Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1, Open-label, Multi-center, Dose-escalation Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of ISU304 in Previously Treated Hemophilia B Patients

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg
* Biological: BeneFIX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Patients must be 12 to 65 years old at the time of screening Patients who have discontinued a previously treated FIX product at least 4 days prior to the administration of investigational product 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 Voluntary consent to participate in the study Exclusion Criteria: Patients with a history or a family history of FIX inhibitors Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from inhibitor tests) at the time of screening Patients who have a history of thromboembolic events (myocardial infarction, cerebrovascular disease, venous thrombosis, etc.) Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX product or hamster protein 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 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 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 Patients with any other co-existing bleeding disorder (Von Willebrand disease, etc.) Patients with positive D-dimer results (≥ 0.5 μg/mL) at the time of screening Patients with platelet counts less than 100,000/μL at the time of screening 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 Active hepatitis patients who are HBs Ag positive or anti-HCV Ab positive at the time of screening Patients scheduled for surgery during the study period Patients participated in another study within 30 days before screening or scheduled to participate in any other study during the study period

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Single intravenous administration of BeneFIX (75 IU/kg) with 72 hours of observation, followed by single intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation | Biological: ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg<br>* ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg by intravenous or subcutaneous<br>* Other names: Dalcinonacog alfa;Biological: BeneFIX<br>* BeneFIX 75 IU/kg, intravenous administration<br>|
| Experimental: Cohort 2<br>Single intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation, followed by single subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation | Biological: ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg<br>* ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg by intravenous or subcutaneous<br>* Other names: Dalcinonacog alfa;|
| Experimental: Cohort 3<br>Single intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation, followed by single subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) with 120 hours of observation | Biological: ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg<br>* ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg by intravenous or subcutaneous<br>* Other names: Dalcinonacog alfa;|
| Experimental: Cohort 4<br>One subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) per day for 6 days with 240 hours of observation | Biological: ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg<br>* ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg by intravenous or subcutaneous<br>* Other names: Dalcinonacog alfa;|
| Experimental: Cohort 5<br>One intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) followed by subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) once daily for 9 days with 312 hours of observation | Biological: ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg<br>* ISU304/CB2679d/Dalcinonacog alfa 75 150 IU/kg by intravenous or subcutaneous<br>* Other names: Dalcinonacog alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | The number of reported AEs (local/systemic/other) after IP administration was calculated by cohort. | Through study completion, an average of 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) | Cmax analysis was conducted by cohort as a Factor IX (FIX) potency percent | 0 to 72 hours for Cohorts 1 to 3, 0 to 120 hours for Cohorts 4 and 5 | 
| Factor IX Inhibitor | The presence/absence of Factor IX (FIX) neutralizing antibodies was assessed by ELISA anti-drug assay [Dalcinonacog alfa and BeneFIX) and if positive, a modified Nijmegen assay for each subject by cohort at end of study visit. Measure description: count of participants with neutralizing antibodies. Bethesda Units >0.6 indicates presence of neutralizing antibodies. 1 BU is defined as a 50% reduction in FIX activity when adding participant plasma to a standard with known FIX activity. | At end of study visit (an average of 8 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FIX, ISU304, previously treated Hemophilia B patients, Factor IX, CB2679d, Dalcinonacog alfa