Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B

Background FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. Methods In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, <= 2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. Results Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84x10(11) vg, 6.40x10(11) vg, 8.32x10(11) vg, or 1.28x10(12) vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. Conclusions Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus.

Automated summary

FLT180a, a liver-directed adeno-associated virus (AAV) gene therapy, showed promising results in normalizing factor IX levels in patients with hemophilia B. This multicenter, open-label, phase 1-2 trial demonstrated sustained factor IX activity in most patients after receiving varying doses of FLT180a, with the use of glucocorticoids and tacrolimus for immunosuppression.