A Long-Term Follow-Up Study in Subjects With Sever Hemophilia B Who Received Adeno-Associated Viral Vectors Expressing Human Factor IX

A prior clinical gene transfer study of intrahepatic adeno-associated virus (AAV) vector administration of the factor IX gene (AAV2-hFIX16) to adult subjects with severe hemophilia B enrolled several subjects from 2001 through 2004. These subjects received various doses of AAV2-hFIX16 manufactured by Avigen, Inc. (Alameda, CA). They were monitored up to at least one year following vector administration for evaluation of adverse events and for indices of efficacy. At the time study enrollment was suspended by Avigen, Inc., and IND 9398 under which the study was conducted was transferred to The Children's Hospital of Philadelphia (May 2005), there were no guidelines for long-term follow-up of the trial subjects. However, in an unrelated study conducted in France, of pediatric subjects administered integrating retrovirus vectors for X-linked severe combined immune deficiency (X-SCID), several leukemias developed years after transfer of the γc common chain gene. The underlying mechanism was attributed to proviral integration near, and upregulation of, proto-oncogenes such as LMO-2, coupled with robust expression of the γc common chain, inducing unregulated cellular proliferation. In response to these events, and in concert with the NIH and gene transfer scientific community, the U.S. Food and Drug Administration (US FDA) issued guidelines for the 'long-term follow-up of gene transfer subjects'. Since AAV vectors have a low rate of genomic integration, the risks of integration are low, but the long-term effect of the persistence of vector particles in humans is unknown. The investigators plan to enroll available subjects from the prior intrahepatic AAV gene transfer study to this observational study to follow them for up to 15 years after gene transfer.

An additional subject received AAV2-hFIX16 vector, manufactured by CCMT at CHOP, via hepatic artery infusion in January 2009. The study AAV2-hFIX-002, an amendment to the prior Avigen, Inc. clinical protocol modified to include transient immunomodulation, was conducted under IND 9398. This subject was monitored for three years following vector administration under clinical study AAV2-hFIX-002; amendment one of the current protocol transfers his annual long-term follow-up visits to AAV2-hFIX16-LTFU-01.

Spark Therapeutics will be the study sponsor; prior vector administration sites or referral/follow up sites will participate as study sites. The long-term follow-up (LTFU) study will consist primarily of endpoints including annual history, physical examination, blood tests, urinalysis, and periodic liver ultrasound. Adverse event reporting will focus on the development of oncologic, hematologic, neurologic and auto-immune events following gene transfer as specified in the November 2006 FDA Center for Biologics Evaluation and Research (CBER) guidance document entitled, "Gene Therapy Clinical Trials - Observing Subjects for Delayed Adverse Events."1 The LTFU study seeks to provide longitudinal information, and should adverse events occur, more timely discovery and treatment.