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

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

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)

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.

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