Highlights from

ASH 2020

62nd Annual Meeting & Exposition of the American Society of Hematology

Virtual 5 - 8 December 2020

Largest gene therapy trial cohort to date in haemophilia B

In the first report of a phase 3 study in patients with severe or moderately severe haemophilia B, the co-primary endpoint was met. Following a single dose of etranacogene dezaparvovec, factor IX activity increased to near-normal levels after 26 weeks. These data support a favourable safety and efficacy profile for this gene therapy.

Treatments for haemophilia B or factor IX deficiency are limited to regular intravenous infusions of factor IX concentrates. The goal of gene therapy in haemophilia B is to deliver a one-time procedure that establishes sustained factor IX activity, providing effective protection against spontaneous bleeding, eliminating the need for continuous prophylaxis, and improving quality of life.

Etranacogene dezaparvovec (AAV5-Padua hFIX variant; AMT-061) is an investigational gene therapy for haemophilia B. It combines an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX gene with a liver specific promoter. In an ongoing phase 2b study, a single dose of etranacogene dezaparvovec provided mean factor IX activity of 44.2% at 2 years; no new treatment-related AEs occurred. Although most clinical studies evaluating gene therapy exclude patients with pre-existing neutralising antibodies (NAbs) to the capsid serotype, early clinical studies and nonhuman primate data suggest that generally prevalent titres of anti-AAV5 NAbs may not preclude successful transduction with etranacogene dezaparvovec.

HOPE-B (Health Outcomes with Padua gene; Evaluation in Hemophilia B) is the first phase 3 study in haemophilia B and has the largest gene therapy cohort to date. Of 75 patients screened, 67 entered a prospective lead-in period. 54 patients were dosed (44 with severe haemophilia B and 10 with moderately severe haemophilia B) and completed 26 weeks of follow-up. About half of these (23/54, 42.6%) had NAbs to AAV5 at baseline. During the lead-in period, 38/54 patients (70.4%) had bleeds despite prophylaxis.

Following treatment, factor IX activity increased rapidly to a mean of 37.2% at week 26, representing a mean change from baseline of 36.0% (p<0.0001). There was no need for prophylactic immunosuppression. Almost all (52/53) patients received a full dose and responded. Patients were able to discontinue prophylaxis and bleeding was abolished in the majority of patients throughout the 26 weeks.

Most common safety findings were transaminase elevations requiring steroid treatment and infusion-related reactions. The safety profile was consistent with early phase AAV5 studies. The final analysis is planned at 1 year, to support marketing authorisation applications of etranacogene dezaparvovec.

  1. Pipe SW, et al. First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies. 62nd ASH Annual Meeting, December 5-8, 2020. Abstract LBA-6.

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