22 July 2022

Bleeding risk among people with haemophilia B could be significantly reduced by a single gene therapy injection, a new UK study has shown.

B-AMAZE, a phase I/II multi-centre clinical trial, found that one-time treatment with FLT180a led to sustained production of Factor IX protein from the liver in nine out of ten patients, removing the need for regular replacement therapy.

Writing in the New England Journal of Medicine, researchers from UCL, Royal Free Hospital and Freeline Therapeutics trialled FLT180a, a new adeno-associated virus (AAV) gene therapy candidate, to treat severe and moderately severe cases of haemophilia B.

Current treatments see people with the condition having to inject themselves regularly, usually weekly, with recombinant Factor IX to prevent excessive bleeding.

This 26-week trial comprised ten men, aged 18 and over, with severe or moderately severe haemophilia B. They are also all enrolled in the long-term follow up study to assess safety and durability of Factor IX expression for 15 years.

AAV gene therapy uses 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.

Participants had to take immune suppressing drugs, from several weeks to several months, to prevent their immune systems from rejecting the therapy.

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

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

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

Lead author Professor Pratima Chowdary, of 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.”

Study co-author and Freeline co-founder Professor Amit Nathwani, of UCL Medical Sciences, added: “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.”

Source: Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, Dolan G, Reiss U, Phillips M, Riddell A, Peralta MR, Quaye M, Patch DW, Tuddenham E, Dane A, Watissée M, Long A, Nathwani A.  (2022) “Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.” New England Journal of Medicine, doi: 10.1056/NEJMoa2119913.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2119913

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