This study is a phase 1, open-label, multi-center, dose-escalation study to investigate the safety, pharmacokinetics and pharmacodynamics of ISU304/CB2679d in previously treated hemophilia B patients.

This study is a phase 1, open-label, multi-center, dose-escalation study to investigate the safety, pharmacokinetics, and pharmacodynamics of ISU304/CB2679d/Dalcinonacog alfa in previously treated Hemophilia B patients.

This study is comprised of 5 cohorts. Each cohort may receive an intravenous administration of 75 IU/kg, with subcutaneous administrations from 75 IU/kg to 150 IU/kg.

During the study period, a subject may be hospitalized to facilitate the collection of blood samples for pharmacokinetic (PK)/pharmacodynamic (PD) analysis. The Data Safety Monitoring Board (DSMB) and Data Monitoring Committee (DMC) will be operated after the end of Cohorts 1 to 4. These committees will monitor the PK/PD and safety data from each cohort to determine the continuation of next cohort (Cohorts 2 to 5), target dose, and blood sampling period for PK/PD (including timing of collection). Additional subjects may be enrolled in all cohorts or cohorts may be canceled depending on the results of PK/PD analysis. A cohort of subcutaneous dosing at 300 IU/kg was cancelled as single-dose PK is uninformative.

Inclusion Criteria:

1. Previously treated male patients with moderate or severe hemophilia B (documented FIX activity ≤ 2% and exposed to any FIX product for ≥ 150 exposure days (estimated) at the time of screening)
2. Patients must be 12 to 65 years old at the time of screening
3. Patients who have discontinued a previously treated FIX product at least 4 days prior to the administration of investigational product
4. HIV negative, or if HIV positive with a CD4 count > 200/μL (documented < 200 particles/μL or ≤ 400,000 copies/mL) at the time of screening
5. Voluntary consent to participate in the study

Exclusion Criteria:

1. Patients with a history or a family history of FIX inhibitors
2. Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from inhibitor tests) at the time of screening
3. Patients who have a history of thromboembolic events (myocardial infarction, cerebrovascular disease, venous thrombosis, etc.)
4. Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX product or hamster protein
5. Patients receiving treatment with a FIX product or a bypass agent within 4 half-lives for the agent used (at least 96 hours) prior to the administration of the investigational product
6. Patients who have been exposed to long-term administration of immunomodulating agents or immunosuppressants such as α-INF or adrenocortical hormones over the past 3 months or who are currently receiving or planning to receive such treatment during the study period
7. Patients who have been administered vaccines during the period of 6 months prior to the administration of the investigational product or plan to receive vaccines during the study period
8. Patients with any other co-existing bleeding disorder (Von Willebrand disease, etc.)
9. Patients with positive D-dimer results (≥ 0.5 μg/mL) at the time of screening
10. Patients with platelet counts less than 100,000/μL at the time of screening
11. Patients with ALT, AST levels 5 times greater than upper normal limit or total bilirubin, serum creatinine levels 2 times greater than upper normal limit at the time of screening
12. Active hepatitis patients who are HBs Ag positive or anti-HCV Ab positive at the time of screening
13. Patients scheduled for surgery during the study period
14. Patients participated in another study within 30 days before screening or scheduled to participate in any other study during the study period

There were 13 unique subjects in the study: 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. Baseline characteristics are reported according to the initial cohort to which subjects were assigned. The 2 subjects who participated in Cohort 5 were previously in Cohort 4.

For 7 to 15 days depending on the cohort: Cohort 1 (7 days), Cohort 2 (7 days), Cohort 3 (9 days), Cohort 4 (10 days), Cohort 5 (15 days)

Two subjects who were cousins developed neutralizing antibodies to dalcinonacog alfa in Cohort 5 that did not cross react with wild-type FIX. Both resumed their prior FIX therapy. Five subjects participated in 2 cohorts each.