Dose-Ranging Study of Recombinant AAV2/6 Human Factor 8 Gene Therapy SB-525 in Subjects With Severe Hemophilia A

The objective of the study is to reduce or eliminate the need for FVIII replacement therapy.
The proposed SB-525 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 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 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