Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors

Study Overview
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Brief Summary
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SPK-8016 is in development for the treatment of patients with inhibitors to FVIII. This Phase 1/2, open-label, non-randomized, dose-finding study is part one of a planned two part study of SPK-8016. Part one will evaluate the safety, efficacy, and tolerability of SPK-8016 in adult males with clinically severe hemophilia A and no measurable inhibitor against FVIII. Data obtained from Part 1 will inform the study design and dose selection for Part 2 in patients with FVIII inhibitors.

Official Title
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Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors

Conditions
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Vector, Adeno-Associated Virus (AAV), Blood Coagulation Disorder, Blood Coagulation Disorders, Inherited, Coagulation Protein Disorders, Factor VIII (FVIII), Factor VIII (FVIII) Deficiency, Factor VIII (FVIII) Gene, Factor VIII (FVIII) Protein, Genetic Diseases, Inborn, Genetic Diseases, X-Linked, Gene Therapy, Gene Transfer, Hematologic Diseases, Hemorrhagic Disorders, Recombinant, Inhibitors

Intervention / Treatment
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* Genetic: SPK-8016


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Part 1: Be male and ≥18 years of age; Have clinically severe hemophilia A, defined as: <1% (<1 IU/dL) endogenous FVIII activity levels as historically documented by a certified laboratory or screening data results; OR 1-2% (1-2 IU/dL) endogenous FVIII activity levels and > 10 bleeding events per year (in the last 52 weeks prior to screening); OR 1-2% (1-2 IU/dL) endogenous FVIII activity levels and on prophylaxis; Have had >150 exposure days (EDs) to any recombinant and/or plasma-derived FVIII concentrates or cryoprecipitates Have no prior history of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration Have no measurable inhibitor against FVIII as assessed by central laboratory, have no confirmed history of clinically significant FVIII inhibitor, and no clinical signs or symptoms of decreased response to FVIII administration (Note: family history of inhibitors will not exclude study participation) Agree to use reliable barrier contraception after the administration of SPK-8016 until notified by the Investigator. Exclusion Criteria for Part 1: Have active hepatitis B or C Have significant underlying liver disease. Have serological evidence of HIV-1 or HIV-2 with CD4 counts ≤200/mm3. Participants who are HIV-positive and stable, with an adequate CD4 count (>200/mm3) and undetectable viral load, and are on an antiretroviral drug regimen are eligible to enroll Have detectable antibodies reactive with AAV-Spark capsid Have history of chronic infection or other chronic disease Have been dosed in a previous gene therapy research trial within the last 52 weeks or with an investigational drug within the last 12 weeks Any concurrent clinically significant major disease (such as liver abnormalities or type I diabetes) or other condition that, in the opinion of the Investigator and/or Sponsor, makes the subject unsuitable for participation in the study; Unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol.

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: SPK-8016<br>All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8016. | Genetic: SPK-8016<br>* adeno-associated viral vector<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of study-related adverse events, including clinically significant abnormal laboratory values. | Adverse events. | 52 weeks | 
| Occurrence of hepatic transaminase elevation requiring immunosuppression. | Number of incidences of hepatic transaminase elevation where immunosuppression is required. | 52 weeks | 
| Number of bleeding events (spontaneous and traumatic) after vector administration. | Bleeding events. | 52 weeks | 
| Number of FVIII infusions after vector administration. | FVIII infusions. | 52 weeks | 
| Peak and steady-state FVIII activity levels. | Peak and steady-state FVIII activity levels assessed by coagulation clotting assays. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vector shedding of SPK-8016 in bodily fluids. | Vector shedding. | 52 weeks | 
| Incidence of immune response to AAV capsid protein and transgene product. |  | 52 weeks |