Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec in Hemophilia A With Active or Prior Inhibitors

Study Overview
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Brief Summary
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This Phase I/II clinical study will evaluate the safety and efficacy of valoctocogene roxaparvovec in patients with severe haemophilia A and inhibitors to FVIII. Part A of the study will involve subjects who have active inhibitors to FVIII, and Part B involving subjects with a prior history of inhibitors.

Official Title
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A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Active or Prior Inhibitors

Conditions
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Hemophilia A With Inhibitor, Hemophilia A With Anti Factor VIII

Intervention / Treatment
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* Biological: Valoctocogene roxaparvovec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males ≥ 18 years of age with hemophilia A and documented prior residual FVIII activity ≤ 1 IU/dL including, but not limited to, at the time of detected inhibitors, at the time of signing the informed consent. History of a positive inhibitor result with the first positive result at least 12 month prior to Screening. Part A: Demonstrated no immunological tolerance to exogenous FVIII. Part B: Demonstrated tolerance to exogenous FVIII and negative FVIII inhibitor screening titer < 0.6 BU. Prophylactic or on-demand hemophilia therapy in the last 12 months. Bleeding, inhibitor & hemophilia therapy Hx over previous 12 months. 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. Willing to abstain from consumption of alcohol 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; patients with HIV infection and undetectable viral load are not excluded. Currently undergoing, or plan to receive during the study, immune tolerance induction therapy or prophylaxis with FVIII (Part A only). Significant renal dysfunction or liver dysfunction, infection or history of hepatic malignancy. Evidence of any bleeding disorder not related to hemophilia A.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valoctocogene roxaparvovec Open Label<br>Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg in Active Inhibitor Population (Part A) and Prior Inhibitor Population (Part B). | Biological: Valoctocogene roxaparvovec<br>* Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A<br>* Other names: BMN 270;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 after administration of BMN 270. |  | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of the median Factor VIII activity. | Changes in the median Factor VIII activity (IU/mL) after administration of BMN 270 which will be measured using the chromogenic FVIII assay. | 60 months | 
| A change in Factor VIII inhibitor titer (Part A) after administration of BMN 270. | FVIII inhibitor titer will be measured using a chromogenic Nijmegen-Bethesda assay. | 60 months | 
| Absence of recurrence of Factor VIII inhibitors (Part B) after administration of BMN 270. | FVIII inhibitor titer will be measured using a chromogenic Nijmegen-Bethesda assay. | 60 months | 
| Change in the annualized utilization of hemophilia therapy after administration of BMN 270 |  | 60 months | 
| Change in the annualized number of bleeding episodes requiring exogenous hemophilia therapy after administration of BMN 270. |  | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Therapy, Clotting Disorders, Blood Disorder, Blood Coagulation Disorders, Inherited Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic DIseases, Factor VIII, Coagulants, Hemophilia A, AAV5 vector