Update on Gene Therapy for Factor IX: North Carolina Team

Horizons in Hemophilia, August 2015

By Jeff Cornett, RN MSN, Vice President of Research & Public Policy

In June, Dr. Paul Monahan of the University of North Carolina Chapel Hill presented results from the clinical trials of BAX 335 during a presentation at the International Society on Thrombosis and Haemostasis Congress in Toronto. BAX 335 is an investigational gene therapy for Factor IX deficiency that is being tested by Baxalta, a subsidiary of Baxter pharmaceutical company. The ongoing clinical trial has enrolled seven patients.

There has been much optimism from many in the hemophilia community about this trial since it offers some potential “improvements” over earlier gene therapy: it uses a viral vector, AAV8, that has a greater affinity for the liver than other AAV subtypes and that is less likely to have previously infected patients; it uses the Padua gene variant for factor IX, so it potentially produces more factor proteins; and it uses improved production techniques so that more of the viral vector that is given to the patient actually contain the factor IX gene. This is a phase 1 and 2 clinical trial, so it is concerned with both safety and how well the treatment works. In the lowest dose given, little benefit was seen but no patients suffered harm and none developed inhibitors.The second group of patients received a higher dose. The treatment was not effective in the first patient – his body did not begin producing factor IX. The second patient had better results. His body has produced factor IX levels of 2.5 – 3% for almost two years and he was able to stop prophylaxis. The third patient has achieved factor IX levels of 20 – 25% for over a year. He has not had any bleeds and has not had to treat with factor. Dr. Monahan described this as “the highest long-term expression ever seen in a human gene therapy trial” but cautioned that “it is partnered with a lack of expression in two other individuals.”

The third group of patients received an even higher dose. The first patient reached a very high level of factor IX (58%!) but then his body’s immune system showed a reaction to the viral vector. Even though he was treated with Prednisone for this, his levels dropped and he had to restart prophylaxis with factor IX concentrate. This pattern of high production of factor IX, followed by an immune response with dropping factor levels, has been the disappointing feature of all the hemophilia gene therapy trials to date. Dr. Monahan presented data from analysis they had conducted to try to determine which patients might have this immune response but no clear patterns emerged. He suggested that, in order to maintain the high levels of factor production, patients may need to be given corticosteroids prophylactically to suppress their immune systems instead of waiting for the immune response to be detected with blood tests.