Durable responses to gene therapy in haemophilia A

The majority of patients with haemophilia A who received SPK-8011 gene therapy expressed FVIII levels within the ‘mild haemophilia A’ range after 5 years of follow-up. In addition, a substantial reduction in annualised bleeding rates and FVIII consumption was reported, without major safety issues.

Prof. Stacy Croteau (Harvard Medical School, MA, USA) presented long-term data from the phase 1/2 SPK-8011 study (NCT03003533/NCT03432520), that evaluated the safety and efficacy of adeno-associated virus (AAV)-mediated FVIII gene transfer for patients with haemophilia A with FVIII levels ≤2% [1]. After a 1-hour outpatient intravenous infusion, the included patients (n=24) were followed up for 52 weeks. Hereafter, a 4-year long-term follow-up study was initiated, with visitations every 3 to 6 months.

After a median follow-up of 191 weeks, no FVIII inhibitor developments, thrombotic events, or deaths were reported. One grade 2 transaminitis, related to SPK-8011 treatment, led to hospitalisation for intravenous steroid administration. Other adverse events (AEs) related to SPK-8011 treatment were 11 cases of elevated alanine transaminase and 1 participant who experienced an acute infusion reaction. Also, vector shedding was undetectable after week 12. Prof. Croteau added that durable FVIII activity was observed in most participants, with expression levels within the ‘mild haemophilia’ range. Furthermore, the annualised bleeding rate was reduced with 82% in participants who received prophylactic FVIII prior to the study and with 99% in participants who were on prior on-demand treatment. Finally, the annualised FVIII infusion rate was 85.5 before infusion with SPK-8011 and 0.3 after infusion.

Prof. Croteau mentioned that there is a need to manage a presumed capsid immune response to further reduce the variability in FVIII expression following AAV-mediated gene transfer for haemophilia A. Studies that address this issue are ongoing.

1. Croteau S, et al. Long-Term Durable FVIII Expression with Improvements in Bleeding Rates Following AAV-Mediated FVIII Gene Transfer for Hemophilia A: Multiyear Follow-up on the Phase I/II Trial of SPK-8011. Abstract 783, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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Posted on 20 February 202317 May 2024