AT 2015 ISTH

TORONTO (FRONTLINE MEDICAL NEWS) – 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 in patients with hemophilia B were generally positive, based on results from the first seven patients.

Dr. Paul E. Monahan of the University of North Carolina Gene Therapy Center and Lineberger Comprehensive Cancer Center, Chapel Hill, reported that BAX 335 consists of a codon-optimized hyperactive FIX transgene driven by the liver-specific transthyretin (TTR) promoter in a nonintegrating adeno-associated viral (AAV) vector carrying a blood-clotting factor IX (FIX) gene.

The trial, the first in-human study of BAX 335, aims to evaluate the safety and kinetics of this gene therapy candidate. Dr. Monahan presented results from a combined follow-up of nearly 100 months on the first seven subjects, who were given one of three dosing schedules.

The adult male patients had hemophilia B and 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 BAX 335 doses were Cohort 1 (2 subjects): 1 x 1012 vg kg-1; Cohort 2 (3 subjects): 2 x 1012 vg kg-1; Cohort 3 (2 subjects): 3 x 1012 vg kg-1.

In the cohort given the lowest dose, some FIX expression was observed. In the intermediate dose cohort, 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. In the highest dose cohort, both subjects have achieved expression levels above 40%, but they also experienced an immune response with variable neutralizing antibody titers to the AAV8 capsid. One study participant has returned to regular FIX infusions.

Previous research efforts to use gene therapy to deliver DNA carrying the genetic sequence encoding FIX have been frustrated by the immune response that these therapies provoke. 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,” Dr. Monahan concluded.

An additional five patients will be included in this study.

The trial is sponsored by Baxalta. Dr. Monahan disclosed that he has consulted for and received research support from Baxalta.

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