Abstract Number: OC 03.5
Meeting: ISTH 2020 Congress
Background: Investigational gene transfer for hemophilia A (HA) provides potential for a one-time, life-long disease altering therapy. While on-going studies are promising, recent long-term follow-up data from the first successful HA gene transfer trial reported declining FVIII expression over time (Pasi 2020), raising concerns about the durability of AAV-mediated liver-directed F8 gene transfer.
Aims: We present data on our initial cohorts of an ongoing Phase I/II trial investigating SPK-8011 for HA (data cut 1/24/2020).
Methods: 5 adult HA males (34-52 years) with FVIII:C ≤ 2% received SPK-8011 at a dose of 5×1011 or 1×1012 vg/kg.
Results: Subjects are 106-142 weeks post-vector. There were no study drug-related AEs/SAEs, or transaminase elevations above normal. No subjects developed FVIII inhibitors or evidence of a FVIII cellular immune response. The 5×1011 vg/kg cohort (n=2) had FVIII:C of 6.9-8.4%. The 1×1012 vg/kg cohort (n=3) FVIII:C was 5.2-19.8%. Two of 3 subjects in the 1×1012 cohort were treated with reactively administered steroids for ~7 weeks, initiated in response to declining FVIII levels without ALT elevation or positive IFN-g ELISPOTs to capsid-derived peptides. After achieving steady-state FVIII expression by 8-12 weeks, there was no change in FVIII:C (Figure 1). Over the >2-year observation period, there was a 95% reduction in annualized infusion rate and a 91% reduction in ABR. Post-vector ABRs were: 0.4, 0.0, 0.4, 3.6, 0.5.
Conclusions: These data demonstrated no major safety concerns to date and provided support for the efficacy of SPK-8011 for the treatment of HA. There is no evidence of decline in FVIII expression following SPK-8011 after >2 years of follow-up. 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.
[Factor VIII Levels Over Time by Participant in the 5E11 vg/kb and 1E12 vg/kg Dose Groups]
To cite this abstract in AMA style:George L, Eyster E, Ragni M, Sullivan S, Samelson-Jones B, Evans M, MacDougall A, Curran M, Tompkins S, Wachtel K, Takefman D, Reape K, Mingozzi F, Monahan P, Anguela X, High K. 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 [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/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/. Accessed May 16, 2021.
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