Hemophilia B Gene Therapy Meets Primary End Points in HOPE-B Trial


CSL Behring plans to submit regulatory applications in the US and EU in the first half of 2022 for the AAV gene therapy etranacogene dezaparvovec.

The phase 3 HOPE-B trial (NCT03569891) of the investigational adeno-associated virus 5 (AAV5) gene therapy etranacogene dezaparvovec (uniQure; CSL Behring) has met its primary end point of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline Factor IX (FIX) prophylactic therapy in hemophilia B.

ABR was 1.51 18 months post-treatment compared with 4.19 (P = .0002) with baseline FIX prophylactic therapy. The study also met its secondary end points of endogenous factor IX activity, reduction in factor IX replacement therapy use, and tolerability as measured via adverse events (AEs).

“We are very pleased with these top-line results from what is the largest and first pivotal trial of a gene therapy for patients with hemophilia B,” Ricardo Dolmetsch, PhD, president, research and development, uniQure, said in a statement. “The HOPE-B data not only achieved the pre-specified primary endpoint of non-inferiority in annualized bleeding rate following 12 months or more of stable FIX expression, but also the secondary endpoint of superiority in reduction of annualized bleeding, while continuing to demonstrate durability and stability in FIX levels and other benefits to this point in the study.”

The open-label, single-arm, HOPE-B study has enrolled 54 participants with moderate –to severe hemophilia B, 53 of which have completed at least 18 months of follow-up. A baseline ABR was established in a lead-in 6-month observational period during which patients continued to use prophylactic FIX replacement therapy. Patients then received 2x10^13 gc/kg of etranacogene dezaparvovec. Pre-existing neutralizing antibodies (NAbs) to AAVs were present in 43% of patients.

READ MORE: Hemophilia A Gene Therapy Placed on Clinical Hold

Investigators found that after stable FIX expression, ABR was 1.51 at 18 months post-treatment compared with 4.19 during the lead-in period (P = .0002). For investigator-adjudicated FIX-treated bleeds, ABR was 0.83 compared with 3.65 (P <.0001) during the lead-in period. At 18 months, participants had a mean 36.9% of normal FIX activity compared to 39% during the lead-in period as measured by a one-stage APTT-based clotting assay.

“On behalf of uniQure, we extend our heartfelt gratitude to all the HOPE-B clinical trial patients and their families, as well as the trial investigators,” he continued. “We now look forward to collaborating with CSL Behring on completing the regulatory submissions that we hope will advance etranacogene dezaparvovec one step closer to reaching hemophilia B patients around the world.”

Etranacogene dezaparvovec was relatively well-tolerated, with mostly mild AEs (>80%). One death, deemed unrelated to treatment, did occur in a 77-year-old patient at 65-weeks following dosing due to urosepsis and cardiogenic shock. One patient experienced a serious AE of hepatocellular carcinoma and this was also deemed unrelated to treatment based on molecular characterization and vector integration analysis. No inhibitors to FIX were reported.

“These encouraging results illustrate the potential that gene therapy has to be a long-term treatment option for patients living with hemophilia B and we look forward to sharing more detailed data with the medical community in the near future,” Brahm Goldstein, MD, MCR, vice president, research and development, hematology, CSL Behring, added to the statement. “This milestone advances our efforts towards expected regulatory submissions in first half of 2022.”

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 earlier this month and CSL Behring plans to submit regulatory applications in the US and EU in the first half of 2022.

uniQure and CSL Behring announce primary endpoint achieved in HOPE-B pivotal trial of Etranacogene Dezaparvovec gene therapy in patients with Hemophilia B. News release. UniQure. December 9, 2021. https://www.cslbehring.com/newsroom/2021/hope-b-gene-therapy-for-hemophilia-b-topline-results
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