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New HOPE for Hemophilia B: One-Time Gene Therapy Abolishes Bleeding in Most Patients

December 30, 2021

A single dose of the gene therapy drug etranacogene dezaparvovec increased factor IX (FIX) activity levels, and eliminated the need for prophylactic FIX, in patients with severe to moderately severe hemophilia B, according to results from the phase III HOPE-B gene therapy trial. The results were presented by Steven W. Pipe, MD, as a late-breaking abstract at the 2020 ASH Annual Meeting. Six months after gene therapy infusion, nearly three-quarters of patients had experienced zero bleeding events.

"The goal of gene therapy for hemophilia B is to deliver a one-time procedure that establishes sustained FIX activity in the mild-to-normal range that should be transformative for the recipient," Dr. Pipe, from the University of Michigan, said. Such therapy would provide "effective protection from spontaneous bleeding, eliminating the need for continuous prophylaxis with accompanying improvement in quality of life," he added.

The HOPE-B trial included men with severe or moderate-severe hemophilia B with FIX activity levels ≤2%. All patients were receiving routine FIX prophylaxis prior to study entry. There was a prospective lead-in period of at least 6 months during which bleeding/factor use was monitored, then patients received a single intravenous dose of etranacogene dezaparvovec. Etranacogene dezaparvovec is an AAV5-mediated, liver-directed gene therapy, which has had the viral genes replaced with a functional copy of the human FIX gene that has been enhanced by a naturally occurring point mutation that encodes for a Padua FIX, Dr. Pipe explained.

While most gene therapy trials for hemophilia B exclude patients with neutralizing antibodies, out of concern that they could prevent successful transduction of the gene therapy candidate, HOPE-B assessed neutralizing antibodies, but did not use them as an exclusion criterion. Per study protocol, participants will be followed for 5 years.

HOPE-B is the first phase III trial for a gene therapy in hemophilia B, with the largest gene therapy cohort to date, Dr. Pipe noted. He presented data from 54 patients who had received etranacogene dezaparvovec and completed at least 26 weeks of follow-up.

Most participants (70%) had bleeds during the lead-in period despite receiving prophylaxis. A little less than half (43%) had neutralizing antibodies directed to the AAV5 capsule.

At week 26, mean FIX activity was 37.2%, representing a mean change from baseline of 36.0% (p<0.0001). Though the patient numbers are small, Dr. Pipe noted that there was continuing FIX expression in patients who had continuing follow-up beyond week 26, including in one participant who has reached 18 months of follow-up.

The researchers did not identify any correlation between preexisting neutralizing antibodies and FIX activity.

Relative to the 6-month lead-in phase, total bleeds decreased by 83% and treated bleeds decreased by 91%, the investigators reported (TABLE). Seventy-two percent of participants experienced zero bleeds post-dosing, compared with only 30% during the lead-in.

About 70% of patients had treatment-related adverse events (AEs), but Dr. Pipe noted that about three-quarters of these were mild. Common AEs included influenza-like illness (n=7; 13%), headache (n=7; 13%), and ALT increase (n=7; 13%). No deaths or treatment-related serious AEs occurred. "Notably, no inhibitors to FIX were reported, and there was no observed relationship between these safety signals and neutralizing antibodies," Dr. Pipe added.

He called these results "very encouraging" and noted that etranacogene dezaparvovec "maximizes eligibility for patients by being able to treat in the presence of preexisting neutralizing antibodies." A final analysis is planned at 1 year to support regulatory review submission, he added.

Study authors report relationships with UniQure, which sponsored the trial.


Pipe SW, Recht M, Key NS, 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. Abstract LBA-6. Presented at the 2020 American Society of Hematology Annual Meeting; December 8, 2020.


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