A recent trial showed that a single intravenous infusion of a vector expressing a high specific-activity factor IX gene safely produces a sustained, effective level of factor IX coagulant activity in patients with hemophilia B. The therapy also made factor IX prophylaxis unnecessary, prevented bleeding, and almost completely eliminated the need for exogenous factor infusions.
This Phase 1 safety trial included 10 adult males whose ages ranged from 18 years to 53 years and who had factor IX coagulant activity of 2% or less of normal value before the trial began. Three patients used factor IX concentrate on demand at the time of entering the trial and the remaining 7 used it as prophylaxis.
Participants were infused with a single-stranded, adeno-associated viral vector (SPK-9001) consisting of a bioengineered capsid, liver-specific promoter and factor IX transgene at a dose of 5x1011 vector genomes per kilogram of body weight. Participants were followed for at least 28 weeks and up to 72 weeks.
Within 1 week of the infusion, investigators observed factor IX coagulant activity, and although participants had varied trial courses, they all experienced sustained coagulant activity at a mean of 33.7% of normal. In addition, the annualized bleeding rate for this group fell significantly, from a mean of 11.1 events per year before vector administration to 0.4 events after. Annual factor use dropped from a mean dose of 2908 IU/kg to 49.3 IU/kg. Indeed, after the vector was administered, 8 of the 10 participants did not use any factor and 9 did not have any spontaneous bleeds. Two participants developed an asymptomatic increase in liver enzyme levels, which resolved with short term prednisone treatment.
Finally, SPK-9001 proved to be safe. Although a total of 40 adverse events were recorded, none was serious—no development of factor IX inhibitors, no thrombosis, and no laboratory evidence of excess activation of coagulation (George LA, et al. N Engl J Med. 2017;377:2215-2227).
Thoughts from Dr. Burke
This is a small trial and one that included only adult patients. However, this article, together with a second New England Journal of Medicine article published in December (N Engl J Med. 2017;377:2519-2530) describing successful gene therapy for hemophilia A, presents results that could have broad implications for children with either hemophilia A or B. The idea of gene therapy for hemophilia is not new, but creative problem solving to overcome early obstacles to the process is. In this study, the researchers found a vector dose high enough to be effective but low enough to avoid an overwhelming immune response. They designed methods to detect early immune response to the vector virus and effective therapy to suppress that response. They modified the vector virus to have it target liver cells for factor production and, for hemophilia B, they inserted a variant of the affected gene that is particularly efficient in producing factor. Other obstacles remain before these therapies can be used to cure hemophilia A and B in children. However, there is new optimism that gene therapy may become a viable option for children with hemophilia or other genetic disorders.