AMT-061 Achieves Sufficient Increases in Factor IX Levels for Patients With Hemophilia B

AMT-061, an AAV5 vector containing factor IX (FIX)-Padua variant, has been shown to increase FIX activity to threshold FIX levels sufficient to significantly reduce the risk of bleeding events without the risk of adverse immune reactions.

Hemophilia B, also called Christmas disease and FIX deficiency, was first discovered in 1952 in a patient named Stephen Christmas. Compared with hemophilia A, hemophilia B is a rarer bleeding disorder, with reported cases only in 1 of every 20,000 people. In patients with hemophilia B, a genetic disorder causes defective or missing FIX, a clotting protein. The genetic defect occurs in the F9 gene located on the X chromosome. Although both genders can be carriers, males are mainly the ones with symptoms because they only have one X chromosome.

Hemophilia B is categorized according to disease severity into mild, moderate, and severe, distinguished through the amount of FIX in the blood (mild; 6% to 49%, moderate; 1% to 5%, severe; <1%). Symptoms dependent on the amount of FIX deficiency may range from prolonged bleeding episodes to spontaneous major bleeds. Current treatment options include recombinant FIX, plasma-derived FIX concentrates, and fresh frozen plasma.

AMT-061, created by uniQure, is an AAV5 vector that carries the Padua variant of FIX. FIX-Padua modifies FIX at position 338 (substitute leucine for arginine) to provide a gain of function effect that exerts an 8 to 10 times greater clotting activity compared with the wild-type recombinant FIX.¹ With greater activity, AMT-061 is expected to increase and sustain FIX levels to reduce the risk of bleeding events.

In the phase 2b study of AMT-061, 3 patients with severe hemophilia B received a single intravenous infusion of AMT-061 at 2 x 10¹³ vc/kg. Six weeks after administration, the mean FIX activity for the 3 patients was 31% of normal, a level considered sufficient enough to reduce the risk of bleeding events. The first patient acquired a FIX activity of 37% of normal at 10 weeks, the second patient acquired a FIX activity of 23% of normal at 8 weeks, and the third patient acquired a FIX activity of 30% of normal at 6 weeks of administration. No patients had any material loss of FIX activity, any reported bleeding events, or required FIX replacement therapy. Only 1 patient had a mild, asymptomatic increase in liver enzyme levels, but it resolved quickly without treatment.

Results from this study have led investigators to begin initiating the phase 3 HOPE-B study that will enroll 50 adult patients with severe or moderately severe hemophilia B. End points that will be examined include annualized bleeding rates, safety, and annualized FIX replacement therapy usage. “The initial data from our phase 2b study suggest this target profile is achievable, and we look forward to providing further clinical updates on the study at medical conferences in 2019,” said Matt Kapusta, chief executive officer of uniQure.

References

1. Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009;361(17):1671-1675. doi: 10.1056/NEJMoa0904377.