A Study of Recombinant AAV2/6 Human Factor 8 Gene Therapy SB-525 (PF-07055480) in Subjects With Severe Hemophilia A

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety, tolerability and time-course profile of FVIII activity after dosing with SB-525 (PF-07055480)

Detailed Description
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The proposed clinical study uses a recombinant adeno-associated virus 2/6 (AAV2/6) vector encoding the cDNA for the B-domain deleted human F8 (hF8). The secreted FVIII has the same amino acid sequence as approved recombinant anti hemophilic factors (Refacto® and Xyntha®). The SB-525 (PF-07055480) vector encodes a liver-specific promotor module and AAV2/6 exhibits liver tropism, thus providing the potential for long-term hepatic production of FVIII in hemophilia A subjects. The constant production of FVIII after a single SB-525 (PF-07055480) administration may provide potential benefit in durable protection against bleeding and the complications thereof without lifelong repetitive IV factor replacement administration.

Official Title
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A PHASE 1/2, OPEN-LABEL, ADAPTIVE, DOSE-RANGING STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF SB-525 (PF-07055480) (RECOMBINANT AAV2/6 HUMAN FACTOR 8 GENE THERAPY) IN ADULT SUBJECTS WITH SEVERE HEMOPHILIA A

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: SB-525 (PF-07055480)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥18 years of age Severe hemophilia A (past evidence of circulating FVIII activity of < 1% normal) Treated or exposed to FVIII concentrates or cryoprecipitate for at least 150 exposure days ≥12 bleeding episodes if receiving on-demand therapy over the preceding 12 months Agree to use double barrier contraceptive until at least 3 consecutive semen samples are negative for AAV 2/6 after SB-525 infusion Exclusion Criteria: Presence of neutralizing antibodies Current inhibitor, or history of FVIII inhibitor (except for transient low titer inhibitor detected in childhood) History of hypersensitivity response to FVIII History of Hepatitis B or HIV-1/2 infection History of Hepatitis C, unless viral assays in two samples, collected at least 6 months apart, are negative Evidence of any bleeding disorder in addition to hemophilia A Markers of hepatic inflammation or overt or occult cirrhosis History of chronic renal disease or creatinine ≥ 1.5 mg/dL Presence of liver mass on magnetic resonance imaging (MRI), or, positive alpha fetoprotein Presence of > grade 2 liver fibrosis on elastography for subjects with history of treated Hepatitis C or suspicion of chronic liver disease

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: Sequential Assignment
Interventional Model Description: Dose selection based on safety and kinetics of circulating FVIII levels observed in previously dosed participants.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential dose escalation<br>SB-525 (PF-07055480) is administered as a single infusion | Biological: SB-525 (PF-07055480)<br>* Single dose of investigational product SB-525 (PF-07055480)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events and serious adverse events |  | Up to 5 years after SB-525 (PF-07055480) infusion | 
| Changes in circulating FVIII activity |  | Up to 5 years after SB-525 (PF-07055480) infusion |