Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B

Hemophilia B is a genetic X-linked bleeding disorder caused by a deficiency in blood-clotting Factor IX (FIX) activity. FIX is synthesized in the liver and circulates in the blood as a proenzyme. Current treatment for hemophilia B is based on replacement of the deficient FIX with IV injections of recombinant FIX protein prophylactically or as needed to treat bleeding episodes. This clinical program will test a gene transfer approach involving the use of a gene delivery vector carrying a FIX gene. This first-in-humans study is intended to evaluate the safety, kinetics, and if possible, the dose of AskBio009 required to achieve stable plasma FIX activity between 10% and 40% of normal activity.

Inclusion criteria

• Males age 18-75 years, inclusive
• Established hemophilia B with ≥3 hemorrhages per year requiring treatment with exogenous FIX OR use of FIX prophylaxis because of history of frequent bleeding episodes
• Plasma FIX activity ≤2% (<1% for first cohort; then per protocol)
• Negative for active Hepatitis C virus (HCV), defined as Hepatitis C virus antibody negative and negative (undetectable) PCR test for plasma Hepatitis C virus ribonucleic acid (RNA) OR if Hepatitis C virus antibody positive must have ≥2 consecutive negative (undetectable) PCR tests for plasma HCV RNA at least 3 months apart, and negative at screening

Exclusion criteria

• Family history of inhibitor to FIX protein or personal laboratory evidence of having developed inhibitors to FIX protein at any time (>0.6 Bethesda Units on any single test)
• Documented prior allergic reaction to any FIX product
• Detectable AAV8 neutralizing antibodies
• Markers of hepatic inflammation or overt or occult cirrhosis as evidenced by one or more of the following:

• Platelet count <175,000/μL
• Albumin ≤3.5 g/dL
• Total bilirubin >1.5 x ULN and direct bilirubin ≥0.5 mg/dL
• Alkaline phosphatase >2.0 x ULN
• ALT or AST >2.0 x ULN (except for subjects who are HIV infected)
• Liver biopsy in the past indicating moderate or severe fibrosis (Metavir staging of 2 or greater)
• History of ascites, varices, variceal hemorrhage or hepatic encephalopathy