Stable and durable factor IX levels in patients with hemophilia B over 3 years after etranacogene dezaparvovec gene therapy.

Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here, we report 3-year outcomes from a phase 2b, open-label, single-dose, single-arm, multicenter trial conducted among adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n = 3) received a single intravenous dose (2 × 1013 gene copies per kg) and will be followed up for 5 years. The primary end point of FIX activity ≥5% at 6 weeks was met. Secondary end points included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 before etranacogene dezaparvovec treatment. After administration, FIX activity rose to a mean of 40.8% in year 1 and was sustained in year 3 at 36.9%. All participants discontinued FIX prophylaxis. Bleeding was completely eliminated in 2 out of 3 participants. One participant required on-demand FIX replacement therapy per protocol because of elective surgical procedures, for 2 reported bleeding episodes, and twice for a single self-administered infusion because of an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late-emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B over 3 years after administration. This trial was registered at www.clinicaltrials.gov as #NCT03489291.

Prospective evaluation of ADAMTS-13 and von Willebrand factor multimers in cardiac surgery.

Acquired thrombotic-thrombocytopenic purpura, one of the main representatives of thrombotic microangiopathies (TMAs), is caused by the accumulation of antibodies against ADAMTS-13. Several cases of postoperative TMAs have been observed during the past few years, but the pathogenesis remains unknown. In addition to this, it is unclear whether the use of extracorporeal circulation (ECC) during cardiac surgery has an influence on the occurrence of cardiac surgery-associated TMA. In this study, we investigated the relationship between ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs 13), ADAMTS-13 inhibitor, von Willebrand factor (VWF) and large VWF multimers in cardiac surgery with and without the use of ECC. Blood samples were taken preoperatively, intraoperatively and up to 6 days postoperatively. A total of 47 patients (median age 70 years, 18 women, 29 men) undergoing cardiac surgery were included; cardiac surgery with the use of ECC (cardiopulmonary bypass) was used in 39 patients, and the off-pump coronary artery bypass technique was used in eight patients. TMA was not diagnosed in any of the patients. Cardiac surgery led to a significantly reduced ADAMTS-13 activity (from 67 to 51%, P < 0.001 in the cardiopulmonary bypass group, from 64 to 48%, P = 0.02 in the off-pump coronary artery bypass group) and higher amounts of large VWF multimers. Development of ADAMTS-13 antibodies was not induced by cardiac surgery. Cardiac surgery led to a slight but significant decrease of ADAMTS-13, but this decrease was not associated with TMA.