Researchers hope one-time gene therapy ‘amounts to a cure’ for hemophilia B
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The FDA’s decision to approve a one-time gene therapy for adults with moderate to severe hemophilia B could have a considerable impact on the treatment landscape, according to a researcher involved in the pivotal trial for the agent.
“We certainly hope the impact can be what essentially amounts to a cure,” Adam Cuker, MD, MS, section chief of hematology and associate professor of medicine in Perelman School of Medicine at University of Pennsylvania, told Healio. “It’s a one-time therapy that brings the patients’ factor levels up — if not into the normal range, into the range of mild hemophilia — such that they don’t have spontaneous bleeds and seldom or potentially never need treatment.”
The FDA approved fidanacogene elaparvovec-dzkt (Beqvez, Pfizer) in April.
The indication applies to patients who use factor IX prophylaxis therapy, or those who have current or historical life-threatening hemorrhage, or those who have had repeated serious, spontaneous bleeding episodes and do not have neutralizing antibodies to adeno-associated virus serotype Rh74var capsid as detected by an FDA-approved test.
Individuals with moderate to severe hemophilia B often remain at risk for spontaneous bleeding episodes despite prophylaxis with standard IV infusions.
Fidanacogene elaparvovec-dzkt, an adeno-associated virus-based gene therapy, is designed to introduce in transduced cells a functional copy of the factor IX gene encoding a high-activity factor IX variant.
The therapy is intended to help patients with hemophilia B produce factor IX, eliminating the need for frequent infusions that temporarily replace or supplement blood-clotting factor levels.
Healio spoke with Cuker about the approval, the broader impact of gene therapy for hemophilia, and potential barriers to adoption of this treatment modality.
Healio: The FDA based approval on results of the BENEGENE-2 study . What did you see from that trial that is most encouraging?
Cuker: In this study, patients had to be observed on factor prophylaxis for at least 6 months with their bleeds counted. Then they received the gene therapy and had their bleeds counted. There are three key points to be made around convenience, efficacy and safety.
From a convenience perspective, patients who responded had a single infusion of this gene therapy and were able to come off their factor prophylaxis, with many of them not requiring any further factor during the next several years of observation. That’s a huge improvement in terms of treatment burden.
In terms of efficacy, more than half of patients who received the gene therapy had no bleeds during the period of observation. Some patients didn’t respond as well and did have bleeds — and a few patients needed to go back on factor prophylaxis — but the majority responded well.
Lastly, this was a well-tolerated treatment. The most significant side effect was an elevation in liver enzymes, which I see as more of an efficacy issue than a safety issue. It means the immune system is attacking the liver cells where this gene therapy is taking up residence. If that process is allowed to go unchecked, the gene therapy may not work because the immune system will destroy the liver cells where the gene therapy is present.
Patients in whom that occurred had to go on steroids, which have their own side effects. But, ultimately, we’re not talking about permanent damage to the liver. This is about catching an immune response and treating it so you don’t lose gene expression.
Healio: How does this approval contribute to the evolution of gene therapy for hemophilia?
Cuker: In the hemophilia world, we’ve been talking about gene therapy with our patients for many years. A lot of technical hurdles needed to be overcome, and 20 years ago when this first got started, we didn’t necessarily realize it would take this long. Now it’s here, and it’s exciting to be able to tell patients we have FDA-approved gene therapy products for them.
I do want to qualify that this isn’t the first or only gene therapy approved for hemophilia, but having FDA-approved gene therapy for hemophilia in general is certainly a big deal.
A much larger vision, looking across society, is that there are so many people with hemophilia in other parts of the world who don’t have access to factor products. Is there a way that we can bring gene therapy to these patients so that a single treatment could basically amount to a cure for them? Right now, patients in certain parts of the world are currently being treated like patients with hemophilia in the United States were treated 50 years ago.
Healio: Do you see potential barriers to treatment access?
Cuker: There are a couple potential barriers to access. One has to do with insurance. This is an extremely expensive product, so a patient’s insurance company needs to be willing to pay. A second barrier is that patients who have neutralizing antibodies against capsid will be ineligible for this treatment, and that represents a substantial fraction of patients with hemophilia B.
There could be a third barrier that we’re still only sort of learning to navigate, and that is that gene therapy is new for health care institutions. They’re still working out the protocols for giving this high-stakes, expensive therapy and making sure that we do it the right way without any errors. This has taken a really long time and it has slowed uptake of the other FDA-approved gene therapies for hemophilia, but it’s an issue that I believe we’re on our way to overcoming.
It’s a downside to having something new in that the infrastructure to support it doesn’t exist — it needs to be built out — and we’re starting to catch up with that infrastructure now. It’s not something I really anticipated. We treated a number of people in the research trials with gene therapy and that wasn’t any problem, but it’s a different kettle of fish when you’re doing it post-approval and dealing with the barriers of insurance, contracting, and other variables.
For more information:
Adam Cuker, MD, MS, can be reached at adam.cuker@pennmedicine.upenn.edu.
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