Researchers have known for decades that genetic medicine has the potential to be a long-lasting, and potentially permanent, fix for hemophilia. On Tuesday, at one of the world's largest medical conferences, fresh data reinforced the possibility that such a treatment might not be far off.
Hemophilia is a rare disorder caused by mutations that derail how the body makes proteins needed to clot blood. Roughly one in five hemophilia patients has the less common, "B" form, meaning they lack a clotting protein known as Factor IX. In the most severe cases, patients have less than 1% the normal amount of protein and require preventive drugs multiple times each week to protect against uncontrolled bleeding.
Though several effective drugs for hemophilia B are available, patients and doctors still hold out hope for a treatment that can stop the disease at its source. UniQure, a Netherlands-based biotech, is closest to achieving this goal, having advanced into the final stages of clinical testing a therapy that delivers a functional Factor IX gene into cells.
The company expects to file its therapy, called AMT-061, for approval next year, based on a clinical trial that tested it in 54 participants with moderately severe to severe hemophilia B. High-level results were released in November, showing that six months after one infusion the average patient was making enough clotting protein to be considered a mild hemophiliac.
And Tuesday, at the American Society of Hematology's annual conference, UniQure offered up a more granular look at the data. The total number of bleeds reported by patients fell 83% between the six-month period before they got AMT-061 and the six months after. The number of bleeds that required treatment declined even further, by 91%.
Overall, 52 of the 54 participants responded to AMT-061. Protein levels in these patients rose from less than 2% to 37% on average, allowing them stop taking replacement Factor IX.
UniQure's therapy met the high expectations set for it, according to Michael Callaghan, an associate professor of pediatric hematology and oncology at Wayne State University. "This is a really good outcome."
Callaghan was not involved in UniQure's study.
Bleeding before and after UniQure's gene therapy
|Lead-in period||26 weeks after treatment|
|Patients without bleeds||16||39|
SOURCE: UniQure. *Other includes bleeds from unrelated medical or dental procedures, or from unknown causes.
While UniQure's trial builds support for AMT-061, some of its findings raise questions. For example, after receiving AMT-061, 15 patients still reported 21 bleeding cases, half of which required treatment. The bleeds are a notable outcome, since gene therapy is meant to largely eliminate the need for such intervention.
Yet researchers have pointed out that some bleeding post-treatment is still to be expected because of who UniQure's study enrolled. Most participants had severe hemophilia, making them more likely to have developed joint disease from decades of major bleeds.
The reporting process isn't always an exact science either, as it relies on diary entries from patients. "If someone felt a burning sensation in their elbow and thought it was a bleed, they put it in their diary," noted Matt Kapusta, UniQure's CEO, in an interview with BioPharma Dive.
Unavoidable or unintended injuries also affected the total bleed count. One patient had a tooth extraction, according to Kapusta.
Callaghan said that because it takes weeks for gene therapy expression to ramp up, the bleeding and treatment use should go down "considerably" in the long term.
"The first 26 weeks is a really muddy period to assess," he said. "I expect the bleeding rate to get better over time."
Of the two patients who didn't respond to UniQure's therapy, one did not get the full dose because he had a reaction during the infusion process. Six more participants had infusion-related reactions, with three needing steroids or antihistamines, but all six eventually got the full dose.
The other patient who didn't respond had a relatively large amount of "neutralizing antibodies," a kind of defense the immune system uses to fight invading pathogens like viruses.
Gene therapies often rely on specially selected viruses to deliver their genetic cargo into cells. AMT-061, for instance, uses what's known as adeno-associated virus serotype 5, as does a high-profile hemophilia A gene therapy from BioMarin Pharmaceutical.
Because neutralizing antibodies can disarm a gene therapy before it ever helps the patient, their presence has become a major concern for drug developers. Indeed, many gene therapy trials won't let patients enroll if they test positive for certain neutralizing antibodies.
But UniQure's trial was different. Following a signal seen in earlier testing, and a theory that AAV5 might be harder to impair than other viral vectors, the company allowed patients with AAV5 antibodies to participate. By the time enrollment completed, 23 patients with neutralizing antibodies were onboard.
UniQure said antibody levels in the one patient who didn't respond to AMT-061 were five times greater than anyone else in that group. In a statement on the data, ASH noted this finding suggests antibodies "may pose a problem only at extremely high levels."
"We'll have to tease apart this data, but it sounds like at least it'll mean that some of the people with [antibodies] could go on therapy," Callaghan said.
|Phenotype||Spontaneous bleeding?||Prophylaxis recommended?||Factor IX activity|
SOURCE: Srivasta A., et al. Hemophilia
On safety, trial researchers recorded 324 adverse events after patients got AMT-061, with 63 of them deemed treatment-related. Three-fourths of the treatment-related adverse events were classified as mild.
Nine patients received steroids to treat liver enzyme elevations, a potential warning sign of inflammation or damage in the organ. All discontinued steroid use before the week 26 cutoff. Callaghan said he thinks 20% of patients on gene therapy needing steroids is acceptable.
The most common adverse events in the trial were influenza-like illness, headache and enzyme elevations.
With these latest findings in hand, UniQure's next task is to gather one year of data for each patient. The company originally set the trial's main goal around Factor IX activity at week 26, but has since added both Factor IX levels and annualized bleeding rates at 52 weeks to its list of primary outcome measurements.
Kapusta said the decision was shaped by conversations between his company and the Food and Drug Administration, which was "very clear about wanting to see a correlation" between the Factor IX levels and the bleeding rates.
Gathering the evidence to support that correlation would have taken nearly as much time as waiting for the one-year data, Kapusta said, so UniQure chose to hold off on moving forward until it had full bleeding data in hand.
The agency's recent rejection of BioMarin's hemophilia A gene therapy, known as Roctavian, didn't play a role in those discussions, according to Kapusta. BioMarin claimed the FDA unexpectedly asked for two years of follow-up data for every patient in the pivotal study of Roctavian, a task it can't complete until late 2021 at the earliest.
While UniQure maintains the lead in hemophilia B gene therapy, a rival treatment from partners Pfizer and Spark Therapeutics, a Roche company, is close behind. There are also therapies from Takeda and Freeline Therapeutics in earlier development.
Ned Pagliarulo contributed reporting