Completion of phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years

Abstract

Etranacogene dezaparvovec (CSL222, formerly AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing the highly active factor IX (FIX) Padua variant controlled by a liver-specific promoter. This phase 2b, open-label, single-dose, single-arm, multicenter trial evaluated the efficacy and safety of etranacogene dezaparvovec. Three adult participants with severe or moderately severe hemophilia B (FIX ≤2%) and AAV5-neutralizing antibodies received a single IV dose (2 × 1013 genome copies per kg) of etranacogene dezaparvovec. The primary end point of FIX activity ≥5 IU/dL at 6 weeks was met (mean, 30.6 IU/dL). Secondary end points included bleed frequency, FIX concentrate use, and adverse events. Here, we report the end-of-study 5-year outcomes. After administration, mean (range) FIX activity increased to 40.8 IU/dL (31.3-50.2) at year 1 and was maintained at 45.7 IU/dL (39.0-51.2) at year 5. Mean annualized bleeding rate (all bleeds) was 0.14 for the cumulative follow-up period years 0 to 5. Two participants had 5 bleed-free years after treatment. Per protocol, 1 participant received episodic FIX replacement therapy after treatment for elective surgeries, 2 bleeding episodes, and 2 single self-administered infusions for unreported reasons. All participants discontinued and remained free of FIX prophylaxis. During the 5-year study period, there were no clinically significant elevations in liver enzymes, requirement for steroids, FIX inhibitor development, thrombotic complications, or late-emergent safety events in any participant. Five years after administration, etranacogene dezaparvovec was effective in adults with hemophilia B with a favorable safety profile. Participants are eligible to participate in an extension study (ClinicalTrials.gov identifier: NCT05962398) for 10-year additional follow-up. This trial was registered at www.clinicaltrials.gov as #NCT03489291.

Graphical abstract

Figure 1.

Overview of the phase 2b study design. After an initial screening period, during which time the participants received their usual standard of care or FIX replacement therapy, patients received a single IV dose of 2 × 10¹³ gc/kg etranacogene dezaparvovec. FIX levels were assessed weekly for the first 6 weeks, before assessments were reduced to biweekly until week 26 after infusion, when they reduced to monthly up to month 12, and twice-yearly up to the study completion of month 60. Quality-of-life assessments (Hem-A-QoL) were performed at week 26, and then annually from year 1 to year 5. Bleeding events, AEs, and any exogenous FIX use were reported throughout the study period. ∗Data from the year before screening were collected retrospectively using medical records. †Data were collected on the day of dosing. Tx, treatment.

Figure 2.

Sustained FIX activity over 5-year follow-up after etranacogene dezaparvovec administration. FIX activity was sustained across the 5 years of follow-up for all study participants, increasing to a mean (SD; range) 30.57% (6.97; 23.9-37.8) at week 6 that remained stable and in the nonhemophilia range from year 1 (40.77% [9.45; 31.3-50.2]) to year 5 (45.7% [6.18; 39.0-51.2]). ∗HemosIL SynthASil reagent. aPTT, activated partial thromboplastin time.

Figure 3.

Total number of bleeds and ABR at baseline and during 5-year follow-up. (A) Total number of bleeds per participant, per year at baseline and during 5-year follow-up after etranacogene dezaparvovec administration. Participants 1 and 2 did not report any bleeding events during the 5-year follow-up period, and participant 3 experienced 2 bleeds during year 2. No bleeding episodes were reported from year 3 to year 5 for all participants. (B) ABR by participant at baseline and during 5 years of follow-up after etranacogene dezaparvovec administration; ABR was 0 for all participants from years 3 to 5. ∗Data collected retrospectively 1 year before screening from medical records.