23rd July 2022

Possible cure for haemophilia B

A potential cure for haemophilia B has been announced by British doctors, which corrects the genetic defect associated with 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 to prevent or stop bleeding. The gene responsible for making this protein is located on the X chromosome, so the severe form of haemophilia B is much more common in men.

A meta-analysis using national registries in several countries, including the UK, has estimated a prevalence in males of 3.8 in 100,000 or about 1 in 30,000. Although mainly affecting boys and men, symptoms can also be experienced by women who carry an affected copy of the coagulation factor gene.

This week, a study published in the New England Journal of Medicine revealed that a single gene therapy injection could dramatically reduce the bleeding risk faced by people with haemophilia B.

Experts from University College London (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.

Currently, patients with haemophilia B need to inject themselves regularly – usually every week – 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 clinical trial, called B-AMAZE, and a long-term (3.5 years) follow up study, found that a one-time treatment with FLT180a alongside a prophylactic immune management regimen led to sustained production of FIX protein from the liver in nine of ten patients. This occurred across four different dose levels and reduced excessive bleeding enough to end the need for weekly injections.

The gene therapy works by using a packaging from the proteins found in the outer coat of the AAV, to deliver a functional copy of a gene directly into tissues, which compensates for the non-functioning gene. Newly synthesised proteins are released into the blood and a one-time infusion can achieve long-lasting effects.

The study authors note the treatment is “generally well tolerated”. No patient discontinued infusion or withdrew from the study. No infusion reactions occurred, and no inhibitors to FIX were detected. Adverse events related to the immune management regimen were consistent with the known safety profiles of corticosteroids and tacrolimus.

“I’ve not had any treatment since I had my therapy, it’s all a miracle really. Well, it’s science, but it feels quite miraculous to me,” said Elliott Mason, one of the trial’s participants, in an interview with BBC News. “My life is completely normal now – there’s nothing that I have to stop and think ‘how might my haemophilia affect this?’.”

“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,” said Pamela Foulds, MD, Chief Medical Officer of Freeline.

“Gene therapy is still a young field that pushes the boundaries of science for people with severe genetic diseases,” said Amit Nathwani, Freeline co-founder and Professor of Haematology at UCL, who co-authored the study. “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.”

Patients treated in B-AMAZE are now being assessed in an ongoing, 15-year follow-up study. A Phase 1/2 dose-confirmation trial of FLT180a called B-LIEVE to finalise a dose for a Phase 3 pivotal trial is in progress.

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