Blood Disorder, Clotting Disorders, Gene Therapy, Hemophilia A
Conditions
Keywords
Hemophilia A, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII, Coagulants, AAV5 antibodies
Brief summary
This study is being conducted by BioMarin Pharmaceutical Inc. as an open label, single dose study to determine the safety of valoctocogene roxaparvovec (an Adenovirus-Associated Virus (AAV) based gene therapy vector) in severe Hemophilia A patients with pre-existing antibodies against AAV5.
Interventions
BIOLOGICALValoctocogene Roxaparvovec
Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in 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 of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent. 2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total antibody ELISA. 3. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. 4. No previous documented history of a detectable FVIII inhibitor, and results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart within the past 12 months (at least one of which should be tested at the central laboratory). 5. Sexually active participants must agree to use an acceptable method of effective contraception. Participants must agree to contraception use for at least 12 weeks post-infusion.
Exclusion criteria
1. Any evidence of active infection including COVID-19, or any immunosuppressive disorder, except for HIV infection. HIV positive patients who meet all other eligibility criteria may be included if they have a CD4 count \> 200/mm3 and an undetectable viral load (unquantifiable viral load as defined as less than the limit of quantification by the testing laboratory's assay is permitted) while receiving an antiretroviral therapy (ART) regimen that does not contain efavirenz or another potentially hepatotoxic ART. 2. Evidence of liver dysfunction as assessed by liver tests and most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used. 3. Chronic or active hepatitis B or C as evidenced by testing at screening. 4. Active malignancy, except non-melanoma skin cancer, or history of hepatic malignancy. 5. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including corticosteroid treatment and/or use of alternative immunosuppressive agents outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events | Up to 5 years post-infusion. | A treatment-emergent adverse event (TEAE) is defined as any AE that newly appeared or worsened in severity following initiation of investigational product administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participant With FVIII Activity >= 5 IU/dL at Week 26. Using Chromogenic Substrate Assay (CSA). | 26 weeks | Prior to BMN270 infusion, screening FVIII activity levels where participants had not received exogenous FVIII within 72 hours of assessment were below the lower limit of quantitation (LLOQ) as measured by CSA (LLOQ = 0.015 IU/mL). |
| Mean Annualized Factor VIII Utilization During Week 5 and Beyond | Week 5 and Beyond (Follow-Up, up to 1782 Days) | The annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy is defined as Sum of FVIII use (IU/kg) during calculation period/Total number of days during the calculation period ×365.25 |
| Mean Annualized Factor VIII Infusion Rate During Week 5 and Beyond | Week 5 and Beyond (Follow-Up, up to 1782 Days) | Annualized FVIII replacement infusion rate=(number of FVFIII replacement infusions during calculation period/sum(follow-up days) of the period)\*365.25 |
| Number of Participants Showed Reduction in the ABR Post-BMN 270 Infusion. Impact of BMN 270 on the Number of Bleeding Episodes Requiring Exogenous FVIII Therapy. | Week 5 and Beyond (Follow-Up, up to 1782 Days) | Annualized bleeding rate (ABR) (counts/yr.)=Number of bleeding episodes during calculation period/Total number of days during the calculation period ×365.25 |
Countries
South Africa, South Korea, Taiwan, United Kingdom
Participant flow
Recruitment details
This study was conducted by 2 principal investigators at 2 study centers in 2 countries (South Africa and United Kingdom). Nine investigational sites were activated, 2 subjects in South Africa and 1 subject in the United Kingdom were enrolled in the study.
Pre-assignment details
10 participants were planned to be enrolled. 3 participants met all eligibility criteria & were enrolled in study. There were 26 screen failures.
Participants by arm
| Arm | Count |
|---|---|
| BMN 270 6E13 vg/kg BMN 270 6E13 vg/kg, given as a single intravenous dose (IV)
Valoctocogene Roxaparvovec: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Early termination of the study by Sponsor | 2 |
Baseline characteristics
| Characteristic | BMN 270 6E13 vg/kg |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 2 Participants |
| Region of Enrollment South Africa | 2 participants |
| Region of Enrollment United Kingdom | 1 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
Number of Participants With Treatment Emergent Adverse Events
A treatment-emergent adverse event (TEAE) is defined as any AE that newly appeared or worsened in severity following initiation of investigational product administration.
Time frame: Up to 5 years post-infusion.
Population: The safety analysis was based on the ITT population.~The intention-to-treat (ITT) population was comprised of all participants who have received the BMN 270 infusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE | 3 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any SAE | 1 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any treatment-related AE | 3 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Treatment-related SAEs | 1 Participants |
| BMN 270 6E13 vg/kg | Number of Participants With Treatment Emergent Adverse Events | Participants with any AE of Grade >= 3 | 1 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 | AEs leading to dose interruption during infusion | 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 who died | 0 Participants |
Secondary
Mean Annualized Factor VIII Infusion Rate During Week 5 and Beyond
Annualized FVIII replacement infusion rate=(number of FVFIII replacement infusions during calculation period/sum(follow-up days) of the period)\*365.25
Time frame: Week 5 and Beyond (Follow-Up, up to 1782 Days)
Population: The intention-to-treat (ITT) population was comprised of all participants who have received the BMN 270 infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 270 6E13 vg/kg | Mean Annualized Factor VIII Infusion Rate During Week 5 and Beyond | 21.9 ml/min | Standard Deviation 30.61 |
Secondary
Mean Annualized Factor VIII Utilization During Week 5 and Beyond
The annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy is defined as 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 (Follow-Up, up to 1782 Days)
Population: The intention-to-treat (ITT) population was comprised of all participants who have received the BMN 270 infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 270 6E13 vg/kg | Mean Annualized Factor VIII Utilization During Week 5 and Beyond | 661.1 IU/kg/yr | Standard Deviation 912.92 |
Secondary
Number of Participants Showed Reduction in the ABR Post-BMN 270 Infusion. Impact of BMN 270 on the Number of Bleeding Episodes Requiring Exogenous FVIII Therapy.
Annualized bleeding rate (ABR) (counts/yr.)=Number of bleeding episodes during calculation period/Total number of days during the calculation period ×365.25
Time frame: Week 5 and Beyond (Follow-Up, up to 1782 Days)
Population: The intention-to-treat (ITT) population was comprised of all participants who have received the BMN 270 infusion.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BMN 270 6E13 vg/kg | Number of Participants Showed Reduction in the ABR Post-BMN 270 Infusion. Impact of BMN 270 on the Number of Bleeding Episodes Requiring Exogenous FVIII Therapy. | Participants showed reduction in the ABR post-BMN 270 infusion | 3 Participants |
| BMN 270 6E13 vg/kg | Number of Participants Showed Reduction in the ABR Post-BMN 270 Infusion. Impact of BMN 270 on the Number of Bleeding Episodes Requiring Exogenous FVIII Therapy. | Participants who did not show reduction in the ABR post-BMN 270 infusion | 0 Participants |
Secondary
Number of Participant With FVIII Activity >= 5 IU/dL at Week 26. Using Chromogenic Substrate Assay (CSA).
Prior to BMN270 infusion, screening FVIII activity levels where participants had not received exogenous FVIII within 72 hours of assessment were below the lower limit of quantitation (LLOQ) as measured by CSA (LLOQ = 0.015 IU/mL).
Time frame: 26 weeks
Population: The intention-to-treat (ITT) population was comprised of all participants who have received the BMN 270 infusion.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BMN 270 6E13 vg/kg | Number of Participant With FVIII Activity >= 5 IU/dL at Week 26. Using Chromogenic Substrate Assay (CSA). | Participant with FVIII activity >= 5 IU/dL | 1 Participants |
| BMN 270 6E13 vg/kg | Number of Participant With FVIII Activity >= 5 IU/dL at Week 26. Using Chromogenic Substrate Assay (CSA). | Participant with FVIII activity < 5 IU/dL | 2 Participants |