AAV8 Gene Therapy for Hemophilia A Patients from China

Background Treatments of hemophilia A patients by adeno-associated virus (AAV) based delivery of coagulation factors VIII (FVIII) have shown great promise, with multiple clinical trials be conducted currently. However, to ensure enough expression level of FVIII, the dosages of AAV capsids are relatively high (up to 6E13vg/kg) in these trials. High dosages of AAV capsid carry the potential risk of toxicity, raise the possibilities of host immune response and increase the economic burden for patients. Besides, the sustainability of efficacy is also a challenge. Current gene therapies showed that the level of FVIII gradually decreased over time. Hence, it is necessary to explore a gene therapy with high expression level of FVIII and sustained efficacy. GS001, an rAAV8 vector expressing B domain deleted FVIII was developed. In the preclinical study, high level of FVIII activity (FVIII:C) (155 IU/dl) was achieved when the hemophilia A mice received a single infusion of GS001 at a dose of 1.1E11 vg/kg. Toxicity studies in monkeys showed good tolerance at the dose of 2E13 vg/kg. Based on these preclinical data, GS001 was investigated in clinical trial for hemophilia A gene therapy. The purpose is to evaluate the safety and efficacy of GS001 in Chinese hemophilia A patients and obtain clinical data for further study.

Method We enrolled Chinese hemophilia A patients (> 18 years) whose baseline FVIII:C was < 1 IU/dl without FVIII inhibitor. All subjects had low titer of neutralizing antibodies (Nab) (≤1:5) against the vector capsid. Eligible participants received a single intravenously infusion of GS001 with a dose of 2E12vg/kg after one week of prophylactic prednisone treatment or prednisone and tacrolimus treatment. The primary endpoint was safety including treatment-related adverse events (AEs), change of alanine aminotransferase (ALT) and antibodies against the vector capsid. Enrollment is now ongoing. This study was registered at ClinicalTrials.gov, NCT04728841.

Results Six patients were enrolled. The first three patients (patients 1 to 3) were infused with GS001 after one week of prophylactic prednisone treatment. The mean follow-up time were 397±52 days. FVIII:C level reached the peak around seven weeks post infusion. After that, the FVIII:C decreased with the elevation of ALT, and the decrease trend was improved after treatment with tacrolimus. Patients 4 to 6 were infused with GS001 after one week of prophylactic prednisone and tacrolimus treatment. The mean follow-up time were 49±8 days. The FVIII:C level quickly reached peak level in the first week compared to the first three participants. No rising trend of ALT was found. The mean annual bleeding rates (ABR) and the factor VIII usage for all the six participants decreased dramatically after GS001 infusion.

There were totally 55 AEs, with 54 AEs were grade 1(54 AE) and only one was grade 2 which was not related to GS001. Twenty-two (40%) AEs were possibly related to the immunosuppressant therapy, only 12.7% of the AEs (7/55) was possibly related to GS001.

No severe adverse events have been observed. None of the six participants had developed a FVIII inhibitor.

Conlcusions This pilot study demonstrated the safety and tolerance of GS001. Vector derived FVIII:C level was sufficient to prevent bleeding events and minimize the need for replacement therapy. Prophylaxis treatment of tacrolimus combined with prednisone could be an effective immunosuppressive regimen against the vector capsid in gene therapy for hemophilia A patients. These findings support further studies.

No relevant conflicts of interest to declare.