joint bleeding episode(s) at any point in the child's medical history requiring infusion(s) to replace factor IX.
5. Subjects must be on prophylaxis or switch to a prophylaxis regimen for the duration of the study.
6. Previously treated patients with a minimum of 50 ED (as documented and determined by the investigator) to a preparation/blood components containing factor IX.
7. Willingness to adhere to the 4-day washout period of any factor IX replacement therapy prior to PK evaluation. In case of previous exposure to a factor IX product with a prolonged half-life, a washout period of 3 half-lives is required in order to achieve steady state factor IX level prior to exposure to APVO101.
8. Immunocompetent (CD4 count \> 400/mm3) and not receiving immune modulating or chemotherapeutic agents.
9. Platelet count at least 150,000/mm3.
10. Liver function: alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 times the upper limit of the normal range.
11. Total bilirubin ≤ 1.5 times the upper limit of the normal range.
12. Renal function: serum creatinine ≤ 1.25 times the upper limit of the normal range.
13. Hemoglobin ≥ 7 g/dL.

Exclusion Criteria:

1. History of factor IX inhibitor ≥ 0.6 Bethesda Units (BU); confirmed by the screening result.
2. Existence of another coagulation disorder.
3. Evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC).
4. Use of an investigational drug within 30 days prior to study entry.
5. Previous use of APVO101.
6. Use of medications that could impact hemostasis, such as aspirin.
7. Known hypersensitivity to the active substance or to any of the excipients in the investigational products.
8. Known allergic reaction to hamster proteins.
9. History of poor compliance, geographic isolation, unreliable transportation, a serious medical or social condition, or any other circumstance that, in the opinion of the investigator, would interfere with participation or compliance with the study protocol.
10. History of adverse reaction to either plasma-derived factor IX or recombinant factor IX that interfered with the subject's ability to treat bleeding episodes with a factor IX product.
11. History of any medical condition that would impact the efficacy evaluation and/or safety evaluation of the study product.