Hemophilia B
Conditions
Keywords
ISU304, previously treated Hemophilia B patients, FIX, Factor IX, CB2679d, Dalcinonacog alfa
Brief summary
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
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.
Interventions
BIOLOGICALISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
ISU304/CB2679d/Dalcinonacog alfa 75\ 150 IU/kg by intravenous or subcutaneous
BIOLOGICALBeneFIX
BeneFIX 75 IU/kg, intravenous administration
Sponsors
Catalyst Biosciences
ISU Abxis Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | Through study completion, an average of 8 days | The number of reported AEs (local/systemic/other) after IP administration was calculated by cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | 0 to 72 hours for Cohorts 1 to 3, 0 to 120 hours for Cohorts 4 and 5 | Cmax analysis was conducted by cohort as a Factor IX (FIX) potency percent |
| Factor IX Inhibitor | At end of study visit (an average of 8 days) | 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. |
Countries
South Korea
Participant flow
Pre-assignment details
There were 11 unique subjects who completed the study; 2 failed screening. Of the 5 subjects in Cohort 4, 1 subject previously participated in Cohort 1 and 2 subjects in Cohort 2. Of the 2 subjects in Cohort 5, 2 subjects previously participated in Cohort 4. As a result, the Safety Analysis Set included 16 subjects. Cohorts were conducted in numerical order.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 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 | 3 |
| Cohort 2 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 | 3 |
| Cohort 3 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 | 3 |
| Cohort 4 One subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) per day for 6 days with 240 hours of observation | 2 |
| Cohort 5 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 | 0 |
| Total | 11 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 5 | Cohort 1 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 10 Participants |
| Age, Continuous | 46.33 years STANDARD_DEVIATION 5.69 | 43.33 years STANDARD_DEVIATION 14.57 | 50.50 years STANDARD_DEVIATION 3.87 | — | 29.00 years STANDARD_DEVIATION 16.7 | 41.55 years STANDARD_DEVIATION 13.68 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 3 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Korea | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 3 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 5 | 0 / 2 |
| other Total, other adverse events | 0 / 3 | 3 / 3 | 3 / 3 | 5 / 5 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 5 | 0 / 2 |
Outcome results
Primary
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.
Time frame: Through study completion, an average of 8 days
Population: 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. 16 subjects were included in the Safety Analysis Set across 5 cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | 0 adverse events |
| Cohort 2 | Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | 10 adverse events |
| Cohort 3 | Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | 10 adverse events |
| Cohort 4 | Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | 69 adverse events |
| Cohort 5 | Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) | 47 adverse events |
Secondary
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.
Time frame: At end of study visit (an average of 8 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Factor IX Inhibitor | 0 Participants |
| Cohort 2 | Factor IX Inhibitor | 0 Participants |
| Cohort 3 | Factor IX Inhibitor | 0 Participants |
| Cohort 4 | Factor IX Inhibitor | 0 Participants |
| Cohort 5 | Factor IX Inhibitor | 2 Participants |
Secondary
Maximum Plasma Concentration (Cmax)
Cmax analysis was conducted by cohort as a Factor IX (FIX) potency percent
Time frame: 0 to 72 hours for Cohorts 1 to 3, 0 to 120 hours for Cohorts 4 and 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa SC | 70.47 FIX potency percent | Standard Deviation 16.92 |
| Cohort 1 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa IV | 71.10 FIX potency percent | Standard Deviation 15.87 |
| Cohort 2 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa SC | 5.30 FIX potency percent | Standard Deviation 3.69 |
| Cohort 2 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa IV | 100.80 FIX potency percent | Standard Deviation 78 |
| Cohort 3 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa IV | 41.70 FIX potency percent | Standard Deviation 7.47 |
| Cohort 3 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa SC | 5.27 FIX potency percent | Standard Deviation 1.16 |
| Cohort 4 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa IV | 15.34 FIX potency percent | Standard Deviation 2.44 |
| Cohort 4 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa SC | NA FIX potency percent | — |
| Cohort 5 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa SC | NA FIX potency percent | — |
| Cohort 5 | Maximum Plasma Concentration (Cmax) | Cmax of ISU304/CB2679d/Dalcinonacog alfa IV | 23.80 FIX potency percent | Standard Deviation 10.04 |