Gene Therapy EtranaDez Allows Hem B Patients to Stop Prophylaxis

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Nearly all men with moderate-to-severe hemophilia B given the experimental gene therapy EtranaDez (etranacogene dezaparvovec) in the HOPE-B trial have stopped using prophylactic therapies, full study results show.

Trial data also indicated that EtranaDez, formerly known as AMT-061, is effective in people with antibodies against the viral vector used in the gene therapy.

“While progress in today’s FIX prophylaxis treatments has made meaningful improvements in the lives of people with hemophilia B, many patients remain at risk of serious bleeds and other complications, despite regular, ongoing treatment,” Steven Pipe, MD, a professor of pediatrics and pathology at the University of Michigan and HOPE-B’s principal investigator, said in a press release.

“Nearly all patients treated with gene therapy in this study were able to discontinue use of prophylaxis. The treatment was also effective in people who have pre-existing neutralizing antibodies, which would typically disqualify someone from this kind of treatment,” Pipe said.

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Data were presented at this year’s European Association of Haemophilia and Allied Disorders (EAHAD) annual meeting by CSL Behring, which acquired commercialization and licensing rights for the investigational treatment from uniQure in 2021. CSL has announced plans to seek approval of EtranaDez in the U.S. and Europe this year.

“The most recent data from the pivotal HOPE-B study demonstrates the transformative potential of this platform to further redefine how we treat this life-long condition,” said Brahm Goldstein, MD, vice president of hematology research and development at CSL.

In hemophilia B, mutations in the F9 gene render the body unable to produce functional factor IX (FIX), a blood clotting protein. EtranaDez is designed to deliver FIX-Padua, a highly active variant of the F9 gene, to a patient’s cells to allow functional FIX production. EtranaDez utilizes a specifically engineered viral vector, called adeno-associated virus variant 5 (AAV5), to deliver the therapy.

The Phase 3 HOPE-B trial (NCT03569891), sponsored by uniQure, enrolled 54 men with moderate-to-severe hemophilia B. All were treated with a single infusion of EtranaDez, and all but one were followed for at least 18 months.

Over the study’s six-month lead-in (pretreatment) period, most patients (70.4%) had some bleeds despite continual prophylactic (preventive) use. One-year data from HOPE-B indicated that EtranaDez increased FIX levels, reduced bleeding rates, and lessened the need for prophylaxis.

Top-line trial results, announced late last year, showed that the average annual bleeding rate at 18 months was 1.51 bleeds per year, a 64% reduction compared to the lead-in period’s rate (4.19 bleeds/year). The rate of bleeds requiring FIX replacement therapy also fell, and levels of FIX activity were, on average, 36.9% of normal by month 18.

Almost all  participants (98%) given a full dose of EtranaDez stopped taking prophylaxis. The overall average yearly usage of FIX replacement therapy decreased by 97% from the study’s lead-in six months to its final six months (from 257,338.8 to 8,486.6 international units per year per participant).

Of note, while the viral vector used in EtranaDez is harmless, the immune system of some patients can make antibodies that target AAV5 due to previous infections with similar viruses. Data from HOPE-B showed EtranaDez also benefitted patients with pre-existing anti-AAV5 antibody titers (levels) as high as 1:678.

Data from a small Phase 2b trial (NCT03489291) evaluating EtranaDez in three patients with antibodies against AAV5 also showed the gene therapy increased FIX levels and lowered bleeding rates, allowing them to stop prophylaxis. Results were presented at EAHAD in the poster, “Multiple-year Durability Data from a Phase 2B trial of Gene Therapy with Etranacogene Dezaparvovec in Patients with Hemophilia B.”

EtranaDez was generally well-tolerated in HOPE-B, with over 80% of reported adverse events being mild. There was one instance of liver cancer and one death due to a urinary tract infection in the study; neither was deemed related to the investigational gene therapy.