In an interview with Dr. Konkle, she stated that “gene therapy represents the next frontier of medicine — providing a potentially curative treatment for diseases by inserting a functioning copy of a gene into patients’ cells to replace a defective gene. Hemophilia A is an ideal candidate for gene therapy because it is a monogeneic disorder with a clear cause and effect relationship. The goal of hemophilia A gene therapy is to eliminate the need for factor replacement therapy,” In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia A that are currently in clinical development, gene therapy holds the promise of a potential cure with single administration. The Alta study is a dose-ranging, single-dose study using SB-525 gene therapy in adult patients with severe hemophilia A, a recombinant adeno-associated virus (rAAV6) vector carrying a F8 gene, designed to assess its safety and tolerability.

Alta study data presented at ISTH include 10 patients treated across four ascending dose cohorts: 9e11 vg/kg (2 patients), 2e12 vg/kg (2 patients), 1e13 vg/kg (2 patients) and 3e13 vg/kg (4 patients).  Endpoints included safety events, changes in circulating FVIII activity, FVIII replacement therapy usage, and the frequency and severity of bleeding.

So what were the initial results of the Alta study? Across all four dose cohorts, SB-525 showed dose-dependent increases in FVIII levels, dose-dependent reduction in the use of FVIII replacement therapy, and sustained increased FVIII levels. The three patients treated at the 3e13 vg/kg dose level, with at least seven weeks of follow-up, achieved Factor VIII activity levels in the normal range. In follow-up from 4-24 weeks since infusion, no patients in the 3e13 vg/kg dose cohort have experienced bleeding events, and none have required factor replacement following initial use of prophylactic factor early after infusion.

Patients in the Alta study were not treated with prophylactic steroids. SB-525 was generally well-tolerated. One treatment-related serious adverse event (SAE) was reported in a patient in the 3e13vg/kg cohort. This patient experienced an infusion related reaction characterized by hypotension and fever six hours after completion of SB-525 infusion of the 3e13 vg/kg dose. This fully resolved with treatment and the patient was discharged as planned within 24 hours. No other patients experienced a similar hypotensive event. Another patient was hospitalized with cellulitis one year following treatment with SB-525, but this SAE was assessed as being unrelated to the study treatment. Two patients in the 3e13 vg/kg cohort experienced a transient grade 1 alanine aminotransferase elevation (>1.5 x baseline) managed by a tapering course of oral steroids.

According to Dr. Konkle from this initial report were, “…the results with SB-525 gene therapy continue to look very promising and warrant further development of SB-525 for the treatment of severe hemophilia A. It is encouraging that patients in the 3e13 vg/kg cohort have sustained FVIII activity in the normal range and no bleeding episodes. It will be important to continue to follow these patients to understand the long-term durability of this gene therapy.”

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