Phase I/II Trial of SPK-8011: Stable and Durable FVIII Expression for >2 Years With Significant ABR Improvements in Initial Dose Cohorts Following AAV-Mediated FVIII Gene Transfer for Hemophilia A


On Sunday, Lindsey George, M.D., of the University of Pennsylvania and Children's Hospital of Philadelphia in Philadelphia, PA, presented results on SPK-8011, an investigational gene therapy being developed for the treatment of hemophilia A. Hemophilia A is caused by mutations in the F8 gene, which encodes factor VIII (FVIII), a clotting factor in the blood. SPK-8011 contains a modified virus that carries the human F8 gene under the control of a specific DNA sequence (promoter), which ensures its protein product, FVIII, is only made in the liver. When infused into a patient, the viral vector infects cells and delivers the bioengineered F8 gene. Recombinant human FVIII protein is then synthesized in the liver, which—if successful—will restore the blood clotting pathway. As George stated, the aim of her research was to present findings on the initial cohorts of an ongoing Phase I/II trial that investigated the use of SPK-8011.

Findings were presented on 14 adult hemophilia A males with FVIII:C ≤2% who received SPK-8011 at a dose of 5 × 1011, 1 × 1012, or 2 × 1012 vg/kg, 14–40 months post vector. Positive findings demonstrated that there were no study drug–related adverse events/serious adverse events or transaminase elevations above normal since their prior update at the American Society of Hematology 2018 meeting. There was also no evidence of any patients developing FVIII inhibitors. The first two dose cohorts (5 × 1011 and 1 × 1012 vg/kg cohorts) were analyzed for durability of expression; preliminary analysis supported that after participants achieved steady-state FVIII expression, there was no change in FVIII:C for up to 3.3 years following vector infusion. Furthermore, among the 12 of 14 participants that maintained expression, there was a 96% reduction in annualized infusion rate and a 91% reduction in ABR.

George remarked that no major safety concerns to date have occurred, and demonstrated preliminary support for the efficacy of SPK-8011 for the treatment of hemophilia A, with no evidence of decline in FVIII expression following SPK-8011 among the 5 × 1011 and 1 × 1012 vg/kg cohorts, who have now been followed for 2 to 3.3 years. While some concerns had been raised regarding long-term follow-up data from the first successful hemophilia A gene transfer trial, which reported declining FVIII expression over time, George said, “Our data represent the longest stable expression of FVIII following gene transfer and support the ability of AAV-mediated hepatocyte-directed gene transfer to achieve durable FVIII expression for the potential treatment of HA.”

Read the full abstract here.

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