Long-term safety and efficacy of factor IX gene therapy in hemophilia B

N Engl J Med. 2014 Nov 20;371(21):1994-2004. doi: 10.1056/NEJMoa1407309.

Abstract

Background: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.

Methods: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring.

Results: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment.

Conclusions: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alanine Transaminase / blood
  • Dependovirus / genetics
  • Factor IX / genetics*
  • Factor IX / metabolism
  • Follow-Up Studies
  • Gene Expression
  • Genetic Therapy* / adverse effects
  • Genetic Vectors / administration & dosage*
  • Hemophilia B / blood
  • Hemophilia B / genetics
  • Hemophilia B / therapy*
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Transgenes
  • Young Adult

Substances

  • Factor IX
  • Alanine Transaminase

Associated data

  • ClinicalTrials.gov/NCT00979238