Researchers may be making some headway in the search for a gene therapy strategy to treat hemophilia B.

Preliminary findings from an ongoing phase 1-2 trial of an investigational gene therapy treatment to address clotting and immune response in patients with hemophilia B were presented Wednesday at the ISTH 2015 Congress.

Previous research efforts to use gene therapy to deliver DNA carrying the genetic sequence encoding blood-clotting factor IX (FIX) have been frustrated by the immune response that these therapies provoke.


Paul E. Monahan

The phase 1-2 study, which was presented by Paul E. Monahan of the University of North Carolina School of Medicine Gene Therapy Center and Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, U.S.A., involves a non-integrating adeno-associated viral (AAV) vector carrying a FIX gene. On the basis of research that has established that AAV vectors induce stable transgene expression with a sound safety profile, Baxalta has developed the gene therapy candidate BAX 335, which consists of a codon-optimized hyperactive FIX transgene, driven by the liver-specific transthyretin (TTR) promoter in an AAV8 capsid.

The trial, the first in-human study of BAX 335, aims to evaluate the safety and kinetics of this gene therapy candidate, and to determine the dose required to achieve stable plasma FIX activity.

Monahan presented results from the first 7 subjects, who were divided into three dosing cohorts, for a combined follow-up of nearly 100 months.

Study inclusion criteria were: males aged 18-75 with established hemophilia B who had more than three hemorrhages per year requiring treatment with FIX, plasma FIX activity less than or equal to 2%, and a negative screen for hepatitis C. Patients with a family history of inhibitor to FIX protein or an allergic reaction to any FIX product were excluded, as were those with evidence of hepatic inflammation or cirrhosis.

The results for these seven subjects were generally positive. The doses were: Cohort 1 (2 subjects): 2 x 1011 vg kg -1; Cohort 2 (3 subjects): 1 x 1012 vg kg-1; Cohort 3 (2 subjects): 3 x 1012 vg kg-1.

In the lowest dosing cohort, some FIX expression was observed. In dose Cohort 2, however, two out of three study subjects remain free of spontaneous hemorrhage without regular infusions of FIX, and one of these patients has had sustained expression levels of 20% for 12 months.

The two subjects in the highest dose cohort have both achieved expression levels above 40%, but both experienced an immune response with variable neutralizing antibody titers to the AAV8 capsid that has led to a significant decrease in FIX expression. One study participant has returned to regular FIX infusions.

Immune responses have been reported in previous studies with gene therapy technology. No study participants have developed FIX inhibitors to date, and no severe product-related adverse events have been reported apart from the two incidents of immune response to treatment.

The overall findings to date “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 concluded.

An additional five patients will be included in this study.

The trial is sponsored by Baxalta. Monahan disclosed that he has consulted for and received research support from Asklepios BioPharmaceutical, NovoNordisk, Pfizer, CSL Behring, Prolor, Chatham Therapeutics, and Baxalta.


By Doug Brunk |June 24, 2015