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

P. Chowdary1,2, S. Shapiro3, M. Makris4, G. Evans5, S. Boyce6, K. Talks7, G. Dolan8, U. Reiss9, M. Phillips1, A. Riddell1, M.R. Peralta1, M. Quaye2, E. Tuddenham1, J. Krop10, G. Short11, S. Kar11, A. Smith11, A. Nathwani1,2

1Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital NHS Foundation Trust, London, United Kingdom

2University College London, London, United Kingdom

3Oxford Haemophilia & Thrombosis Centre and Oxford NIHR BRC, Oxford, United Kingdom

4University of Sheffield, Sheffield, United Kingdom

5Kent & Canterbury Hospital, Canterbury, United Kingdom

6University Hospital Southampton, Southampton, United Kingdom

7Newcastle Haemophilia Comprehensive Care Centre, Newcastle, United Kingdom

8Guy’s & St Thomas’ NHS Foundation Trust, London, United Kingdom

9St Jude Children's Research Hospital, Memphis, United States

10Freeline, Boston, United States

11Freeline, Stevenage, United Kingdom

Key Data Points

This figure summarizes the composition of the FLT180a vector (left panel) and the in vitro transduction efficiency of the AAVS3 capsid (right panel). The vector is composed of a rationally designed, synthetic human liver tropic capsid (AAVS3), a potent liver specific promotor with optimized introns, and a codon-optimized Padua variant of the FIX gene. In primary hepatocyte cell culture, the AAVS3 capsid demonstrates an efficiency of transduction that is 4 times greater than the next most efficient capsid, AAV3.

The main objective of the FLT180a phase 1/2 study was to assess the safety and efficacy of the vector in patients with moderate to severe hemophilia B and no liver disease or neutralizing antibodies to the AAVS3 capsid. In order to achieve the target FIX expression levels of 70-150%, an adaptive dosing regimen was utilized (right panel), starting with 2 patients at the lowest dose of 4.5 x 1011 vg/kg and adjusting subsequent doses to optimize FIX expression while minimizing risk of thrombosis. The 3 patients who have been infused with the final dose of the trial, 9.75 x 1011 vg/kg, have achieved FIX levels within the normal range.

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