ASH: UniQure/CSL hem B gene therapy curbs bleeding in phase 3—even in patients with anti-AAV antibodies

red blood cells
A study of uniQure and CSL Behring’s hemophilia B gene therapy found "no correlation" between the gene therapy's efficacy and the presence of antibodies that neutralize the virus used to deliver the treatment. (Arek Socha)

People with hemophilia B lack a protein that helps their blood clot, so they rely on lifelong infusions of that protein to manage their disease. UniQure and CSL Behring’s hemophilia B gene therapy could transform chronic care into a one-time treatment—and its latest data suggest it could work for patients considered unsuitable for gene therapy.

The treatment, etranacogene dezaparvovec, curbed bleeding episodes and nearly eliminated the need for infusions of clotting Factor IX (FIX) in a phase 3 study testing it in severe or moderately severe hemophilia B. The study, HOPE-B, found that 26 weeks after treatment, the gene therapy had reduced bleeds that needed treatment by 91%, with 87% of 54 patients reporting such bleeds. Eighty-three percent of the patients reported no bleeds at all, including suspected bleeds that did not require treatment.

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The treatment also boosted FIX activity to an average of 37.2%, up from less than 2% at the start of the trial, meeting its primary endpoint.

The study, to be presented virtually Tuesday at the annual meeting of the American Society of Hematology, found that nearly all the patients—52 out of 54, or 98%—no longer needed infusions of FIX to prevent bleeding episodes. Of the remaining two patients, one suffered an infusion reaction during treatment and did not get the full gene therapy dose, while the other had very high levels of antibodies that neutralize the adeno-associated virus (AAV) used to deliver the treatment.

Many people have a natural immunity to AAVs because they’re exposed to them in the environment. Though useful for fighting off infection, this immunity can render gene therapies ineffective. That appears not to be the case with uniQure and CSL’s treatment. The patient for whom the gene therapy did not work was an outlier, with antibody levels nearly five times as high as the level expected in more than 95% of the general population. In patients with more typical antibody levels, investigators saw “no correlation” between the presence of those antibodies and FIX activity, the company said in a statement.

“Importantly, these data also show that those patients in the trial who may not have been eligible for other gene therapies because they had pre-existing neutralizing antibodies (NAbs) have achieved results with etranacogene dezaparvovec that are comparable to the results of patients who did not have pre-existing NAbs,” Steven Pipe, M.D., a professor of pediatrics and pathology at the University of Michigan and the study’s lead investigator, said in a statement.

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“This is an important distinction as this is the only known clinical trial that has maximized patient eligibility in this way. The initial data also show that etranacogene dezaparvovec has been generally well tolerated to date,” he said.

Most of the side effects were mild (82%). The most common treatment-related side effect was elevated liver enzymes, which affected 17% of patients but was treated effectively with steroids. Infusion reactions and flu-like symptoms each affected 13% of patients.

The data come five months after CSL picked up the global rights to etranacogene dezaparvovec for $450 million upfront. These latest data set up the companies in a battle to bring a new hemophilia B gene therapy to market, pitting them against the likes of Pfizer and Spark/Roche.