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.

Silent ischemic lesion recurrence on magnetic resonance imaging predicts subsequent clinical vascular events.

BACKGROUND: Previous studies identified a high frequency of silent ischemic lesion recurrence on magnetic resonance imaging (MRI) after an index stroke. OBJECTIVE: To investigate whether ischemic lesion recurrence on MRI predicts subsequent clinical events. DESIGN: Retrospective cohort study. SETTING: General community hospital. Patients We recruited 120 patients who experienced an acute ischemic stroke (IS) and who underwent initial MRI within 24 hours of onset and subsequent MRI on day 5. Of those patients, 68 underwent follow-up MRI up to 90 days after onset. MAIN OUTCOME MEASURES: Early silent lesion recurrence was defined as new asymptomatic ischemic lesions on 5-day MRI, and late silent lesion recurrence was defined as those on 30- or 90-day MRI. Patients were followed up for recurrent vascular events by interviews. RESULTS: Among the 104 patients (86.7%) who had available clinical outcome data, 35 (33.7%) had early silent lesion recurrence; 15 (22.1%) of 68 patients had late silent lesion recurrence. Of the patients, 8 experienced a recurrent IS, 3 experienced a transient ischemic attack, and 3 had vascular deaths during a mean +/- SD follow-up of 19.3 +/- 9.0 months. For recurrent IS as a clinical end point, late silent lesion recurrence independently predicted recurrent IS (odds ratio, 6.55; 95% confidence interval, 1.09-39.55) by the Cox proportional hazards model. For combined clinical end points, early (odds ratio, 3.19; 95% confidence interval, 1.02-10.00) and late (odds ratio, 8.09; 95% confidence interval, 1.29-50.91) silent lesion recurrences independently predicted clinical recurrent IS, transient ischemic attack, or vascular deaths. CONCLUSION: These data suggest that silent ischemic lesion recurrence on MRI may be a potential surrogate marker of clinical recurrence.