A new gene therapy could reduce the risk of bleeding

A single injection of gene therapy could significantly reduce the risk of bleeding faced by people with haemophilia B, according to a study involving researchers from UCL.

For the article, published in the New England Journal of Medicineexperts from UCL, the Royal Free Hospital and biotech company Freeline Therapeutics have tested and continue to evaluate a new type of adeno-associated virus (AAV) gene therapy candidate, called FLT180a, to treat cases severe and moderately severe disease.

Hemophilia B is a rare, inherited, genetic bleeding disorder caused by low levels of factor IX (FIX) protein, which is needed to form blood clots that help prevent or stop bleeding. The gene responsible for making the FIX protein is located on the X chromosome, so the severe form of hemophilia B is much more common in men.

Currently, patients with hemophilia B must regularly – usually weekly – inject recombinant FIX, ie regular replacement therapy to prevent excessive bleeding. Despite advances in treatment, patients may continue to see debilitating joint damage.

The Phase I/II multi-center clinical trial, called B-AMAZE, and related long-term follow-up study found that a single treatment with FLT180a resulted in sustained production of FIX protein by the liver in nine out of ten patients , through four different dose levels, eliminating the need for regular replacement therapy.

Of 17 screened male patients aged 18 or older, ten with severe or moderately severe hemophilia B participated in the 26-week trial of FLT180a. They are also all enrolled in the long-term follow-up study to assess the safety and durability of FIX expression for 15 years.

Lead author Professor Pratima Chowdary (Royal Free Hospital, UCL Cancer Institute) said: “Eliminating the need for haemophilia patients to regularly inject the missing protein is an important step in improving their quality of life. . The long-term follow-up study will monitor patients for durability of expression and monitoring for late effects.

AAV gene therapy works by using packaging from proteins found in the outer coat of the virus, to deliver a working copy of a gene directly to patient tissues to compensate for the malfunctioning one. The newly synthesized proteins are released into the bloodstream and a single infusion can have lasting effects.

Patients were required to take immunosuppressive drugs for several weeks to months, to prevent their immune system from rejecting the therapy, and any known side effects reported.

Although the treatment was generally well tolerated, all patients experienced some form of adverse events, with an abnormal blood clot in the one who received the highest dose of FLT180a and who had the highest levels of protein FIX.

Freeline co-founder Professor Amit Nathwani (UCL Medical Sciences), co-author of the study, said: “Gene therapy is still a young field pushing the boundaries of science for people with diseases serious genetics.

“The long-term data from B-AMAZE adds to the growing body of evidence that gene therapy has the potential to free patients from the challenges of lifelong therapy adherence or could provide treatment where it is not. doesn’t exist today.”

In nine of the ten patients, treatment resulted in a sustained increase in FIX protein production, which led to a decrease in excessive bleeding. They also no longer need weekly FIX protein injections.

After 26 weeks, five patients had normal levels of FIX protein, three had low but high levels, and one patient treated at the highest dose had an abnormally high level.

Pamela Foulds, MD, Chief Medical Officer of Freeline, said, “The long-term data from B-AMAZE supports our belief that a single dose of FLT180a may protect people with hemophilia B from bleeding and the need for a lifetime FIX replacement through an expression of FIX at protection levels.

In June 2022, UCL received government funding of £6.5 million to continue translating research into global impact – the second highest amount awarded to organizations across the country.

Professor Geraint Rees (UCL Vice-Rector for Research, Innovation and Global Engagement and Non-Executive Director of UCL Business), said: “The results of this important study are an example of how UCL’s research and innovation can translate into the real world. and life-changing impact.

The phase I/II trial was sponsored by UCL and funded by Freeline Therapeutics.

Freeline was supported by UCL Business (UCLB), UCL’s marketing company.

Notes to Editors

For more information or to speak to the researchers involved, please contact Sophie Vinter, UCL Media Relations, T: +44 (0)20 3108 7787, E: s.vinter@ucl.ac.uk.

Pratima Chowdary, MD, Susan Shapiro, Ph.D., Mike Makris, MD, Gillian Evans, MB, Ch.B., Sara Boyce, MD, Kate Talks, MD, Gerard Dolan, MD, Ulrike Reiss, MD, Mark Phillips , M.Sc., Anne Riddell, M.Sc., Maria R. Peralta, MD, Michelle Quaye, B.Sc., David W. Patch, MD, Edward Tuddenham, MD, Allison Dane, Ph.D., Marie Watissée, M.Sc., Alison Long, MD, and Amit Nathwani, MB, Ch.B., Ph.D., “Phase 1–2 trial of AVS3 gene therapy in patients with hemophilia B” will be published in the New England Journal of Medicine on Wednesday, July 20, 2022, 10:00 p.m. UK time / 5:00 p.m. Eastern US time and is under strict embargo until that time.

The DOI for this article will be 10.1056/NEJMoa2119913.

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About Freeline Therapeutics

Freeline is a clinical-stage biotechnology company developing transformative systemic gene therapies mediated by adeno-associated virus (AAV). The company is dedicated to improving the lives of patients through innovative, timely treatments that can provide functional cures for debilitating inherited systemic diseases.

Freeline uses its proprietary, rationally designed AAV vector, along with novel promoters and transgenes, to deliver a functional copy of a therapeutic gene into human liver cells, thereby expressing a persistent functional level of the missing or dysfunctional protein in the patient’s blood circulation.

The Company’s integrated gene therapy platform includes in-house research, clinical development and commercialization capabilities. The company has clinical programs in haemophilia B, Fabry disease and Gaucher disease type 1. Freeline is headquartered in the UK and has operations in Germany and the United States.


About the Royal Free London NHS Foundation Trust

The mission of the Royal Free London is to provide world-class expertise and local care.

We attract patients from across the country and beyond to our services specializing in liver and kidney transplantation, hemophilia, HIV, infectious diseases, plastic surgery, immunology, neurology, Parkinson’s disease, vascular surgery, cardiology, amyloidosis and scleroderma. We are a member of the UCL Partners University Health Sciences Partnership, which brings together people and organizations to transform the health and well-being of the population. The Royal Free London aims to become a center of excellence for rare diseases, including haemophilia.

The Royal Free London is one of four NHS trusts to be chosen to develop a group model allowing us to more effectively share services and resources between hospitals to improve the experience of patients and staff. More information can be found here https://www.royalfree.nhs.uk/the-royal-free-london-group-model/

Barnet Hospital, Chase Farm Hospital and Royal Free Hospital are part of the Royal Free London group, and North Middlesex University Hospital NHS Trust became its first clinical partner in September 2017.

For more information on our group structure visit www.royalfree.nhs.uk/the-royal-free-london-group-model and for general information about the trust visit www.royalfree.nhs.uk

Irene B. Bowles