Introduction: Hemophilia A is an X-linked (FⅧ gene mutation) disorder of hemostasis that results in insufficient endogenous factor VIII activity. GS1191-0445 is constructed with wild-type AAV8 and an optimized liver-specific expression cassette to express B domain-deleted factor Ⅷ (FⅧ BDD-V3). An investigator-initiated trial (IIT) (NCT04728841) and a phase Ⅰ/Ⅱ trial (CTR20231730) of GS1191-0445 have been conducted in Chinese patients with severe Hemophilia A to evaluate long-term efficacy and safety.

Method: Nineteen adults with severe Hemophilia A (factor Ⅷ level ≤1%) have been recruited and injected with a single treatment of AAV8-hFⅧ infusion. There were three dose cohorts from both studies. In the first in human IIT study, the first 6 participants have been injected a low dose of 2×1012vector genomes (vg) per kilogram of body weight, then escalated to the high dose of 4×1012vg/kg in next 6-participant cohort. In phase Ⅰ/Ⅱ trial, 7 participants have been recruited and infused with a middle dose of 3×1012vg/kg. Two immunosuppressive regimens, prophylactic prednisone or prednisone plus tacrolimus, can be selected to control the potential AAV capsid immune response from the 7-day prior to study drug infusion to at least 12 weeks post study drug administration. Trial objectives included the evaluation of the safety, efficacy of GS1191-0445, as well as the expression and durability of factor Ⅷ maintained in a bleeding prophylaxis level.

Results: In the 12 participants of IIT study, the factor Ⅷ activity increased rapidly within the first week, and the factor Ⅷexpression was sustained. The initial peak factor Ⅷ activity occurred 6 to 8 weeks after GS1191-0445 administration. The low dose cohort of 6-participant injected with 2×1012vg/kg had been followed up to 2.5 years, and the factor Ⅷ activity detected with one-stage assay was maintained as 14% (range: 0.5%-46.9%). The high dose 6-participant group of 4×1012vg/kg had been observed for 1.5 years, and ahigh level factor Ⅷ activity were durable over time (mean: 60.1%, range: 44.9%-110.1%). Compared with the low dose group, six participants high dose cohort had a significantly 99.2% reduction in the annualized bleeding rate (13.0 bleeding events per year [range: 8.0 to 20.0] before administration vs. 0.11 bleeding events per year [range: 0 to 0.7] after injection).

In the phase Ⅰ/Ⅱ trial, a middle dose as 3×1012vg/kg was chosen to treat on 7 participants. At the end of 52-week, the factor Ⅷ activity can be achieved to a high level as 77.0% (range: 5.9%-324.2%), and the annualized bleeding rate reduced a lot to99.1%, from 15.0 bleeding events at baseline to 0.14 bleeding events 52 weeks post infusion.

In all three cohorts, a total of 129 treatment-related adverse events (TRAE) occurred in 18 participants. The most common TRAE were mild ALT increase as CTCAE 1-2 grade (11/19, 57.9%). No Grade ≥3 treatment-emergent adverse events (TEAEs) were observed. SAE were reported in 5 participants (1 in 2×1012 cohort, 2 in 4×1012 cohort, and 2 in 3×1012 cohort). Three participants occurred GS1191-0445 related SAE. Two participants in 4×1012 cohort experienced increased factor Ⅷ (grade 1-2). One of them uses Nadroparin calcium injection and Aspirin enteric-coated tablets to prevent blood clots. The other one did not take any action. No factor Ⅷ inhibitor development, thrombosis, persistent elevation in liver enzyme were observed. No spontaneous bleeding except low dose.

Conclusion: Gene therapy with AAV8-hFVIII vector in Chinese patients with Hemophilia A demonstrated a good safety profile and sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor Ⅷ use in participants who had received 3×1012vg/kg or 4×1012vg/kg. The factor Ⅷ activity of 2×1012vg/kg cohort was not as good as the other two cohorts due to the lower dose. No major safety concerns were reported.

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2025
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