Severe Haemophilia A
Conditions
Keywords
Haemophilia A, Gene Therapy, Clotting Disorders, Blood Disorder, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII, Coagulants, AAV5 vector
Brief summary
This study is being conducted by BioMarin Pharmaceutical Inc. as an open label, dose escalation study in order to determine the safety and efficacy of valoctocogene roxaparvovec (an Adenovirus-Associated Virus based gene therapy vector in participants with severe haemophilia A.
Interventions
BIOLOGICALvaloctocogene roxaparvovec
Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males 18 years or older with established severe Haemophilia A (endogenous FVIII level ≤1 IU/dL) as evidenced by their medical history. 2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs) 3. Greater than or equal to 12 bleeding episodes for patients on on-demand FVIII replacement therapy over the previous 12 months. Does not apply to patients on prophylaxis 4. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within the past 12 months 5. Sexually active patients must be willing to use an acceptable method of contraception.
Exclusion criteria
1. Detectable pre-existing immunity to the AAV5 capsid as measured by adeno-associated virus 5 (AAV5) transduction inhibition (TI) or AAV5 total antibodies 2. Any evidence of immunosuppressive disorder or active chronic infection including hepatis B, hepatitis C, HIV 3. Significant liver dysfunction as defined by abnormal elevation ofliver function tests, or for patients who have undergone liver imaging or biopsy and found to have evidence of grade 3 or higher fibrosis 4. Evidence of any bleeding disorder not related to haemophilia A 5. 12\. Treatment with any investigational product within 30 days prior to the end of the screening period, or any previous exposure to any gene transfer therapy 6. Any disease or condition that per the physician's discretion would prevent the patient from fully complying with the requirements of the study including possible corticosteroid treatment outlined in the protocol. The physician may exclude patients unwilling or unable to agree on not using alcohol for the 16-week period following the viral infusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events | Approximately up to 7 years after dosing | Adverse events (AEs) with onset or worsening after the investigational product were included. Participants with more than one AE of the same category were counted only once for that category. Serious adverse event (SAE) |
| Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA) | Week 13-16 post-BMN 270 infusion | Responder/Non responder status, where a responder was defined as a participant with median FVIII activity of \>= 5 IU/dL during Week 13-16 post-BMN 270 infusion |
| Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion | Week 13-16 post-BMN 270 infusion | Values for FVIII activity were excluded from analysis if obtained within 72 hours since the last infusion of exogenous FVIII replacement therapy FVIII activity levels below the Lower limit of quantitation (LLOQ) will be imputed with 0 IU/dL Q1: 25% Percentile; Q3: 75% Percentile |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond | Week 5 and Beyond (Approximately 7 years post Infusion) | ABR= \[Number of bleeding episodes during calculation period\] / \[Total number of days during the calculation period\] ×365.25 A bleeding episode (treated) was defined as a bleed or symptoms associated with the development of a bleed (or multiple bleeds occurring in the same day) requiring FVIII replacement treatment within 72 hours of the start of the bleed. The baseline values for the secondary efficacy endpoints were based on the historical data prior to study enrollment. Annualized bleeding rate (ABR) |
| Annualized Factor VIII Utilization During Week 5 and Beyond | Week 5 and Beyond (Approximately 7 years post Infusion) | Annualized FVIII use (IU/kg/yr.) =\[Sum of FVIII use (IU/kg) during calculation period\] / \[Total number of days during the calculation period\] ×365.25 |
| Annualized Factor VIII Infusion Rate During Week 5 and Beyond | Week 5 and Beyond (Approximately 7 years post Infusion) | Annualized FVIII infusion rate (count/yr.) = \[Number of FVIII replacement infusions during calculation period\] / \[Total number of days during the calculation period\] ×365.25 |
Countries
United Kingdom
Participant flow
Recruitment details
This study was conducted at 5 sites in United Kingdom (Basingstoke, Cambridge, Birmingham, Royal London, London, & Guy's and St. Thomas', London).
Pre-assignment details
Total of 21 subjects were screened. Of those 21, 6 did not meet the eligibility criteria for enrollment in the study: 5 were found to be adeno-associated virus5 (AAV5) transduction inhibition (TI) or total antibody (TAb) positive, and 1 was assessed as being unable to comply with the requirements of the trial. Fifteen participants were enrolled in 270-201 and received BMN 270 in 1 of 4 dose cohorts
Participants by arm
| Arm | Count |
|---|---|
| BMN 270 6E12 vg/kg Cohort 1: 6E12 vector genomes (vg) per kilogram of body weight, given as a single intravenous dose (IV)
valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A | 1 |
| BMN 270 2E13 vg/kg Cohort 2: 2E13 vg per kilogram, given as a single intravenous dose (IV)
valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A | 1 |
| BMN 270 4E13 vg/kg Cohort 4: 4E13 vg per kilogram, given as a single intravenous dose (IV)
valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A | 6 |
| BMN 270 6E13 vg/kg Cohort 3: 6E13 vg per kilogram, given as a single intravenous dose (IV)
valoctocogene roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | BMN 270 2E13 vg/kg | Total | BMN 270 6E13 vg/kg | BMN 270 6E12 vg/kg | BMN 270 4E13 vg/kg |
|---|---|---|---|---|---|
| Age, Continuous | 43.0 years | 31.3 years STANDARD_DEVIATION 7.8 | 30.4 years STANDARD_DEVIATION 5.8 | 25.0 years | 31.3 years STANDARD_DEVIATION 9.6 |
| Age, Customized 18 to < 40 years | 0 Participants | 12 Participants | 6 Participants | 1 Participants | 5 Participants |
| Age, Customized 40 to < 60 years | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Baseline ABR (treated bleeds) | 3.00 bleeds/year | 13.40 bleeds/year STANDARD_DEVIATION 14.26 | 17.57 bleeds/year STANDARD_DEVIATION 14.71 | 2.00 bleeds/year | 12.17 bleeds/year STANDARD_DEVIATION 15.35 |
| Baseline annualized FVIII usage | 3022.48 IU/kg/year | 4389.70 IU/kg/year STANDARD_DEVIATION 1965.51 | 4444.48 IU/kg/year STANDARD_DEVIATION 1969.5 | 3486.66 IU/kg/year | 4704.16 IU/kg/year STANDARD_DEVIATION 2345.75 |
| Baseline annualized number of FVIII infusions | 103.77 infusions/year | 125.93 infusions/year STANDARD_DEVIATION 45.11 | 120.12 infusions/year STANDARD_DEVIATION 45.94 | 87.35 infusions/year | 142.83 infusions/year STANDARD_DEVIATION 48.78 |
| Baseline Bleed Counts (treated bleeds) 0 bleeds/year | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Baseline Bleed Counts (treated bleeds) > 0 to 4 | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 2 Participants |
| Baseline Bleed Counts (treated bleeds) > 10 | 0 Participants | 7 Participants | 4 Participants | 0 Participants | 3 Participants |
| Baseline Bleed Counts (treated bleeds) > 4 to 10 | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 15 Participants | 7 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| History of previous diseases Hepatitis B(HepB) | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| History of previous diseases Hepatitis C(HepC) | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 2 Participants |
| History of previous diseases Human immunodeficiency virus(HIV) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| History of previous diseases Liver disease(LD) | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Number of target joints 0 | 0 Participants | 4 Participants | 1 Participants | 0 Participants | 3 Participants |
| Number of target joints 1 | 0 Participants | 4 Participants | 3 Participants | 0 Participants | 1 Participants |
| Number of target joints 2 | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants |
| Number of target joints 3 | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Number of target joints > 3 | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 12 Participants | 6 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 15 Participants | 7 Participants | 1 Participants | 6 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 / 1 | 0 / 1 | 0 / 6 | 0 / 7 | 0 / 15 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 6 / 6 | 7 / 7 | 15 / 15 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 3 / 6 | 5 / 7 | 9 / 15 |
Outcome results
Primary
Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion
Values for FVIII activity were excluded from analysis if obtained within 72 hours since the last infusion of exogenous FVIII replacement therapy FVIII activity levels below the Lower limit of quantitation (LLOQ) will be imputed with 0 IU/dL Q1: 25% Percentile; Q3: 75% Percentile
Time frame: Week 13-16 post-BMN 270 infusion
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BMN 270 6E12 vg/kg | Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion | 0.00 IU/dL |
| BMN 270 2E13 vg/kg | Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion | 0.00 IU/dL |
| BMN 270 4E13 vg/kg | Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion | 16.30 IU/dL |
| BMN 270 6E13 vg/kg | Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion | 50.40 IU/dL |
Primary
Number of Participants With Treatment Emergent Adverse Events
Adverse events (AEs) with onset or worsening after the investigational product were included. Participants with more than one AE of the same category were counted only once for that category. Serious adverse event (SAE)
Time frame: Approximately up to 7 years after dosing
Population: Safety analysis Population: The Safety analysis population was defined as all enrolled participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose interruption during infusion | 0 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose adjustment during infusion | 0 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants who died | 0 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Treatment-related SAEs | 0 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any treatment-related AE | 1 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any SAE | 1 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to study drug discontinuation | 0 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE of Grade >= 3 | 1 Participants |
| BMN 270 6E12 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE | 1 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE of Grade >= 3 | 1 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose interruption during infusion | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose adjustment during infusion | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any SAE | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE | 1 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any treatment-related AE | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants who died | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to study drug discontinuation | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Treatment-related SAEs | 0 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE of Grade >= 3 | 1 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE | 6 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any SAE | 3 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any treatment-related AE | 6 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Treatment-related SAEs | 1 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose adjustment during infusion | 0 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose interruption during infusion | 0 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to study drug discontinuation | 0 Participants |
| BMN 270 4E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants who died | 0 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose interruption during infusion | 0 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Treatment-related SAEs | 0 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any treatment-related AE | 7 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants who died | 0 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to study drug discontinuation | 0 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any SAE | 5 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | AEs leading to dose adjustment during infusion | 0 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE of Grade >= 3 | 2 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE | 7 Participants |
Primary
Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA)
Responder/Non responder status, where a responder was defined as a participant with median FVIII activity of \>= 5 IU/dL during Week 13-16 post-BMN 270 infusion
Time frame: Week 13-16 post-BMN 270 infusion
Population: Full Analysis Set (FAS) population: defined as all enrolled participants who receive study drug and have at least one Baseline and post-Baseline assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BMN 270 6E12 vg/kg | Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA) | 0 Participants |
| BMN 270 2E13 vg/kg | Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA) | 0 Participants |
| BMN 270 4E13 vg/kg | Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA) | 5 Participants |
| BMN 270 6E13 vg/kg | Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA) | 7 Participants |
Secondary
Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond
ABR= \[Number of bleeding episodes during calculation period\] / \[Total number of days during the calculation period\] ×365.25 A bleeding episode (treated) was defined as a bleed or symptoms associated with the development of a bleed (or multiple bleeds occurring in the same day) requiring FVIII replacement treatment within 72 hours of the start of the bleed. The baseline values for the secondary efficacy endpoints were based on the historical data prior to study enrollment. Annualized bleeding rate (ABR)
Time frame: Week 5 and Beyond (Approximately 7 years post Infusion)
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 270 6E12 vg/kg | Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond | 1.87 bleeds/year | — |
| BMN 270 2E13 vg/kg | Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond | 6.20 bleeds/year | — |
| BMN 270 4E13 vg/kg | Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond | 1.58 bleeds/year | Standard Deviation 1.97 |
| BMN 270 6E13 vg/kg | Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond | 0.75 bleeds/year | Standard Deviation 1.43 |
Secondary
Annualized Factor VIII Infusion Rate During Week 5 and Beyond
Annualized FVIII infusion rate (count/yr.) = \[Number of FVIII replacement infusions during calculation period\] / \[Total number of days during the calculation period\] ×365.25
Time frame: Week 5 and Beyond (Approximately 7 years post Infusion)
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 270 6E12 vg/kg | Annualized Factor VIII Infusion Rate During Week 5 and Beyond | 77.98 Infusions/ year | — |
| BMN 270 2E13 vg/kg | Annualized Factor VIII Infusion Rate During Week 5 and Beyond | 10.09 Infusions/ year | — |
| BMN 270 4E13 vg/kg | Annualized Factor VIII Infusion Rate During Week 5 and Beyond | 10.25 Infusions/ year | Standard Deviation 9.06 |
| BMN 270 6E13 vg/kg | Annualized Factor VIII Infusion Rate During Week 5 and Beyond | 6.38 Infusions/ year | Standard Deviation 8.19 |
Secondary
Annualized Factor VIII Utilization During Week 5 and Beyond
Annualized FVIII use (IU/kg/yr.) =\[Sum of FVIII use (IU/kg) during calculation period\] / \[Total number of days during the calculation period\] ×365.25
Time frame: Week 5 and Beyond (Approximately 7 years post Infusion)
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 270 6E12 vg/kg | Annualized Factor VIII Utilization During Week 5 and Beyond | 2536.47 IU/kg/yr | — |
| BMN 270 2E13 vg/kg | Annualized Factor VIII Utilization During Week 5 and Beyond | 279.27 IU/kg/yr | — |
| BMN 270 4E13 vg/kg | Annualized Factor VIII Utilization During Week 5 and Beyond | 331.65 IU/kg/yr | Standard Deviation 360.19 |
| BMN 270 6E13 vg/kg | Annualized Factor VIII Utilization During Week 5 and Beyond | 228.72 IU/kg/yr | Standard Deviation 311.68 |