Patients with haemophilia B treated with a gene therapy developed by Baxter spin-off Baxalta have started making their own clotting factors and – in some cases – control of bleeding episodes.
However, the first-in-human dosing study for the therapy also revealed evidence of an immune response to the treatment that could make dosing critical and potentially limit its long-term use.
The interim data from the ongoing phase I/II trial provides the first glimpse of the potential of the therapy, which if effective could transform treatment for haemophilia B patients, who lack the ability to produce clotting factor IX and so have to be administered the factor by infusion.
On the plus side, data reported at the 2015 International Society on Thrombosis and Haemostasis (ISTH) congress in Toronto, Canada, clearly showed that the gene therapy – called BAX 335 – was able to transfect cells in the liver and re-engineered them to start producing factor IX.
All told, seven patients were treated with BAX 335 – an adeno-associated virus (AAV) carrying the gene for factor IX which is delivered by a one-off infusion – at varying doses.
There was clear evidence of a dose-dependent response, according to Paul Monahan of the University Of North Carolina School Of Medicine, who presented the study at ISTH.
At the lowest dose, given to three patients, there was some evidence of expression of factor IX in the liver. Two patients given a middle dose experienced no bleeds over 12 months despite not being given any factor IX infusions, and one showed expressions levels in the 20%-25% range over the period.
At the highest dose tested, expression levels peaked above 50%, but at this level the two treated patients started to develop an immune response against the viral carrier, reducing expression levels, although there was no evidence of the formation of neutralising antibodies being against factor IX itself.
Neutralising antibodies are a recognised side effect of many drug therapies based on a large protein molecule and is seen on occasion with current plasma-derived and recombinant factor IX infusions.
One of the high-dose patients in the study has had to return to routine factor IX infusions, according to Monahan, who told the ISTH that this “underscores the difficulty of thinking that we can easily interrupt an immune response once the process has begun.”