Study of Next-Generation Recombinant Factor IX Variant in Adult Subjects With Hemophilia B

Study Overview
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Brief Summary
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Phase 2b, single-center, open-label study designed to evaluate the pharmacokinetics, pharmacodynamics, efficacy and safety of subcutaneous (SC) prophylaxis treatment regimens with CB2679d in 6 adult, male subjects with severe congenital hemophilia B.

Detailed Description
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Single-center, open-label Phase 2b study will evaluate the PK, PD, efficacy and safety parameters of SC prophylaxis treatment regimens with CB2679d in adult subjects with hemophilia B. The study will enroll and dose subcutaneously, a total of 6 adult male subjects with severe congenital hemophilia B. During the Treatment Period, the subject will receive an IV dose of 50 IU/kg followed 35 ± 5 minutes later by a SC dose of 100 IU/kg. Daily SC doses of 100 IU/kg will be administered until Day 28 (28 total SC doses). On Day 1, PK, PD, and safety assessments will be done at pre-IV dose and repeated 35 (± 5) minutes later prior to the SC dose. Subsequent PK, PD and safety assessments will be performed pre-dose on days 2, 3, 7, 14, 21 and 28. During the Washout Period, PK, PD, and safety assessments will be done on Days 29, 30, 31, 32 and 33. Daily FIX activity levels will be measured, unless FIX activity level is known to be < 5%, as measured by local laboratory. An End of Study visit will occur 30 days (± 2 days) after the last dose of study drug.

Official Title
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Phase 2b Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of a Subcutaneous Prophylaxis Treatment Regimen of CB2679d, in Adult Subjects With Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: Coagulation Factor IX variant
* Biological: Coagulation Factor IX variant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of severe (<2%) congenital hemophilia B. Male, age 18 or older. Agreement to use highly effective birth control throughout the study. Affirmation of informed consent with signature confirmation before any trial-related activities. Stated willingness to comply with all study procedures and availability for the duration of the study. Exclusion Criteria: History or a family history of FIX inhibitors. Positive antibody to FIX detected by central laboratory at screening. Previous participation in and subsequent treatment in a clinical trial within the previous 30 days or 3-half-lives, whichever is longer, or absence of clinical effect. Have a coagulation disorder other than congenital hemophilia B. Factor IX gene mutation 128G>A. Significant contraindication to participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Intravenous Dose<br>Coagulation Factor IX variant, 50 IU/kg by intravenous route | Biological: Coagulation Factor IX variant<br>* Single intravenous injection of CB2679d/Dalcinonacog alfa<br>|
| Experimental: Subcutaneous Dosing<br>Coagulation Factor IX variant, 100 IU/kg by subcutaneous route | Biological: Coagulation Factor IX variant<br>* Daily subcutaneous injections of CB2679d/Dalcinonacog alfa for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Achieved FIX Level ≥12% | Subjects who achieved a FIX activity level ≥12% during the treatment period in the PK Population | Days 7, 14, 21, 28, 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FIX Activity Levels (Actual and Change From Baseline) in All Subjects | FIX Activity Levels measured by percent activity. Baseline was defined as the lowest assessment before the first administration of study drug. Maximum change from baseline was calculated as the maximum of the changes from baseline over all visits during treatment period. FIX activity level below the limit of quantification (BLQ) were set to zero. In case of retest, the average of the different test results were considered for the summary analyses. 1 subject received a higher IV dose than allowed per protocol (150 IU/kg) at Day 1 thus this subject's values at Day 1 (SC Dose), Day 2, & Day 3 were excluded from this analysis & the total number of participants was lowered by 1 at these timepoints. Additionally, mean (standard deviation) for the maximum change from baseline in the FIX activity level (%) during SC dosing was calculated by excluding actual values at Day 1 IV dose, Day 1 SC dose, Day 2 & Day 3 for all 6 subjects. | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). | 
| Pharmacokinetic (PK) Analysis - AUC | Summary of Pharmacokinetic Parameters - AUC Infinity Observation and AUC to Last Non-zero Concentration | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). | 
| PK Analysis - Clearance | Summary of PK Parameters - Clearance | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). | 
| PK Analysis - Maximum Concentration During SC Dosing | Summary of PK Parameters - Maximum Concentration during SC dosing | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). | 
| PK Analysis - Half-Life and Residence Time | Summary of PK Parameters - Half-Life-1(alpha), Half-Life-1(beta), and Mean Residence Time | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). | 
| PK Analysis - Volume of Distribution at Steady-State Observed | Summary of PK Parameters - Volume of Distribution at Steady-State Observed | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). | 
| Occurrence of Clinical Thrombotic Event | Rate of occurrence of clinical thrombotic event not attributable to another cause | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28 | 
| Occurrence of an Antibody Response | Rate of occurrence of an antibody response to CB2679d and cross-reactive with wild-type recombinant coagulation FIX | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28 | 
| Thrombogenicity Assessment - Fibrinogen | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). | 
| Thrombogenicity Assessment - D-Dimer | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). | 
| Thrombogenicity Assessment - Prothrombin Fragments 1 + 2 | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). | 
| Thrombogenicity Assessment - Thrombin/Antithrombin | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |