Clinical trial NCT03520712: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Hemophilia a
Gene Therapy
Clotting Disorders
Blood Disorder
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
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2018-05-11
Enrollment: 3
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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.
timeFrame: 61 months
Secondary outcomes:
measure: Efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26.
timeFrame: 26 weeks
measure: Impact of BMN 270 on usage of exogenous FVIII replacement therapy.
timeFrame: 61 months
measure: Impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII therapy.
timeFrame: 61 months
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital at Gangdong
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Academic Hospital, Hemophilia Comprehensive Care Center
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: BioMarin Pharmaceutical
name: Medical Director, MD
role: STUDY_DIRECTOR
References: