BACKGROUND AND PURPOSE:

• Hemophilia B is an X-linked bleeding disorder, caused by a deficiency in coagulation factor IX
• Current treatment requires IV exogenous factor replacement
• George et al. (NEJM, 2017) examined the use of gene therapy as a single therapeutic intervention that could replace further IV treatments

METHODS:

• Nonrandomized, multicenter study
• Patients had hemophilia B and had factor IX coagulant activity of 2% or less of the normal value
• 10 patients received high-specific-activity factor IX that due to a variant, was 8 to 12 times as active as normal, nonmutant factor IX
• Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values
• Patients were followed for 52 weeks and then invited to enroll in a long-term follow-up protocol
• Researchers assessed the safety and kinetics of the gene therapy treatment

RESULTS:

• No adverse events were identified
• The factor IX coagulant activity was sustained in all 10 patients
• Cumulative follow-up of 492 weeks
  • Individual follow-up ranged from 28 to 78 weeks
• The annualized bleeding rate was significantly reduced
  • Mean rate was 11.1 events per year before gene therapy administration vs 0.4 events per year after administration (P=0.02)
• Factor use was significantly reduced
  • Mean dose was 2908 IU per kilogram before gene therapy administration vs 49.3 IU per kilogram (P=0.004)
• 8/10 participants did not require use of exogenous IV factor replacement
• 9/10 participants did not have bleeds after gene therapy administration
• An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment

CONCLUSION:

• Gene transfer therapy resulted in significantly sustained therapeutic expression of factor IX coagulant activity
• A one-time gene therapy infusion was not associated with adverse events and most patients no longer required exogenous factor replacement
• Larger long-term studies are now required to determine safety and efficacy

Learn More – Primary Sources:

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.

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