Gene Therapy a Potential 'Game Changer' for Hemophilia B

By Megan Brooks

December 18, 2020

NEW YORK (Reuters Health) - An investigational gene therapy for hemophilia B substantially increased production of the blood-clotting protein factor IX and reduced the number of bleeding episodes and need for prophylactic therapy in a phase-3 trial.

"Most patients with hemophilia B are bound to a prophylactic factor regimen of one to two intravenous infusions per week from birth through the rest of their life," senior investigator Dr. Steven Pipe of the University of Michigan, Ann Arbor, said in a statement.

"Gene therapy offers the chance to liberate patients from the burden of their prior treatments, allowing for spontaneity and the freedom to do more in day-to-day life," he added.

Dr. Pipe reported 26-week results from the HOPE-B trial of etranacogene dezaparvovec during a late-breaking abstract session at the American Society of Hematology (ASH) 2020 annual meeting.

Etranacogene dezaparvovec consists of an adeno-associated virus serotype 5 (AAV5) vector containing codon-optimized Padua variant human factor IX (FIX) gene with a liver-specific promoter. In a phase-2b study, a single dose of etranacogene dezaparvovec provided 41% sustained FIX activity on average one year after dosing in three patients with hemophilia B.

The HOPE-B study included 54 adult men with hemophilia B. All were dependent on FIX replacement therapy, and 70% had bleeding episodes in the six months prior to the study despite prophylactic treatment.

About 40% of participants had pre-existing neutralizing antibodies (NAbs) to AAV5. "In any other trial protocol, these patients would not have been eligible to participate," Dr. Pipe said in the release.

Following a single intravenous infusion of etranacogene dezaparvovec, FIX activity increased rapidly from a baseline of up to 2% (moderate to severe hemophilia) to an average of 37% (very mild hemophilia) at 26 weeks, representing a significant 36% change from baseline and meeting the trial's primary endpoint.

"I think most people would accept that these are functionally curative levels, meaning that patients should no longer be bleeding into joints on a regular basis," Dr. Pipe said during an ASH press briefing.

Fifty-two patients (96.3%) successfully discontinued routine prophylaxis. Nearly three-fourths of patients (72%) had no bleeding events in the 26 weeks after dosing. Fifteen patients reported a total of 21 bleeds.

There was no correlation of pre-existing NAbs with FIX activity up to a titer of 678.2. One patient who had a NAb titer level "well over 3000" did not respond, suggesting that these antibodies may pose a problem only at extremely high levels, Dr. Pipe noted. The one other patient who did not respond received only a partial dose due to an infusion reaction.

Adverse events were reported in 68% of patients, but most were mild and related to the infusion itself. Nine patients showed evidence of an immune response to the therapy, which was resolved in all cases with a course of corticosteroids. There were no treatment-related serious adverse events.

The safety profile was consistent with earlier studies and together with these data "support a favorable safety and efficacy profile for etranacogene dezaparvovec," the researchers conclude in their conference abstract. The patients in the HOPE-B trial will be followed for five years.

"My observation from the patients that I follow in this trial is that they tell me that they don't have to think about their hemophilia anymore so this is pretty transformative for patients. And it's kind of a game changer in not having to screen out patients with neutralizing antibodies," Dr. Pipe told the briefing.

These early results are "outstanding," said briefing moderator Dr. Robert A. Brodsky of Johns Hopkins School of Medicine, in Baltimore, Maryland. "What's so important about this study" is that they didn't exclude people with pre-existing neutralizing antibodies. "This is a huge advance in this field."

The study was funded by UniQure, which is developing etranacogene dezaparvovec for hemophilia B. Several authors have disclosed financial relationships with the company.

SOURCE: American Society of Hematology (ASH) 2020 annual meeting.