# Etranacogene dezaparvovec in people with hemophilia B with preexisting adeno-associated virus 5 neutralizing antibodies: 4-year subgroup results from the HOPE-B trial

## TL;DR

This study shows that gene therapy for hemophilia B works safely in people who already have antibodies to the virus used in treatment.

## Contribution

It is the first trial to show long-term efficacy and safety of gene therapy in hemophilia B patients with preexisting antibodies to the viral vector.

## Key findings

- Participants with preexisting AAV5 NAbs showed sustained FIX activity (mean 34 IU/dL) 4 years post-treatment.
- Bleeding rates dropped by 74.4% over 4 years, with no late hepatotoxicity observed.
- Gene therapy reduced FIX consumption by over 90% compared to pre-treatment levels.

## Abstract

Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) is the first phase 3 trial of adeno-associated virus (AAV) serotype 5 vector-based gene therapy for hemophilia B to have enrolled participants with neutralizing antibodies (NAbs) to the viral vector.

Evaluate the efficacy and safety of etranacogene dezaparvovec in a post hoc subgroup of participants with preexisting AAV5 NAbs 4 years posttherapy.

After a ≥6-month lead-in period on continuous prophylaxis, people with moderately severe/severe hemophilia B (factor [F]IX ≤ 2%) received a single infusion of etranacogene dezaparvovec. AAV5 NAb status prior to infusion was determined. FIX activity, annualized bleeding rates (ABRs), and safety were evaluated in participants with preexisting AAV5 NAbs.

A total of 21/54 participants had detectable preexisting AAV5 NAbs (titer: 8.5-678, n = 20; titer: 3212, n = 1). Two participants did not respond to treatment (high titer: 3212, n = 1; received partial dose, n = 1). The mean FIX activity was 36 IU/dL (SD, 18) at 1 year (n = 18) and 34 IU/dL (SD, 16) at 4 years (n = 15) posttreatment. Unadjusted ABRs for all bleeds (treated and untreated) decreased by 74.4% from 4.64 during lead-in to 1.18 during months 7 to 48 (n = 21). ABRs for spontaneous and joint bleeds decreased by 79% and 82%, respectively. The mean FIX consumption decreased from 245,476 IU/y (SD, 144,497) during lead-in to 23,975 IU/y (SD, 48.928) during years 1 to 4 (P < .0001). The most frequent treatment-related adverse events were infusion-related reactions (23.8%) and transient alanine aminotransferase elevations (14.3%). No late hepatotoxicity was observed.

Etranacogene dezaparvovec demonstrated long-term efficacy and safety in individuals with preexisting AAV5 NAb titers ≤ 678, expanding eligibility for gene therapy to a broader hemophilia B population.

•Conventionally, people with antibodies to viral vectors were excluded from gene therapy trials.•Patients with antibodies to the vector were included in HOPE-B and treated with etranacogene dezaparvovec.•The 4-year follow-up showed sustained FIX activity and lasting reduction in bleeding rates.•Etranacogene dezaparvovec is safe, with no late hepatotoxicity detected post-therapy.

Conventionally, people with antibodies to viral vectors were excluded from gene therapy trials.

Patients with antibodies to the vector were included in HOPE-B and treated with etranacogene dezaparvovec.

The 4-year follow-up showed sustained FIX activity and lasting reduction in bleeding rates.

Etranacogene dezaparvovec is safe, with no late hepatotoxicity detected post-therapy.