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Grand Rounds

Gene Therapy – Are We on the Cusp of a Cure for Hemophilia B?

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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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