Abstract Number: LB/CO01.1
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy
Background: FLT180a is an investigational gene therapy medicinal product candidate intended for treating HB patients. It includes a novel synthetic capsid, AAVS3, with a higher liver transduction efficiency than wild type AAV, and a codon optimised F9 gene with a gain of function mutation.
Aims: To assess the safety and efficacy of a single systemic administration of FLT180a in adult patients with HB.
Methods: Phase 1/2, multi-centre, ongoing, open-label and long-term follow-up study assessing FLT180a dose levels in an escalating/descending adaptive design, to identify a dose that consistently normalises FIX activity (50-150%). Participants have severe or moderately severe HB and are negative for neutralising AAVS3 antibodies. Pre-emptive immunosuppression is given to mitigate vector related transaminitis and associated reduction in FIX expression.
Results: Ten patients with severe HB have been treated across 4 dose levels, with week 3 FIX activity levels ranging between 24 and 168%. The first two patients, receiving the 4.5e11vg/Kg dose, have stable, therapeutic, FIX activity levels through week 104. No patient has had a bleeding episode requiring FIX concentrates. The most common drug related serious adverse event was transient transaminitis (in four patients) requiring supplemental immunosuppression. FIX activity levels above 150% have been observed, which were individually assessed for risk of thrombosis, and one patient is being treated with DOACs. Refinement of the immunosuppression regimen for the latest three patients (9.75e11 vg/kg dose) prevented transaminitis during the critical phase (4- 16 weeks).
Conclusions: FLT180a achieves clinically meaningful, durable FIX activity levels in patients with HB, associated with independence from FIX replacement therapy and zero treated bleeds. Transient transaminitis was largely averted by prophylactic immunosuppression. A dose between 7.5 to 9.75e11vg/Kg can potentially create sustained, normal FIX activity levels in patients with severe HB.
| Dose Level vg/kg | Mean FIX activity % (range) | ||||
| Week 3 | Week 26 | Week 52 | Week 78 | Week 104 | |
| 4.5e11 (n=2) | 24.5 (24-25) | 40.0 (35-45) | 37.5 (36-39) | 43.5 (40-47) | 37.5 (37-38) |
| 1.5e12 (n=2) | 130.0 (92-168) | 160.0 (i) (67-253) | – | – | – |
| 7.5e11 (n=2) | 25.5 (25-26) | 32.0 (i) (9-55) | 31.0 (i) (2-60) | – | – |
| 9.75e11 (n=4) | 100.5 (73-142) | 98.0 (ii) (57-139) | – | – | – |
| Arithmetic means, per dose level for FIX activity levels (%) at corresponding study visits. FIX activity levels (%) measured by local assay (results for minimum of 2 patients). (i) Includes one patient with reduction in FIX expression following transaminitis. (ii) Data from 2 patients and includes one patient with reduction in FIX expression following transaminitis | |||||
[Table 1: Mean FIX activity levels at certain timepoints]
[Figure 1: Dosing Schematic for FLT180a B-AMAZE Phase 1/ 2 Study]
To cite this abstract in AMA style:
Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, Dolan G, Reiss U, Phillips M, Riddell A, Peralta MR, Quaye M, Tuddenham E, Krop J, Short G, Kar S, Smith A, Nathwani A. A Novel Adeno Associated Virus (AAV) Gene Therapy (FLT180a) Achieves Normal FIX Activity Levels in Severe Hemophilia B (HB) Patients (B-AMAZE Study) [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-novel-adeno-associated-virus-aav-gene-therapy-flt180a-achieves-normal-fix-activity-levels-in-severe-hemophilia-b-hb-patients-b-amaze-study/. Accessed November 30, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-novel-adeno-associated-virus-aav-gene-therapy-flt180a-achieves-normal-fix-activity-levels-in-severe-hemophilia-b-hb-patients-b-amaze-study/