Etranacogene Dezaparvovec Superior to FIX Prophylaxis in Hemophilia B


Results from the final analysis of the HOPE-B trial were presented at the 2022 EAHAD meeting.

Etranacogene dezaparvovec (EtranaDez, AMT-061; CSL Behring) is superior to Factor IX (FIX) prophylactic therapy in reducing annualized bleeding rate (ABR) in patients with hemophilia B, meeting the primary endpoint of the phase 3 HOPE-B study (NCT03569891).1

The findings were presented at the European Association of Haemophilia and Allied Disorders (EAHAD) 2022 Annual Meeting, February 2-4, 2022, by investigator Wolfgang Miesbach, MD, PhD, professor and head of coagulation disorders and Comprehensive Care Centre, University Hospital of Frankfurt, Germany.

“The HOPE-B trial was the first phase 3 study in hemophilia B and has the largest cohort of gene therapy for hemophilia B to report to date. It is also the only trial to include participants with neutralizing antibodies to AAV and this is really unique,” Miesbach told GeneTherapyLive in an interview.

Etranacogene dezaparvovec was previously granted breakthrough therapy designation by the FDA and access to Priority Medicine (PRIME) regulatory initiative by the EMA. uniQure developed the gene therapy before entering into a Commercialization and License Agreement with CSL Behring in June 2020 for exclusive global rights to the therapy. uniQure completed manufacturing validation processes for etranacogene dezaparvovec in December 2021 and CSL Behring plans to submit regulatory applications in the US and EU in the first half of 2022. Notably, the Committee for Medicinal Products for Human Use (CHMP) at the EMA accepted CSL Behring’s request for accelerated assessment of its Marketing Authorization Application.

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The phase 3 HOPE-B trial evaluated etranacogene dezaparvovec in 54 male participants with severe or moderately severe hemophilia B. Participants were dosed with a single intravenous administration of 2x1013 gc/kg of the gene therapy after a prospective, 6-month observational period to establish a baseline ABR on current standard-of-care therapy. Fifty-three patients completed 18-month follow-up.

Treatment with the therapy yielded mean FIX activity of 39.0 IU/dL at 6 months and 36.9 IU/dL at 18 months post-infusion. Miesbach and colleagues found that, after the 6-month lead-in period, adjusted ABR was reduced by 64% (P = .0002) and FIX-treated bleeds reduced by 77% (P <.0001) over months 7 to 18. With these data, HOPE-B also met its secondary endpoints in FIX activity and ABR.

Almost all participants (98%) treated with the full dose of etranacogene dezaparvovec were able to discontinue prophylaxis. These participants had an overall 97% reduction in mean unadjusted annualized FIX consumption, from 257338.8 IU/year/participant to 8486.6 IU/year/participant from months 13 to 18. Participants were not excluded from the trial based on pre-existing neutralizing antibodies (NAbs) and efficacy and safety was observed in both populations of patients. Around 40% of participants enrolled had NAbs to AAV5.

The gene therapy was generally well-tolerated, with most adverse events (AEs; 80.4%) considered mild. No FIX inhibitors were reported. One participant death, due to urosepsis and cardiogenic shock at 77 years of age and at 65-weeks post-dosing was ruled unrelated to treatment. A serious AE of hepatocellular carcinoma was also deemed unrelated to treatment.

“To summarize, the study has shown that after 1 single intravenous infusion the patients were able to stop prophylaxis, and in the future, I think hemophilia centers should be able to offer gene therapy after it has been approved. One possibility, for example, would be to initiate a hub and spoke modelin which there would be a close cooperation between experienced and non-experienced centers to enable patients to be treated with gene therapy,” Miesbach told GeneTherapyLive.

1. Final analysis of pivotal HOPE-B study demonstrates durable and sustained therapeutic effect of etranacogenedezaparvovec gene therapy in hemophilia B – Data presented at EAHAD 2022. News release. CSL Behring. February 4, 2022.
2. CSL Behring Receives Accelerated CHMP Assessment for Etranacogene Dezaparvovec for European Patients Living with Hemophilia B. News release. CSL Behring. December 15, 2021.
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