Novel gene therapy could reduce bleeding risk for haemophilia patients

A single gene therapy injection could dramatically reduce the bleeding risk faced by people with haemophilia B, finds a study involving UCL researchers.

For the paper, published in the New England Journal of Medicine, experts from UCL, Royal Free Hospital and biotechnology company Freeline Therapeutics trialled and continue to evaluate a new type of adeno-associated virus (AAV) gene therapy candidate, called FLT180a, to treat severe and moderately severe cases of the condition.

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

Currently, patients with haemophilia B need to inject themselves regularly – usually weekly – with recombinant FIX, i.e. regular replacement therapy to prevent excessive bleeding. Despite advances in treatment, patients may continue to see debilitating joint damage.

The Phase I/II multi-centre clinical trial, called B-AMAZE, and the related long-term follow up study found that one-time treatment with FLT180a led to sustained production of FIX protein from the liver in nine of ten patients, across four different dose levels, removing the need for regular replacement therapy.

Out of 17 male patients aged 18 or over who underwent screening, ten with severe or moderately severe haemophilia B took part in the 26-week trial of FLT180a. They are also all enrolled in the long-term follow up study to assess safety and durability of FIX expression for 15 years.

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

AAV gene therapy works by using a packaging from the proteins found in the outer coat of the virus, to deliver a functional copy of a gene directly to patient tissues to compensate for one that is not working properly. Newly synthesised proteins are released into the blood and a one-time infusion can achieve long-lasting effects.

Patients needed to take immune suppressing drugs over several weeks to several months, to prevent their immune systems from rejecting the therapy, and all reported known side effects.

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

Freeline co-founder Professor Amit Nathwani (UCL Medical Sciences), who co-authored the study, said: “Gene therapy is still a young field that pushes the boundaries of science for people with severe genetic diseases.

“The B-AMAZE long-term data add to the growing body of evidence that gene therapy has the potential to free patients from the challenges of having to adhere to lifelong therapy or could provide treatment where none exists today.”

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

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

Pamela Foulds, MD, Chief Medical Officer of Freeline, said: “The B-AMAZE long-term data continue to support our confidence that a single dose of FLT180a could protect people with haemophilia B from bleeding and the need for lifelong FIX replacement through durable expression of FIX at protective levels.”

In June 2022 UCL received £6.5m government funding to continue translating research into global impact - the second highest amount given to organisations across the country.

Professor Geraint Rees (UCL Vice-Provost Research, Innovation and Global Engagement, and Non-Executive Director of UCL Business), said: “The results of this important study are a perfect example of how UCL research and innovation can translate to 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 commercialisation 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, M.D., Susan Shapiro, Ph.D., Mike Makris, M.D., Gillian Evans, M.B., Ch.B., Sara Boyce, M.D., Kate Talks, M.D., Gerard Dolan, M.D., Ulrike Reiss, M.D., Mark Phillips, M.Sc., Anne Riddell, M.Sc., Maria R. Peralta, M.D., Michelle Quaye, B.Sc., David W. Patch, M.D., Edward Tuddenham, M.D., Allison Dane, Ph.D., Marie Watissée, M.Sc., Alison Long, M.D., and Amit Nathwani, M.B., Ch.B., Ph.D., ‘Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B’ will be published in the New England Journal of Medicine on Wednesday 20 July 2022, 22:00 UK time / 17:00 US Eastern time and is under a strict embargo until this time.

The DOI for this paper will be 10.1056/NEJMoa2119913.

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About Freeline Therapeutics

Freeline is a clinical-stage biotechnology company developing transformative adeno-associated virus (AAV) vector-mediated systemic gene therapies. The company is dedicated to improving patient lives through innovative, one-time treatments that may provide functional cures for inherited systemic debilitating 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 into the patient’s bloodstream.

The company’s integrated gene therapy platform includes in-house capabilities in research, clinical development and commercialization. The company has clinical programs in hemophilia B, Fabry disease, and Gaucher disease Type 1. Freeline is headquartered in the UK and has operations in Germany and the U.S.

www.freeline.life

About the Royal Free London NHS Foundation Trust

The Royal Free London’s mission is to provide world class expertise and local care.

We attract patients from across the country and beyond to our specialist services in liver and kidney transplantation, haemophilia, HIV, infectious diseases, plastic surgery, immunology, neurology, Parkinson’s disease, vascular surgery, cardiology, amyloidosis and scleroderma. We are a member of the academic health science partnership UCL Partners, which brings people and organisations together to transform the health and wellbeing of the population. The Royal Free London is aiming to become a centre of excellence for rare disorders, which includes haemophilia.

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

Barnet Hospital, Chase Farm Hospital and the 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 about 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