Phase 3 Study for Efficacy and Safety Outcomes Data in Japanese Patients With Severe Hemophilia A

This Phase III clinical study will evaluate the safety and effectiveness of valoctocogene roxaparvovec in Japanese patients with severe hemophilia A.

This is a Phase 3, single-arm, open-label study in Japanese hemophilia A (HA) participants with endogenous coagulation factor VIII (FVIII) activity levels \<1 IU/dL treated continuously with prophylactic exogenous FVIII for a minimum of 1 year prior to enrollment. Participants will be enrolled at approximately 10 sites in Japan. Participants must have high-quality, well-documented historical data available concerning previous bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. Approximately 6 Japanese adult participants with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a single intravenous infusion.

Eligibility Criteria:
Inclusion Criteria:

* Japanese males ≥18 years of age with HA and endogenous FVIII activity levels \<1 IU/dL as evidenced by medical history, at the time of signing the informed consent
* Must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. High-quality, well-documented historical data concerning bleeding episodes and FVIII usage over the previous 12 months must be available.
* Treated/exposed to FVIII concentrates for a minimum of 150 exposure days.
* 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.
* 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 1 week apart within the past 12 months (at least 1 of which should be tested at the central laboratory).
* Sexually active participants must agree to use an acceptable method of effective contraception
* Willing to abstain from alcohol consumption for at least the first 52 weeks following BMN 270 infusion.

Exclusion Criteria:

* Detectable pre-existing antibodies to the AAV5 capsid.
* Any evidence of active infection or any immunosuppressive disorder, except for human immunodeficiency virus (HIV) infection. HIV-positive participants who meet all other eligibility criteria may be included.
* Significant liver dysfunction
* Most recent, prior FibroScan or liver biopsy showing significant fibrosis
* Evidence of any bleeding disorder not related to HA.
* Platelet count of \<100E9/L.
* Creatinine ≥1.5 mg/dL.
* Liver cirrhosis of any etiology as assessed by liver ultrasound.
* Chronic or active hepatitis B
* Active hepatitis C
* Active malignancy, except non-melanoma skin cancer
* History of hepatic malignancy
* History of arterial or venous thromboembolic events
* Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation
* Treatment with any investigational product (IP) within 30 days or 5 half-lives of the IP prior to the Screening period.
* Any condition that, in the opinion of the investigator or sponsor would prevent the participant from fully complying with the requirements of the study
* Prior treatment with any vector or gene transfer agent.
* Major surgery planned in the 52-week period following the infusion with BMN 270.
* Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the BMN 270 infusion.
* 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 efficacy and safety of BMN 270 and with prior consultation with the medical monitor.
* Known allergy or hypersensitivity to BMN 270 IP formulation.
* Unwilling to receive blood or blood products for treatment of an AE and/or a bleeding episode.