乌鸦传媒

A single injection of a viral-mediated gene therapy vector reduced the bleeding rate among patients with Factor IX-related hemophilia B by 91% over the course of 6 months, researchers reported.

In most cases, patients were able to discontinue prophylaxis to prevent bleeding episodes after receiving the injection, which can be performed on an out-patient basis, Steven Pipe, MD, of the University of Michigan in Ann Arbor, said in a presentation at the .

"The patients achieved expression within the first couple of weeks post-dosing sufficient so they could stop their prophylaxis," Pipe told 乌鸦传媒 at a virtual press conference. "All the patients in the trial were on a regular prophylactic treatment so we could collect their bleed data. Post-dosing the number of bleeding episodes fell by 91%; I think this is the primary efficacy finding."

Prior to beginning the trial the patients were experiencing more than 100 bleeding episodes despite prophylaxis, and 6 months after the trial that had been reduced to just seven bleeding episodes, Pipe said.

A total of 52 of 54 patients with moderate to severe hemophilia B responded to treatment with the etranacogene dezaparvovec vector in the Phase III

"I think most people would agree that these patients have achieved a functional cure -- meaning that patients should no longer be bleeding into joints on a regular basis," Pipe said. "The patients that I follow in this trial tell me they don't have to think about their hemophilia anymore. This is pretty transformative for the overall phenotype. The second thing is that this is kind of a game changer by not having to screen out patients with neutralizing antibodies."

The moderator of the press conference, Robert Brodsky, MD, director of hematology at Johns Hopkins Medicine in Baltimore, called the study "a huge advance" in the field.

"This is the most inclusive gene therapy study of its type in which these patients were producing their own Factor IX for at least 6 months, and these results may open the door for patients previously not included in other gene therapy trials," Brodsky said. "What is so important about this study is that these researchers didn't exclude people with naturally occurring antibodies."

In fact, Pipe reported that 42% of the patients in the study did have positive neutralizing antibodies present when they began the trial, but in only one case did it appear that the level of antibodies had an impact on treatment. One patient who did not respond had a titer level over 3,000, and the other non-responders had levels no higher than 678. The research team is now trying to determine if there is a threshold titer level at which the adeno-associated virus vector would not be effective, Pipe noted.

The second patient with a suboptimal result had an infusion reaction and received only 10% of the active dose.

Brodsky questioned, however, whether the high volume of virus infused could be a long-term problem: "These early results are outstanding, but could there be downstream toxicities that we don't know about?"

Pipe noted that there had been no evidence of virus-related tumors in previous studies, "but there is no question that these patients will have to be followed long-term over their lifespan."

In addition, he said, the durability of response seen with other viral vector studies appears to be long-term, with some patients in other studies showing a durability of response up to 5 to 10 years.

"We are expecting the same observation with this large Phase III construct, and in most subjects who have gone beyond 26 weeks we are seeing durability of those steady-state levels," he said.

"All other adeno-associated virus-mediated gene therapy trials to date have excluded patients with pre-existing neutralizing antibodies," Pipe continued. "This was based on preclinical work that suggested that transduction would be impaired and there were some early observations in other trials where that was the issue. We had evidence in earlier-phase trials that patients who had evidence of neutralizing antibodies still had good transduction. We tested that in the Phase IIb with three subjects who had positive neutralizing antibodies titers, and all had good transduction. That led us to test this in the Phase III trial in a much larger cohort."

"Hemophilia B is a life-long bleeding disorder in which patients are at risk for bleeds into joints and are destined for severe arthropathy in adulthood unless they are tethered to a regular prophylactic regimen," Pipe explained. "What we are offering here is a single, outpatient intravenous infusion using this adeno-associated virus vector with a capsid serotype 5, and the viral genes have been replaced with a functional copy of the human Factor IX gene that has also been enhanced with a naturally occurring point mutation that codes for this hyperactive form of Factor IX. This boosts the effective activity by about 6- to 8-fold. The subjects in the trial are achieving a mean Factor IX activity of 37% at 26 weeks post-dosing.

"That was our first co-primary endpoint," Pipe said. "The additional endpoints are going to be the 52-week activity for the whole cohort, which will help us address durability, and we will look at the annualized bleed rates over the whole 52 weeks."

Comment