Gene Therapy for Hemophilia Gains Ground


After a checkered past, gene therapy for hemophilia A and B is finally scoring some clinically meaningful successes, according to leading researchers in the field. Hopes are high that the promising results, most recently seen in Phase I/II trials, will progress to Phase III trials and then the clinic setting.

“The current landscape of gene therapy for hemophilia A and B is quite promising,” said Lindsey George, MD, an attending physician in the Division of Hematology, Children’s Hospital of Philadelphia. “The most progress in clinical gene therapy has been made in hemophilia B,” she noted, adding that currently, there are four active clinical trials recruiting such patients for the treatment.

Dr. George said gene therapy has the potential to be a treatment-changing paradigm—one that can achieve sufficient hemostatic improvement to help patients live functional lives equivalent to someone without a bleeding disorder (Semin Hematol 2016;53[1]:46-54). Despite dramatic improvements in hemophilia care, the defined terminal half-life of traditional factor replacement products requires infusions approximately two to three times per week. Gene therapy offers the possibility of replacing this burdensome routine.

Hemophilia gene therapy trials began more than 20 years ago. Gene therapy research stumbled after the death, in 1999, of a patient in a gene therapy trial for ornithine transcarbamylase deficiency. It wasn’t until 2011 that the first successful human clinical trial for hemophilia was reported in The New England Journal of Medicine (2011;365[25]:2357-2365). In this study, an adenovirus-associated virus vector (AAV)-mediated gene transfer resulted in human factor IX (FIX) transgene expression at levels sufficient to improve the bleeding hemophilia B phenotype, with few side effects. Although early work in hemophilia gene therapy included in vivo and ex vivo hemophilia A and B trials using various vector approaches, more recent clinical investigation has focused on the use of AAV-mediated gene transfer for hemophilia B.

In 2014, another important study involving 10 patients with severe hemophilia B showed that the infusion of a single dose of AAV8-mediated in vivo FIX gene transfer resulted in long-term therapeutic FIX expression associated with clinical improvement. No late toxic effects were found in a three-year follow-up (N Engl J Med 2014;371[21]:1994-2004).

Dr. George said ultimately, the hope is that lessons learned from hemophilia B trials will translate to successes in hemophilia A, although there are additional obstacles specific to hemophilia A. These include designing a vector cassette to accommodate a larger cDNA, avoiding development of inhibitory antibodies and ensuring adequate expression efficiency.

Other challenges in gene therapy for hemophilia, experts noted, include overcoming the cellular immune responses to the AAV capsid; preexisting AAV-neutralizing antibodies, which immediately exclude approximately 50% of the target population; and the ability to scale up vector manufacturing for widespread application.

Dr. George echoed the point that gene therapy, as it currently stands, is a mixed bag. “Early clinical trial success is promising, but needs to be recapitulated to demonstrate continued safety and efficacy,” she said. Still, “many in the field are hopeful gene therapy will be in broader clinical use within the next decade.”

As far as widespread clinical use, “this is not clear and is dependent on a number of factors, including demonstrated sustained expression of the transgene, continued safety, scaling up of vector production and efforts to train providers to care for patients who receive gene therapy,” Dr. George said. “The time frame for general use appears shorter for factor IX than factor VIII, but I expect there will be additional trials for hemophilia A gene transfer in the near future.”

She added that a well–laid-out path is lacking for gene therapy products to gain approval in the United States; the first and only single gene therapy product licensed is in Europe and treats lipoprotein lipase deficiency.

A Pharmacist’s Perspective

Sheh-Li Chen, PharmD, BCOP, a clinical pharmacy specialist in benign hematology at the University of North Carolina Medical Center, in Chapel Hill, said she doesn’t expect to see gene therapy in the clinic soon except in the context of a clinical trial. “The various studies in both FVIII and FIX gene therapy have demonstrated a huge variation in the sustainability of the factor levels after the therapy,” she said. “There are a lot of issues that still need to be worked out.”

She said the most successful gene therapy trial she has seen so far is a Phase I/II open-label trial of BAX335 (Baxter), an AAV8 vector. At the 2015 Congress of the International Society on Thrombosis and Haemostasis, a study showed that two of three subjects who received BAX335 remained free of spontaneous hemorrhage without the need for regular FIX infusions (abstract LB101).

Dr. Chen said although gene therapy has the potential to offer a cure for hemophilia, researchers are exploring other avenues, including “the novel nonfactors like the monoclonal antibody to TFPI [tissue factor pathway inhibitor], the ACE910 molecule [which mimics FVIII function, but is distinct in structure and antigenicity] and inhibitors against antithrombin.”


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