The first results from a late-stage study of a gene therapy for hemophilia B show the treatment can readily replace the blood-clotting protein missing in people with the inherited disease, confirming tantalizing findings from years of earlier research.
For most of the 54 patients enrolled in the trial, called HOPE-B and run by the biotech UniQure, that was enough to eliminate bleeding events over the six months following infusion with the company's gene therapy, data released Thursday show. All but two participants in the trial discontinued the routine preventive treatment people with severe hemophilia must take several times per week.
The results are an encouraging step for UniQure and its would-be medicine. Yet, they leave some questions, too.
Fifteen patients still experienced bleeds following treatment, some more than once. While UniQure didn't break out specific data, the 21 total events observed across those 15 participants included spontaneous bleeds, as well as bleeds related to surgical procedures or injury.
In some cases, the bleed needed to be treated by standard clotting replacement treatment, an intervention researchers hope gene therapy can do away with for hemophilia patients.
Yet the fact that some patients experienced bleeds after treatment isn't necessarily cause for concern, according to Courtney Lawrence, a hematologist at Johns Hopkins Medicine.
Gene therapy trials like UniQure's are enrolling adult patients with moderate to severe hemophilia, she noted, and many of those individuals are likely to have joint disease due to decades of major bleeds.
"For nearly three quarters of high-risk patients to experience no bleeds in a six month period would be considered by most clinical providers to be a truly excellent clinical response," Lawrence added. She was not involved with UniQure's study.
Further details won't be available until December, when data from HOPE-B will be presented at a virtual meeting of the American Society of Hematology. The data released Thursday are from a "late-breaking" trial abstract made available ahead of the conference, which UniQure confirmed in a release of its own.
UniQure's therapy, called etranacogene dezaparvovec or AMT-061, is the most advanced gene therapy for hemophilia B and the first to deliver results from a Phase 3 trial. Another, from Pfizer, is also in late-stage testing, with data expected next year. Others from Freeline Therapeutics and Takeda are earlier in clinical development.
Based in Lexington, Massachusetts, and Amsterdam, UniQure has been working on hemophilia B gene therapy for nearly a decade, extending the work of its precursor company Amsterdam Molecular Therapeutics.
Etranacogene dezaparvovec is a second-generation treatment, designed to be more potent than an earlier gene therapy known as AMT-060.
Both work by delivering, via a special type of virus, a functional copy of the gene that's damaged in patients with hemophilia B. The newer therapy uses a naturally occurring gene variant discovered in Padua, Italy, that's been shown to spur greater production of blood-clotting protein.
Development of the treatment has put UniQure at the forefront of efforts to use genetic medicine to definitely treat inherited conditions like hemophilia, which was one the first diseases to be linked to mutations in a single gene.
Earlier this year, CSL Behring paid UniQure $450 million — and promised another $1.6 billion in conditional payments — to secure global rights to UniQure's treatment.
HOPE-B is the key test of the therapy's potential. UniQure expects results from the trial would support an application to the Food and Drug Administration for approval in severe and moderately severe hemophilia B next year.
Thursday's data are from the first half of the study, which measured levels of a key clotting protein, known as Factor IX, in the blood. Six months post-treatment, average Factor IX activity increased from less than 2% at baseline to 37%, high enough to be classified as mild hemophilia and close to what's considered a normal range.
"I think all of us feel pretty comfortable that, the closer we get to the normal range, this is probably going to be a meaningful transformation for patients, such that they really don't have to think about their hemophilia any more," said Steven Pipe, a hemophilia specialist and lead author on the HOPE-B study results, in an interview.
Lawrence, from Johns Hopkins, put it more practically.
"I would be much less worried about my patient with a factor level of 35% who wants to go hiking in the mountains two hours from the nearest hospital than I would be [about] my patient with a factor level of 3%, unless they were armed with factor concentrate at the ready," she wrote.
Originally, measuring Factor IX activity at 26 weeks was the sole primary goal of the trial. After conversations with the Food and Drug Administration, however, UniQure decided to make Factor IX activity at one year, as well as the annualized bleeding rate, "co-primary endpoints."
The change, which does not appear to have been previously disclosed, could suggest the regulator may be putting more emphasis on measuring how long Factor IX levels stay elevated as well as how well that translates to elimination of bleeds.
A spokesperson for UniQure said the company would further discuss the endpoint change with the FDA during a pre-application meeting.
The FDA's views on hemophilia gene therapy are newly a point of discussion, after the agency in August unexpectedly rejected a gene therapy for hemophilia A developed by BioMarin Pharmaceutical. In that case, the FDA appeared to want more information on the durability of the treatment's effect, which had seemed to lessen in later stages of testing.
"Many people did learn something about the regulator's view on things," said Pipe, of the rejection.
"The FDA is clearly showing they want to see the totality of data because they want to assess the key outcomes, like predictability, reliability, durability and safety."
To date, two gene therapies for inherited diseases have been approved in the U.S.: a treatment from Roche for a type of blindness, and a spinal muscular atrophy medicine from Novartis. Both conditions are severe and, at the time of the approval, lacked treatment options.
Hemophilia, however, presents a different challenge. Patients with the disease, particularly more severe forms, have a very high treatment burden, but are able to control their worst symptoms with an array of drugs. Gene therapy could allow patients to go without regular factor replacement infusions and, researchers hope, free them from the ever-present threat of spontaneous bleeds.
But for patients already stable on medicines they know well, gene therapy could represent an uncertain bet. Scientists expect patients treated with one gene therapy generally wouldn't be able to receive a second dose of the same, or similar, treatment, potentially posing issues if a therapy's benefits wane over time.
Some patients might not even be able to receive treatment with gene therapy in the first place, due to pre-existing immunity to the virus used to deliver the corrected gene.
With HOPE-B, however, UniQure was able to show that likely won't be a major issue with its treatment. Early data had suggested that even patients whose immune systems produced antibodies to the virus used to deliver the therapy still benefited.
UniQure replicated that finding in HOPE-B, showing, in the 23 patients who had an immune response to the delivery virus, no correlation between neutralizing antibodies and Factor IX activity. One patient with particularly high levels of neutralizing antibodies did not respond.
Catherine Bollard, a director of the Center for Cancer and Immunology Research at Children's National Research Institute, called the trial "highly exciting" for that very reason, noting most gene therapy studies exclude patients with pre-existing immune responses to the delivery virus.
Some 40% of patients with hemophilia B might have immune responses to UniQure's delivery virus, according to Pipe, the study investigator, making HOPE-B's findings potentially important in proving some of those individuals could still benefit.
Shares in UniQure rose 7% on news of the HOPE-B trial results Thursday, pushing the biotech's market value up above $2 billion.