Gene Therapy Study in Severe Hemophilia A Patients With Antibodies Against AAV5 (GENEr8-AAV5+)

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

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.

Study Overview

• Status: Terminated
• Conditions: Hemophilia A; Gene Therapy; Blood Disorder; Clotting Disorders
• Intervention / Treatment: Biological: Valoctocogene Roxaparvovec

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Kyung Hee University Hospital at Gangdong
  • Seoul, Korea, Republic of
    • Severance Hospital, Yonsei University Health System
• South Africa
  • Johannesburg, South Africa
    • Charlotte Maxeke Johannesburg Academic Hospital, Hemophilia Comprehensive Care Center
• Taiwan
  • Kaohsiung, Taiwan
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Taipei, Taiwan
    • TRI-Service General Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
• United Kingdom
  • London, United Kingdom
    • Royal Free Hospital
  • Southampton, United Kingdom
    • University Hospital Southampton NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: BMN 270

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 5 years post-infusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	26 weeks
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	Week 5 and Beyond (Follow-Up, up to 1782 Days)
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	Week 5 and Beyond (Follow-Up, up to 1782 Days)
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	Week 5 and Beyond (Follow-Up, up to 1782 Days)

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Medical Director, MD, BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2018
• Primary Completion (Actual): August 7, 2024
• Study Completion (Actual): August 7, 2024

Study Registration Dates

• First Submitted: April 10, 2018
• First Submitted That Met QC Criteria: April 27, 2018
• First Posted (Actual): May 11, 2018

Study Record Updates

• Last Update Posted (Actual): August 22, 2025
• Last Update Submitted That Met QC Criteria: August 5, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Hematologic Diseases; Genetic Diseases, Inborn; Blood Coagulation Disorders; Factor VIII; Hemorrhagic Disorders; Hemophilia A; Coagulants; Coagulation Protein Disorders; Blood Coagulation Disorders, Inherited; AAV5 antibodies
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Hemorrhagic Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemophilia A; Hematologic Diseases; Hemostatic Disorders; Blood Coagulation Disorders
• Other Study ID Numbers: 270-203; 2017-000662-29 (EudraCT Number)

Drug and device information, study documents

• 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