Brief Title
Gene Therapy Study in Severe Hemophilia A Patients With Antibodies Against AAV5
Official Title
A Phase 1/2 Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL and Pre-existing Antibodies Against AAV5
Brief Summary
This study is being conducted by Biomarin Pharmaceutical Inc. as an open label, single dose
study in order to determine the safety of valoctocogene roxaparvovec (an
Adenovirus-Associated Virus (AAV) based gene therapy vector in participants with severe
Haemophilia A who also have pre-existing antibodies against AAV5.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Percentage of participants with treatment-related adverse events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for 5 years following valoctocogene roxaparvovec infusion.
Secondary Outcome
Efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26
Condition
Haemophilia A
Intervention
Valoctocogene Roxaparvovec
Study Arms / Comparison Groups
valoctocogene roxaparvovec Open Label
Description: Single administration of BMN270 at a dose of 6E13 vg/kg
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
10
Start Date
April 3, 2018
Completion Date
June 2025
Primary Completion Date
June 2025
Eligibility Criteria
Inclusion Criteria:
Individuals eligible to participate in this study must meet all of the following 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. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure
days (EDs)
4. Subject must have been on prophylactic FVIII replacement therapy for at least 12
months prior to study entry.
5. Willing and able to provide written, signed informed consent after the nature of the
study has been explained and prior to any study-related procedures.
6. 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)
7. Sexually active participants must agree to use an acceptable method of effective
contraception, either double barrier contraception (ie, condom + diaphragm; or condom
or diaphragm + spermicidal gel or foam) or their female partner either using hormonal
contraceptives or having an intrauterine device. Participants must agree to
contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may
stop contraception use only if they have had 3 consecutive semen samples with viral
vector DNA below the limit of detection.
8. Willing to abstain from consumption of alcohol for at least the first 52 weeks
following BMN 270 infusion.
Exclusion Criteria:
Individuals who meet any of the following exclusion criteria will not be eligible to
participate in the study:
1. Any evidence of active infection or any immunosuppressive disorder, including HIV
infection.
2. Significant liver dysfunction with any of the following abnormal laboratory results:
- ALT (alanine aminotransferase) > 1.25x ULN;
- AST (aspartate aminotransferase) > 1.25x ULN;
- GGT (gamma-glutamyltransferase) > 1.25x ULN;
- Total bilirubin > 1.25x ULN;
- Alkaline phosphatase > 1.25x ULN; or
- INR (international normalized ratio) ≥ 1.4 Subjects whose laboratory assessments
fall outside of these ranges may undergo repeat testing of the entire liver test
panel within the same Screening window and, if eligibility criteria are met on
retest, may be enrolled after confirmation by the Medical Monitor.
3. Prior 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
4. Evidence of any bleeding disorder not related to hemophilia A
5. Platelet count of < 100 x 10^9/L
6. Creatinine ≥ 1.5 mg/dL
7. Liver cirrhosis of any etiology as assessed by liver ultrasound
8. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B
surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core
antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease
Control (CDC) table for the interpretation of serological test results.
9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral
therapy
10. Active malignancy, except non-melanoma skin cancer
11. History of hepatic malignancy
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis,
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus),
with the exception of catheter-associated thrombosis for which anti-thrombotic
treatment is not currently ongoing.
13. Known inherited or acquired thrombophilia, including conditions associated with
increased thromboembolic risk, such as atrial fibrillation.
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg,
vasculitis).
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the
investigational product (whichever is longer) prior to the screening period. For
subjects who have received a prior investigational product, all ongoing adverse events
(AEs) experienced while receiving that investigational product must have resolved
prior to screening for this study
16. 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 possible
corticosteroid treatment outlined in the protocol) and/or would impact or interfere
with evaluation and interpretation of subject safety or efficacy result.
17. Prior treatment with any vector or gene transfer agent
18. Major surgery planned in the 52-week period following the infusion with BMN 270
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live
vaccines within 30 days before the BMN 270 infusion
20. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study that does not interfere with the requirements of
the current protocol or have the potential to impact the evaluation of safety and
efficacy of BMN 270 and with prior consultation with the Medical Monitor
21. Known allergy or hypersensitivity to investigational product formulation
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or
a bleed
Gender
Male
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Medical Director, MD, ,
Location Countries
France
Location Countries
France
Administrative Informations
NCT ID
NCT03520712
Organization ID
BMN 270-203
Secondary IDs
2017-000662-29
Responsible Party
Sponsor
Study Sponsor
BioMarin Pharmaceutical
Study Sponsor
Medical Director, MD, Study Director, BioMarin Pharmaceutical
Verification Date
April 2020