Hemophilia B
Conditions
Keywords
Hemophilia,, Gene Therapy, Bleeding, Factor IX, FIX, viral vector, Padua
Brief summary
This is an open-label, single-dose, single-arm, multi-center trial, with a screening, a treatment + post-treatment follow-up phase, and a long-term follow-up phase. The IMP AMT-061 is a recombinant adeno-associated viral vector of serotype 5 (AAV5) containing the Padua variant of a codon-optimized human FIX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter. The IMP is identified as AAV5-hFIXco-Padua (AMT- 061). The pharmaceutical form of AMT-061 is a solution for intravenous infusion. The administered dose of AMT-061 will be 2 x 10\^13 gc/kg.
Interventions
GENETICAAV5-hFIXco-Padua (AMT-061)
Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-label, single-dose, single-arm, multi-center trial
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male 2. Age ≥18 years 3. Subjects with congenital hemophilia B classified as severe or moderately severe 4. \>20 previous exposure days of treatment with FIX protein
Exclusion criteria
1. History of FIX inhibitors 2. Positive FIX inhibitor test at screening 3. Select screening laboratory values \> 2 times upper normal limit: 4. Positive human immunodeficiency virus (HIV) at screening, not controlled with anti-viral therapy 5. Active infection with Hepatitis B or C virus at screening 6. History of Hepatitis B or C exposure, currently controlled by antiviral therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Factor IX Activity Levels | 6 weeks post-dose | To confirm that a single dose of 2x10\^13 gc/kg AMT-061 (CSL222) resulted in factor IX activity levels of ≥5% at 6 weeks after dosing measured by the one-stage (activated partial thromboplastin \[aPTT\]-based) assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Exogenous Factor IX Usage | 52 weeks post-dose | Annualized use was calculated as the normalized amount of therapy administered per baseline weight, extrapolated where necessary from any time period less or greater than 1 year. Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included. |
| Annualized Bleeding Rate (ABR) | 5 years post-dose | ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25. |
| Factor IX Activity Levels | 52 weeks post-dose | Measured by the one-stage (aPTT-based) assay. |
| Number of Participants Remaining Free of Continuous Prophylaxis | 1 year post-dose | Participants with no usage of continuous factor IX prophylaxis after AMT-061 (CSL222) treatment were considered free from continuous factor IX prophylaxis use. |
| Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis | Up to 5 years post-dose | The post-continuous-prophylaxis period began on the day after the end of continuous (routine) prophylaxis.Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included. |
| Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Up to 5 years post-dose | — |
| Number of Participants With Clinically Meaningful Findings in Hematology and Serum Chemistry Parameters | Up to 5 years post-dose | Clinically meaningful findings were defined as values which were outside the standard normal reference ranges for hematology and serum chemistry parameters. |
| Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Changes in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels | From baseline and up to 5 years post-dose | Post-baseline newly occurring or worsening potentially clinically significant ALT and AST levels were defined as values greater than twice the baseline value. |
| Number of Participants Receiving Corticosteroids for AST and ALT Elevations | Up to 5 years post-dose | — |
| Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum | Baseline and at 5 years post-dose | — |
| Number of Participants With AAV5 Capsid-specific T Cell Response | Up to Week 52 | — |
| Number of Participants With Inflammatory Marker Levels Outside Normal Ranges | Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 26, 31, 36, 40, 44, 48 and 52 | Inflammatory markers included interleukin (IL)-1β, IL-2, IL-6, interferon gamma (IFNγ), and monocyte chemotactic protein-1 (MCP-1). Only those biomarkers for which the data were higher than the normal range at the specified timepoints have been presented. |
| Time to First Negative Results for Vector Deoxyribonucleic Acid (DNA) From Semen and Blood | Up to 5 years post-dose | Time in weeks until the first negative result confirmed by negative result in 3 consecutive timepoints. A participant was considered to no longer be shedding vector DNA if they had a negative laboratory result for 3 or more consecutive timepoints. |
| Number of Participants With Abnormal Values in Alpha-fetoprotein (AFP) Levels | Up to 5 years post-dose | Participants who were outside the normal limit range were to be reported. |
| Number of Participants With Abnormal Results in Abdominal Ultrasound | At Months 36, 42, 48, 54, and 60 post-dose | Ultrasounds were evaluated by qualified personnel and abnormalities were assessed by the Investigator. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AMT-061 (CSL222) AAV5-hFIXco-Padua (AMT-061 \[CSL222\]): Single intravenous infusion of AMT-061 (CSL222). | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | AMT-061 (CSL222) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 46.7 years STANDARD_DEVIATION 3.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 |
Outcome results
Primary
Factor IX Activity Levels
To confirm that a single dose of 2x10\^13 gc/kg AMT-061 (CSL222) resulted in factor IX activity levels of ≥5% at 6 weeks after dosing measured by the one-stage (activated partial thromboplastin \[aPTT\]-based) assay.
Time frame: 6 weeks post-dose
Population: All subjects treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMT-061 (CSL222) | Factor IX Activity Levels | 30.6 Factor IX activity (%) | Standard Deviation 6.97 |
Secondary
Annualized Bleeding Rate (ABR)
ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25.
Time frame: 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AMT-061 (CSL222) | Annualized Bleeding Rate (ABR) | Joint bleeds | 0.00 bleeds/year/subject |
| AMT-061 (CSL222) | Annualized Bleeding Rate (ABR) | All bleeds (Spontaneous + Traumatic + Joint) | 0.14 bleeds/year/subject |
| AMT-061 (CSL222) | Annualized Bleeding Rate (ABR) | Spontaneous bleeds | 0.07 bleeds/year/subject |
| AMT-061 (CSL222) | Annualized Bleeding Rate (ABR) | Traumatic bleeds | 0.07 bleeds/year/subject |
Secondary
Annualized Exogenous Factor IX Usage
Annualized use was calculated as the normalized amount of therapy administered per baseline weight, extrapolated where necessary from any time period less or greater than 1 year. Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.
Time frame: 52 weeks post-dose
Population: All subjects treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMT-061 (CSL222) | Annualized Exogenous Factor IX Usage | 7.1 International units (IU)/kg/year | Standard Deviation 6.4 |
Secondary
Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis
The post-continuous-prophylaxis period began on the day after the end of continuous (routine) prophylaxis.Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.
Time frame: Up to 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMT-061 (CSL222) | Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis | 342.1 IU/year | Standard Deviation 592.5 |
Secondary
Factor IX Activity Levels
Measured by the one-stage (aPTT-based) assay.
Time frame: 52 weeks post-dose
Population: All subjects treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMT-061 (CSL222) | Factor IX Activity Levels | 40.8 Factor IX activity (%) | Standard Deviation 9.45 |
Secondary
Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum
Time frame: Baseline and at 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMT-061 (CSL222) | Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum | At Baseline for AAV5 | 3 Participants |
| AMT-061 (CSL222) | Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum | At 5 years post dose for AAV5 | 3 Participants |
| AMT-061 (CSL222) | Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum | At Baseline for FIX | 0 Participants |
| AMT-061 (CSL222) | Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum | At 5 years post dose for FIX | 0 Participants |
Secondary
Number of Participants Receiving Corticosteroids for AST and ALT Elevations
Time frame: Up to 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMT-061 (CSL222) | Number of Participants Receiving Corticosteroids for AST and ALT Elevations | 0 Participants |
Secondary
Number of Participants Remaining Free of Continuous Prophylaxis
Participants with no usage of continuous factor IX prophylaxis after AMT-061 (CSL222) treatment were considered free from continuous factor IX prophylaxis use.
Time frame: 1 year post-dose
Population: All subjects treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMT-061 (CSL222) | Number of Participants Remaining Free of Continuous Prophylaxis | 3 Participants |
Secondary
Number of Participants With AAV5 Capsid-specific T Cell Response
Time frame: Up to Week 52
Population: All subjects treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMT-061 (CSL222) | Number of Participants With AAV5 Capsid-specific T Cell Response | 1 Participants |
Secondary
Number of Participants With Abnormal Results in Abdominal Ultrasound
Ultrasounds were evaluated by qualified personnel and abnormalities were assessed by the Investigator.
Time frame: At Months 36, 42, 48, 54, and 60 post-dose
Population: All subjects treated. Here, the Number Analyzed (n) included participants who were evaluable at specific timepoints.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMT-061 (CSL222) | Number of Participants With Abnormal Results in Abdominal Ultrasound | Month 36 | 3 Participants |
| AMT-061 (CSL222) | Number of Participants With Abnormal Results in Abdominal Ultrasound | Month 42 | 2 Participants |
| AMT-061 (CSL222) | Number of Participants With Abnormal Results in Abdominal Ultrasound | Month 48 | 3 Participants |
| AMT-061 (CSL222) | Number of Participants With Abnormal Results in Abdominal Ultrasound | Month 54 | 2 Participants |
| AMT-061 (CSL222) | Number of Participants With Abnormal Results in Abdominal Ultrasound | Month 60 | 3 Participants |
Secondary
Number of Participants With Abnormal Values in Alpha-fetoprotein (AFP) Levels
Participants who were outside the normal limit range were to be reported.
Time frame: Up to 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMT-061 (CSL222) | Number of Participants With Abnormal Values in Alpha-fetoprotein (AFP) Levels | 0 Participants |
Secondary
Number of Participants With Clinically Meaningful Findings in Hematology and Serum Chemistry Parameters
Clinically meaningful findings were defined as values which were outside the standard normal reference ranges for hematology and serum chemistry parameters.
Time frame: Up to 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMT-061 (CSL222) | Number of Participants With Clinically Meaningful Findings in Hematology and Serum Chemistry Parameters | 0 Participants |
Secondary
Number of Participants With Inflammatory Marker Levels Outside Normal Ranges
Inflammatory markers included interleukin (IL)-1β, IL-2, IL-6, interferon gamma (IFNγ), and monocyte chemotactic protein-1 (MCP-1). Only those biomarkers for which the data were higher than the normal range at the specified timepoints have been presented.
Time frame: Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 26, 31, 36, 40, 44, 48 and 52
Population: All subjects treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMT-061 (CSL222) | Number of Participants With Inflammatory Marker Levels Outside Normal Ranges | Baseline: MCP-1 | 1 Participants |
| AMT-061 (CSL222) | Number of Participants With Inflammatory Marker Levels Outside Normal Ranges | Week 1: MCP-1 | 1 Participants |
| AMT-061 (CSL222) | Number of Participants With Inflammatory Marker Levels Outside Normal Ranges | Week 8: MCP-1 | 1 Participants |
| AMT-061 (CSL222) | Number of Participants With Inflammatory Marker Levels Outside Normal Ranges | Week 40: IL-6 | 1 Participants |
Secondary
Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Changes in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels
Post-baseline newly occurring or worsening potentially clinically significant ALT and AST levels were defined as values greater than twice the baseline value.
Time frame: From baseline and up to 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMT-061 (CSL222) | Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Changes in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels | AST | 1 Participants |
| AMT-061 (CSL222) | Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Changes in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels | ALT | 1 Participants |
Secondary
Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs
Time frame: Up to 5 years post-dose
Population: All subjects treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participant with TEAEs | 3 Participants |
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participant with mild TEAEs | 3 Participants |
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participant with moderate TEAEs | 2 Participants |
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participant with severe TEAEs | 2 Participants |
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participants with TEAEs related to study treatment | 1 Participants |
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participants with TEAEs unrelated to study treatment | 3 Participants |
| AMT-061 (CSL222) | Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs | Participants with serious TEAEs | 1 Participants |
Secondary
Time to First Negative Results for Vector Deoxyribonucleic Acid (DNA) From Semen and Blood
Time in weeks until the first negative result confirmed by negative result in 3 consecutive timepoints. A participant was considered to no longer be shedding vector DNA if they had a negative laboratory result for 3 or more consecutive timepoints.
Time frame: Up to 5 years post-dose
Population: All subjects treated. Here, the Number Analyzed (n) included participants who were evaluable at specific parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AMT-061 (CSL222) | Time to First Negative Results for Vector Deoxyribonucleic Acid (DNA) From Semen and Blood | Semen | 26.21 Weeks |
| AMT-061 (CSL222) | Time to First Negative Results for Vector Deoxyribonucleic Acid (DNA) From Semen and Blood | Blood | 78.29 Weeks |
Post Hoc
Factor IX Activity Levels
To confirm that a single dose of 2x10\^13 gc/kg AMT-061 (CSL222) resulted in factor IX activity levels of ≥5% at 5 years after dosing measured by the one-stage (activated partial thromboplastin \[aPTT\]-based) assay.
Time frame: 5 years post dose
Population: All subjects treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMT-061 (CSL222) | Factor IX Activity Levels | 45.67 Factor IX activity (%) | Standard Deviation 6.18 |
Post Hoc
Number of Participants Remaining Free of Continuous Prophylaxis
Participants with no usage of continuous factor IX prophylaxis after AMT-061 (CSL222) treatment were considered free from continuous factor IX prophylaxis use.
Time frame: 5 years post dose
Population: All subjects treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMT-061 (CSL222) | Number of Participants Remaining Free of Continuous Prophylaxis | 3 Participants |