A Novel Adeno Associated Virus (AAV) Gene Therapy (FLT180a) Achieves Normal FIX Activity Levels in Severe Hemophilia B (HB) Patients (B-AMAZE Study)


Today, Pratima Chowdary, M.D., presented Phase I/II safety and efficacy results on FLT180a in hemophilia B (HB) patients. FLT180a is an investigational gene therapy medicinal product candidate that includes AAVS3, a rationally designed capsid designed to deliver higher levels of liver transduction than wild-type adeno-associated virus (AAV), and a codon optimized F9 gene with a gain-of-function mutation. FLT180a was administered intravenously in an escalating/descending adaptive design to identify a dose that would achieve factor IX (FIX) activity levels within the normal range (50% to 150%). The study aimed to restore normal coagulation, thus eliminating the need for prophylaxis and additional treatment during surgery, trauma, and activity.

Transaminitis is the main vector-related complication of AAV gene transfer, which is not associated with clinical symptoms but has the potential to markedly reduce the peak expression and the duration of expression. As a result, a key feature of this study was the development of a strategy for prevention and control of transaminitis during the high-risk period.

Chowdary presented data on 10 patients treated across four dose levels utilizing the adaptive design. The first two patients received 4.5e11 vg/kg, with FIX activity levels just below the normal range that has been maintained stably for over 24 months. A dose of 7.5e11 vg/kg resulted in a modest increase in FIX expression in two patients, compared with a dose of 4.5e11 vg/kg. As part of the adaptive design, two additional patients received a dose of 1.5e12 vg/kg, one of whom demonstrated supraphysiological FIX activity levels and was commenced on prophylactic anticoagulation after an individualized risk assessment. The anticoagulation was stopped during long-term follow-up following multidisciplinary discussion including the patient, and, off anticoagulation, he went on to develop a thrombosis of his arteriovenous fistulae. The remaining four patients received a lower dose of 9.75e11 vg/kg, leading to FIX activity levels within the normal range in those patients that were beyond the six-month study period. Prophylaxis for transaminitis instituted with corticosteroids and tacrolimus was effective in preventing transaminitis in the high-risk period in these patients. No evidence of neutralizing anti-FIX antibodies or infusion reactions was seen in any patients.

Chowdary concluded that the FLT180a achieves clinically meaningful, durable FIX activity levels in patients with HB, associated with independence from FIX replacement therapy and zero treated bleeds. Transaminitis has been averted by prophylactic immunosuppression. Careful dose titration was needed to identify the dose range required for sustained FIX activity in the normal range. 

Read the full abstract here.

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