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

• ClinicalTrials.gov Identifier: NCT03520712
• Recruitment Status: Active, not recruiting
• First Posted: May 11, 2018
• Last Update Posted: April 24, 2024
• Sponsor: BioMarin Pharmaceutical
• Information provided by (Responsible Party): BioMarin Pharmaceutical

Tracking Information

• First Submitted Date: April 10, 2018
• First Posted Date: May 11, 2018
• Last Update Posted Date: April 24, 2024
• Actual Study Start Date: April 3, 2018
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 12, 2020): 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. [ Time Frame: 61 months ]

Original Primary Outcome Measures (submitted: April 27, 2018)

Assess the safety of a single intravenous administration of valoctocogene roxaparvovec in severe Hemophilia A (HA) subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody [ Time Frame: 61 months ]

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.

Current Secondary Outcome Measures (submitted: November 12, 2020)

• Efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26. [ Time Frame: 26 weeks ]
• Impact of BMN 270 on usage of exogenous FVIII replacement therapy. [ Time Frame: 61 months ]
• Impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII therapy. [ Time Frame: 61 months ]

Original Secondary Outcome Measures (submitted: April 27, 2018)

• Assess the efficacy of valoctocogene roxaparvovec defined as FVIII activity at or above 5 IU/dL at Week 26 [ Time Frame: 26 weeks ]
• Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy [ Time Frame: 61 months ]
• Assess the impact of valoctocogene roxaparvovec on the number of bleeding episodes requiring exogenous FVIII therapy [ Time Frame: 61 months ]
• Evaluate the FVIII antigen and activity level following IV infusion of valoctocogene roxaparvovec [ Time Frame: 61 months ]
• Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Quality of Life for Adults (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 a higher value representing a better outcome
• 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
• Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Activities List (HAL) [ Time Frame: 61 months ]
  HAL is a questionnaire that has several activities listed that could be difficult for people with hemophilia. Subjects are asked to rate their level of difficulty with activities of daily living on a 6-point scale from 1 (Impossible) to 6 (Never)
• 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: 61 months ]
  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. WPAI+CIQ:HS outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hemophilia A
• Gene Therapy
• Clotting Disorders
• Blood Disorder

Intervention

Biological: Valoctocogene Roxaparvovec

Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A

Other Name: BMN 270

Study Arms

Experimental: valoctocogene roxaparvovec Open Label

Single administration of BMN270 at a dose of 6E13 vg/kg

Intervention: Biological: Valoctocogene Roxaparvovec

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 25, 2023): 3
• Original Estimated Enrollment (submitted: April 27, 2018): 10
• Estimated Study Completion Date: November 2024
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Biological males only.

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of, South Africa, Taiwan, United Kingdom
• Removed Location Countries: France

Administrative Information

• NCT Number: NCT03520712
• Other Study ID Numbers: 270-203; 2017-000662-29 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: BioMarin Pharmaceutical
• Original Responsible Party: Same as current
• Current Study Sponsor: BioMarin Pharmaceutical
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director, MD; BioMarin Pharmaceutical

• PRS Account: BioMarin Pharmaceutical
• Verification Date: April 2024