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Gene Therapy Study in Severe Hemophilia A Patients With Antibodies Against AAV5 (270-203)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03520712
Recruitment Status : Enrolling by invitation
First Posted : May 11, 2018
Last Update Posted : April 24, 2020
Information provided by (Responsible Party):
BioMarin Pharmaceutical

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.

Condition or disease Intervention/treatment Phase
Haemophilia A Gene Therapy Clotting Disorders Blood Disorder Biological: Valoctocogene Roxaparvovec Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 3, 2018
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: valoctocogene roxaparvovec Open Label
Single administration of BMN270 at a dose of 6E13 vg/kg
Biological: Valoctocogene Roxaparvovec
Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A
Other Name: BMN 270

Primary Outcome Measures :
  1. 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. [ Time Frame: 61 months ]
    Safety of a single intravenous administration of BMN 270 in severe HA subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody.

Secondary Outcome Measures :
  1. Efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26 [ Time Frame: 26 weeks ]
  2. Impact of BMN 270 on usage of exogenous FVIII replacement therapy [ Time Frame: 61 months ]
  3. Impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII therapy [ Time Frame: 61 months ]
  4. Pharmacodynamics of FVIII expression following IV infusion of BMN 270 roxaparvovec [ Time Frame: 61 months ]
  5. Impact of BMN 270 on patient-reported outcomes (PROs) [ Time Frame: 61 months ]

Other Outcome Measures:
  1. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemo-QoL-A. [ Time Frame: 61 months ]
    Haemo-QoL-A is a hemophilia-specific, health-related quality of life questionnaire for adults on a scale of 0-5 with the lower value representing a better outcome.

  2. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) EQ-5D-5L [ Time Frame: 61 months ]
    EQ-5D-5L is a general questionnaire designed to measure health status on a scale of 0-100 with the higher value representing a better outcome.

  3. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Activities List (HAL) [ Time Frame: 52 weeks ]
    HAL is a questionnaire that has several activities are listed that could be difficult for people with hemophilia. The aim of the questionnaire is to see how easy it is for participates to do those activities.

  4. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) [ Time Frame: 52 weeks ]
    WPAI+CIQ:HS is a questionnaire that is designed to measure the effect of symptom severity due to hemophilia on work productivity and activity/classroom impairment

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03520712

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Nantes University Hospital Center - Hotel Dieu Hospital
Nantes, France
South Africa
Charlotte Maxeke Johannesburg Academic Hospital, Hemophilia Comprehensive Care Center
Johannesburg, South Africa
United Kingdom
Royal Free Hospital
London, United Kingdom
University Hospital Southampton NHS Foundation Trust
Southampton, United Kingdom
Sponsors and Collaborators
BioMarin Pharmaceutical
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Study Director: Medical Director, MD BioMarin Pharmaceutical
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Responsible Party: BioMarin Pharmaceutical Identifier: NCT03520712    
Other Study ID Numbers: BMN 270-203
2017-000662-29 ( EudraCT Number )
First Posted: May 11, 2018    Key Record Dates
Last Update Posted: April 24, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by BioMarin Pharmaceutical:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
AAV5 antibodies
Additional relevant MeSH terms:
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Hemostatic Disorders
Hemophilia A
Hematologic Diseases
Blood Coagulation Disorders
Pathologic Processes
Blood Coagulation Disorders, Inherited
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Vascular Diseases
Cardiovascular Diseases