Spk-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B Achieves Sustained Mean Factor IX Activity Levels of >30% without Immunosuppression

• Published in: Blood 2016-12, Vol.128 (22), p.3-3
• Main Authors: George, Lindsey A., Sullivan, Spencer K., Giermasz, Adam, Ducore, Jonathan M., Teitel, Jerome M., Cuker, Adam, Sullivan, Lisa M., Majumdar, Suvankar, McGuinn, Catherine E., Galvao, Aline M., Luk, Alvin Y., Wright, J. Fraser, Chen, Yifeng, Hui, Daniel J., Wachtel, Katie, Urich, Teresa, Takefman, Daniel, Couto, Linda B., Carr, Marcus E., Anguela, Xavier M., High, Katherine A.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.3.3

▪ Background: Earlier data demonstrated long-term expression of factor IX (mean FIX:C ~5.1%) following AAV8-mediated gene transfer at 2 x1012 vg/kg in hemophilia B (Nathwani et al., 2014). While the clinical improvement imparted by stable FIX levels is clear, these levels of expression fall short of trough values obtained by long-acting FIX prophylaxis (Santagostino et al. 2016), and of natural history data suggesting that levels of ~12% are required to eliminate spontaneous hemarthroses (den Uijl et al. 2011). Achieving higher levels of FIX:C with dose escalation has not been possible without eliciting a dose-dependent, capsid-specific immune response that may prevent sustained expression and efficacy (Mingozzi et al. 2007, Monahan et al. 2015). We sought to develop a highly efficient vector capsid and expression cassette that could be administered at low doses to achieve hemostatic FIX expression without need for immunosuppression. Methods: The investigational product, SPK-9001, utilizes a bioengineered AAV capsid (Spark100) with liver specific tropism. The prevalence of neutralizing antibodies (NAb) to Spark100 among sampled hemophilia B sera was 40% (Anguela et al. 2015). The expression cassette is a codon-optimized, single-stranded transgene encoding FIX Padua, a naturally occurring variant with a single amino acid substitution (R338L) that confers ~8-fold greater specific activity compared to wild-type FIX (Simioni et al. 2009). Data on bleeding and factor infusions in the year prior to enrollment were retrospectively compiled. Laboratory values, bleeding frequency, FIX consumption, changes in activity and quality-of-life via Haem-A-QoL were prospectively evaluated after vector infusion. Results: We enrolled 9 subjects, of whom 2 failed screening for liver fibrosis and 7 were infused with SPK-9001 at a dose of 5 x1011 vg/kg. Infused subjects were adult males ages 18-52 years with baseline FIX:C