A final analysis of the pivotal HOPE-B study was presented at ASGCT 2022.
uniQure's biologics license application (BLA) for etranacogene dezaparvovec (EtranaDez) has been accepted by the FDA for priority review for the treatment of hemophilia B.1
"Etranacogene dezaparvovec has the potential to be the first gene therapy approved in hemophilia B and the acceptance of the BLA marks an important milestone in uniQure’s mission of delivering the promise of gene therapy to people living with rare diseases,” Matt Kapusta, chief executive officer, uniQure, said in a statement.1
EtranaDez, which is developed in collaboration with CSL Behring as part of a Commercialization and License Agreement as of June 2020, is designed to restore production of Factor IX (FIX) by using an adeno-associated virus (AAV) vector to deliver the Padua variant of the FIX gene. The gene therapy has been granted breakthrough therapy designation by the US Food and Drug Administration and access to Priority Medicine (PRIME) regulatory initiative by the European Medicines Agency (EMA). The EMA is currently reviewing a Marketing Authorization Application for EtranaDez in hemophilia B.
The BLA is supported by positive data from the pivotal phase 3 HOPE-B trial (NCT03569891), which has enrolled 54 patients with hemophilia B and a baseline FIX of < 2%. Of these participants, 33 had pre-existing AAV5 neutralizing antibodies (NAbs) and 21 did not. All participants underwent a > 6-month lead in period of FIX prophylaxis before being dosed with 2x1013 gc/kg EtranaDez. All but one participant (n = 53) completed at least 18 months of follow-up.
The HOPE-B trial has met its primary endpoint of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline FIX prophylactic therapy.2 Previous data showed that mean FIX activity was 39.0 IU/dL (standard deviation ±18.7; minimum 8.2, maximum 97.1) at 6 months post-treatment and 36.9 IU/dL (±21.4; 4.5, 122.9) at 18 months.
Among participants who received a full dose of EtranaDez, FIX prophylaxis was discontinued by all whose AAV5 NAbs were undetected or who had pre-dosing NAbs up to a titer of 678, constituting an overall 97% reduction in mean unadjusted annualized FIX consumption. The 52-week adjusted ABR for all bleeds was reduced by 64% (P = .0002) from 4.19 during the ≥ 6-month lead-in period to 1.51 during months 7-18.
Mild AEs occurred in most participants (>80%) but EtranaDez was mostly well-tolerated. One death, deemed unrelated to treatment, occured in a 77-year-old patient at 65-weeks following dosing due to urosepsis and cardiogenic shock. A serious AE of hepatocellular carcinoma was also deemed unrelated to treatment based on molecular characterization and vector integration analysis. No inhibitors to FIX were reported.
A final analysis of the trial presented at the American Society of Gene & Cell Therapy 25th Annual Meeting (ASGCT), held in Washington, DC, and virtually May 16-19, 2022 demonstrated durable hemostatic correction and improvements in hemophilia-related quality of life (HRQoL).3
Significant improvements were seen across HRQoL domains, resulting in a 21.5% total score percentage improvement (least square means, -5.50; P < .0001). Notably, large increases were seen in Feelings (current emotions associated with having hemophilia; 45.7%) and Treatment (burden of hemophilia treatments, 59.0%) after treatment with EtranaDez.
“... if approved, etranacogenedezaparvovec would represent our second gene therapy to complete its journey to patients...” Kapusta added to the statement.1 “We are pleased with the promising results generated from our HOPE-B pivotal study, the largest gene therapy trial in hemophilia B to date and, assuming FDA approval, we look forward to partnering with our colleagues at CSL Behring to bring this life-changing treatment option to people with hemophilia B.”