Experimental Gene Therapy May Reduce Bleeding Risk in Patients With Hemophilia B

A one-time treatment with an experimental gene therapy resulted in sustained production of factor IX protein in patients with hemophilia B, according to findings published last week in the New England Journal of Medicine. Hemophilia B is a rare and inherited genetic bleeding disorder caused by low levels of the factor IX protein. To prevent excessive bleeding, patients with hemophilia B must regularly inject themselves with recombinant factor IX protein.

In this Phase I/II trial, a team of investigators from University College London, Royal Free Hospital and the biotechnology company Freeline Therapeutics administered a new type of adeno-associated virus (AAV) gene therapy candidate called FLT180a to 10 patients with moderate-to-severe hemophilia B (defined as factor IX level less than or equal to 2% of normal value).

All patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. Patients then received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×10¹¹ vg, 6.40×10¹¹ vg, 8.32×10¹¹ vg, or 1.28×10¹² vg.  The primary endpoints were safety and efficacy, as assessed by factor IX levels at week 26.

At a median follow up of 27.2 months, nine patients displayed sustained factor IX activity, while the 10th patient resumed factor IX prophylaxis. By the data cutoff date (Sept. 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had an abnormally high level of 260%. The treatment was well-tolerated overall, but all patients experienced adverse events; approximately 10% were related to FLT180a and 24% were related to immunosuppression.

All patients are enrolled in a long-term follow-up study to assess the safety and durability of factor IX expression for 15 years.

According to investigators, the findings add to a growing body of evidence that gene therapy has the potential to free patients from the challenges of having to adhere to lifelong therapy. “Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” said lead author Pratima Chowdary, MRCP, FRCPath. “The long-term follow-up study will monitor the patients for durability of expression and surveillance for late effects.”