A Novel Adeno Associated Virus (AAV) Gene Therapy (FLT180a) Achieves Normal FIX Activity Levels in Severe Hemophilia B (HB) Patients (B-AMAZE Study)
Highlights From the ISTH 2020 Virtual Congress

Gene therapy is quickly becoming one of the most promising treatments for hemophilia, as the current treatment requires a lifetime of injections or infusions beginning in early childhood. Therefore, education on gene therapy, which can be found within the International Society on Thrombosis and Haemostasis (ISTH), is critical for patients to understand the process and the benefits of this treatment.

Understanding the Safety and Efficacy of Clinical Trials

Gene therapy uses a non-pathogenic and replication-deficient virus to encode missing clotting factors in patients with hemophilia. Gene therapy for hemophilia uses an AAV vector as a delivery system. Vectors such as this have a natural ability to enter cells and deliver necessary instructions to the nucleus, which, for patients with hemophilia, results in normal clotting factor production.

The B-AMAZE study presented at the ISTH 2020 Conference is one of the three that uses a Factor IX gene that has been modified to increase efficiency in transduction. The goal was to determine the safety and efficacy of a single dose of FLT180a in adult patients with hemophilia. The adaptive trial design allowed the clinical trial team to determine the optimal dose of the vector. An important exclusionary criteria for the study was the presence of neutralizing antibodies to the vector.

The dose range used for the two initial patients led to expression of Factor IX at levels just below the normal range. The addition of prophylactic immunosuppression treatments helped to reduce adverse reaction to the vector.

The adaptive trial design permitted researchers to control doses for subsequent patients in the study. It also gave them a chance to gauge the amount of immunosuppressant to provide. As a result, reachers concluded that the gene therapy treatment using a single dose of FLT180a at the proper dose can result in Factor IX expression within normal ranges.

The Importance of Hemophilia Education

Hemophilia education teaches patients and their families about the benefits of gene therapy, especially viral vector gene therapy. Gene therapy viral vectors may prove to be the key to long-lasting treatment for this life-long and potentially deadly condition.

Gene therapy research from 2020 shows that this treatment may allow patients with hemophilia to discontinue factor replacement therapy. In addition, it indicates that a bleeding phenotype correction is possible. For people living with hemophilia, gene therapy could prove to be a life-changing treatment.

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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Supported by educational grants from Bayer, BioMarin, Freeline Therapeutics Limited, Pfizer Inc., Shire, Spark Therapeutics, and uniQure, Inc.

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