Early Trial of Gene Therapy Option for Patients with Hemophilia B

Early results from an open-label phase I/II study of a new gene therapy product, named BAX335, offer promise of a long-term alternative to Factor IX (FIX) infusions for patients with hemophilia B. The first-in-human study was presented at the International Society on Thrombosis and Haemostasis (ISTH) meeting by Paul E. Monahan, MD, of the University of North Carolina School of Medicine Gene Therapy Center and Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“BAX335 appears to be well-tolerated in the subjects dosed to date,” the researchers concluded, “and hemostatically effective plasma FIX levels were achieved in two dosing cohorts.”

Approximately 40 percent of patients with hemophilia B (an X-linked recessive disease associated with a deficiency of coagulation Factor IX) have less than 1 percent of normal plasma Factor IX levels and experience recurrent bleeding episodes, Dr. Monahan noted. Gene therapy may provide long-term benefit by enabling persistent endogenous production of Factor IX with a single administration.

BAX335 is a non-integrating adeno-associated viral (AAV) vector carrying a Factor IX gene. BAX335 was developed based on previous research that has established that AAV induces stable transgene expression with a sound safety profile. However, in previous efforts to use gene therapy to deliver DNA carrying the genetic sequence encoding Factor IX have been thwarted by the immune response that these therapies provoked.

In the current ongoing trial, Dr. Monahan and colleagues tested the safety and pharmacokinetics of the experimental therapy in humans, with the goal of determining the dose required to achieve stable plasma Factor IX activity without triggering an immune response. Inclusion criteria were: men 18 to 75 years old with established hemophilia B who had more than three hemorrhages per year requiring treatment with Factor IX, plasma Factor IX activity ≤2 percent, and a negative screen for hepatitis C.

At the time of the study presentation, seven patients have been treated with BAX335 in three dosing cohorts, with follow-up ranging from seven weeks to two years:

  • Cohort 1: 2 x 1011 vg kg-1 (2 patients)
  • Cohort 2: 1 x 1012 vg kg-1 (3 patients)
  • Cohort 3: 3 x 1012 vg kg-1 (2 patients)

BAX335 was administered in a single intravenous dose with up to four sequentially ascending doses. Pharmacodynamic (plasma FIX activity) and safety data (immune response, adverse events [AEs]) were collected.

In the lowest-dose cohort, patients achieved therapeutic Factor IX levels of 3 percent. Factor IX activity was greater in the middle-dosing cohort, with subjects sustaining Factor IX levels of 0.5 to 20 percent observed at six months post-dosing – one of whom sustained a stable plasma Factor IX activity between 20 to 25 percent at 52 weeks after treatment. Two of the three study subjects in this cohort also remained free of spontaneous hemorrhage without the need for regular FIX infusions.

There were, however, setbacks in the highest-dosing cohort: Although the two subjects achieved expression levels above 40 percent, both experienced an immune response that led to decreased FIX expression. One patient returned to regular FIX infusions.

Importantly, though, no patients developed FIX inhibitors against BAX335. The researchers noted that no severe treatment-related AEs have been observed in this small cohort at this time – apart from the two incidents of immune response to treatment. In the future, the trial will enroll up to 16 male adults with severe hemophilia B.

According to Dr. Monahan, these preliminary findings “underscore the difficulty of thinking that we can easily interrupt an immune response once the process has begun but, thankfully, there have been no inhibitors observed against FIX or against the variant used in this vector.”


Monahan PE, Walsh CE, Powell J. Update on a phase 1/2 open-label trial of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for hemophilia B. Abstract #LB101. Presented at the International Society on Thrombosis and Haemostasis 2015 Congress, June 24, 2015, Toronto, Canada.