Gene Therapy for Factor IX Deficiency Hemophilia

Factor IX deficiency (hemophilia B; Christmas disease) is a hemorrhagic disorder that is clinically indistinguishable from factor VIII deficiency (classical hemophilia). Individuals with factor IX levels <5% of normal often have recurrent bleeding into their knees, elbows, and ankles and become disabled if they do not receive regular intravenous infusions of factor IX concentrates.

To evaluate the safety and efficacy of gene therapy for this disorder, investigators conducted an industry-supported, phase I–IIA study of an adeno-associated viral (AAV) capsid containing a highly expressed mutant factor IX gene. A single intravenous infusion of this construct was given to 10 patients who had severe factor IX deficiency and AAV neutralizing antibodies of 1:5 or less.

At a mean follow-up of 49 weeks, results were as follows:

• There was no evidence of serious adverse effects, development of factor IX inhibitors, or hypercoagulability. Two participants had grade ≤1 liver enzyme increases that declined with prednisone therapy.

• Factor IX activity rose within 1 week of gene infusion and reached a steady state of 33.7% ±18.5% of the normal value by 14 weeks; it was 18% of the normal value in one participant who had a pretreatment AAV neutralizing antibody titer of 1:1.

• The annualized bleeding rate declined from a mean 11.1 to 0.4 events per year (P=0.02).

• Clotting factor concentrate consumption declined from 2908 to 49.3 IU per kg (P=0.004).

• The mean number of infusions declined from 67.5 to 1.2 (P=0.004).

• Eight participants used no exogenous factor IX; cost savings for all participants were $3.6 million, based on 2016 concentrate prices.