No more bleeding into joints with single-dose gene therapy for haemophilia B

The gene therapy etranacogene dezaparvovec reduces bleeds in patients with moderate or severe haemophilia B after only one infusion, preliminary data from the HOPE-B study have shown.

There were clinically meaningful increases in factor IX production regardless of whether patients had anti-capsid neutralizing antibodies prior to therapy. An even greater finding was that nearly all patients discontinued use of factor IX replacement after receiving the single-dose treatment. [ASH 2020, abstract LBA-6]

“The results show functionally curative levels, which means that patients should no longer be bleeding into joints on a regular basis,” said Dr Steven Pipe, professor of paediatrics and pathology at University of Michigan in Ann Arbor, Michigan, US.  “The patients that I follow in this trial tell me that they don’t have to think about their haemophilia anymore. This is pretty transformative for patients.”

The HOPE-B trial is the first phase III study of  haemophilia B, with the largest cohort of gene therapy thus far, said Pipe.  Sixty-seven patients were enrolled in the study, with 54 patients receiving a single infusion of etranacogene dezaparvovec at a dose of 2 × 10¹³ genome copies/kg. Most patients had severe haemophilia B at the time of diagnosis, and half had previous hepatitis C infection.

Factor IX levels up in 26 weeks

Pipe said there was a “robust” factor IX expression by week 3 after infusion. Another good finding was that mean factor IX activity increased by 37.2 percent (±19.6) at 26-weeks of follow-up. This translates to a 36.01 percent (±19.69) increase from baseline factor IX levels (p< 0.0001).

At baseline, 23 patients had detectable neutralizing antibodies at a maximum titre of 3,212.3 and had good transduction after infusion. Pipe said this was good news as other AAV-mediated, liver-directed liver therapy studies had excluded patients with neutralizing antibodies.

There were 123 cumulative bleeding events in the lead-in period before therapy vs 21 cumulative bleeding events after therapy. Sixteen patients had no bleeding events during the lead-in period whereas 39 patients had no bleeding events after therapy.

Bleeding events decreased by 83 percent overall and bleeding requiring treatment decreased by 91 percent.

“Mean factor IX levels increased to near-normal levels by 26 weeks,” said Pipe. “Nearly all patients in the per-protocol population discontinued factor IX prophylaxis after therapy and remained prophylaxis-free at 26 weeks.”

The most common adverse events reported were  flu-like illness, headache, and increased alanine transaminase levels.

Great option for patients

The presence of neutralizing antibodies had no effect on factor IX expression. “It’s a game changer not to screen patients with neutralizing antibodies. But the biggest impact is that it provides patients with haemophilia B an effective choice at any point after their diagnosis,” Pipe emphasized.  

Commenting on the study, Dr Robert Brodsky from the Johns Hopkins University School of Medicine, Baltimore, Maryland, US, who is unaffiliated with HOPE-B, said the ability to have a single infusion that allows patients to forget about their haemophilia for a period is “the type of treatment that we have always been looking for.”

While acknowledging the need for longer-term follow-up, he said this single-dose gene therapy has practice-changing potential. “We should all be excited that there are now great options for patients with haemophilia.”