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After decades of development, gene therapy appears to be nearing the clinic for hemophilia B, with hemophilia A not far behind.

"This is one of the most exciting times in the course of hemophilia and managing monogenic congenital disease," said Margaret Ragni, MD, MPH, of the University of Pittsburgh Medical Center and director of the Hemophilia Center of Western Pennsylvania in Pittsburgh.

"Especially in hemophilia, gene therapy as well as other novel therapies that are in the pipeline have the potential to greatly reduce bleeding, reduce morbidity, and to reduce cost by eliminating factor treatments, while improving efficacy and quality of care," she told MedPage Today.

After 3 decades of talking about gene therapy and 2 decades of clinical trials in hemophilia, "we've now been able to move towards a safety benefit ratio that I think is going to lead to commercial availability of a gene therapy product for both hemophilia A and hemophilia B in the next probably 12 to 18 months," added Steven Pipe, MD, pediatric medical director of the Hemophilia and Coagulation Disorders Clinic at the University of Michigan in Ann Arbor. "This is the most excited I've been about a truly transformative medicine to come to this field."

Clinical Need

Advances in recombinant factor VIII and IX -- the clotting factors missing in hemophilia A and B, respectively -- have helped in extending the time frame between infusions.

However, patients have still been tied to their prophylactic therapy appointments and damage continues to accumulate from the typically two to five significant bleeding events per year despite them, Pipe noted. Fully restoring coagulation for all patients across the board just hasn't been possible.

But that's the aim of gene therapy, which uses a protein shell from an adeno-associated virus (AAV) to deliver the transgene for factor VIII or IX to hepatocytes, where it goes into the nucleus and uses the natural machinery there to synthesize these factors.

Because people fight off a variety of AAVs starting in early childhood, although not pathogenic, some quarter to half of hemophilia patients are ineligible for gene therapies in development because they have too many antibodies with cross reactivity to the one used by the gene therapy platforms.

Also, a healthy liver is required, with no cirrhosis or fibrosis and eradication of any hepatitis C, Pipe said.

The reason is that a period of immunosuppression is used to reduce risk that the gene therapy won't "take." When the vector's protective protein coat is broken down before the gene therapy vector reaches the hepatocyte, the immune system can learn that it is a foreign invader and then trigger a cytotoxic T-cell attack against treated hepatocytes.

If left unchecked, this immune reaction can kill off the gene therapy-treated cells that are pumping out the clotting factor patients need. And once lost, there's no way to get them back, Pipe warned.

However, for the patients who are eligible, the durable response rate has been high in the clinical trials with current vectors and immunosuppression regimens.

In the recently reported follow-up of a phase I/II trial with Spark Therapeutics' SPK-8011 in hemophilia A, the 16 responders out of 18 treated had a 91% reduction in annualized bleeding events over that period and maintained their expression levels of factor VIII. The other two had immune responses that couldn't be overcome with steroids.

And in Pipe's phase III HOPE B trial, 52 of the 54 patients with moderate to severe hemophilia B essentially experienced a "functional cure" with the etranacogene dezaparvovec vector, with a 91% reduction in bleeding rate over 6 months. The newly reported data at showed superiority in bleeding response compared with factor IX treatment and actually higher mean factor IX activity than at 6 months.

"We have evidence of durable responses from multiple years, out at least 5 years now for hemophilia A and approaching 10 years for hemophilia B," Pipe noted. With the dramatic reductions in bleeding episodes and the vast majority of treated patients no longer needing factor treatment have come big improvements in quality of life, he said.

"What we most commonly hear from patients is their amazement that they don't really have to think about their hemophilia anymore," he added. "I've observed it influencing career choices in younger patients. It's transformed the physical activity levels for many patients who have undergone this treatment. I think I haven't seen another platform of therapy truly change the clinical phenotype like gene therapy can do."

More Work Ahead

However, the knowledge base is also being laid for the next generation of work on gene therapy in hemophilia, noted Lindsey A. George, MD, a hematologist at the Children's Hospital of Philadelphia, who has also been heavily involved in gene therapy clinical trials.

"The main question is how long will this last," she said. "The spoiler is we don't know and we need time."

The data look pretty stable, but two of the hemophilia A trials showed an unexpected decrease by about 40% in factor VIII expression from year 1 to 2, with one showing decline continuing out to 5 years.

While the majority of patients still haven't needed to return to receiving factor VIII treatment despite those declines, Pipe agreed that further data will be helpful.

Modifications to the vectors and to the immunosuppressive protocols continue to be developed, he pointed out. Different AAV vectors with different tropism for the liver that can impact efficient transfection of the liver and potentially improve eligibility for patients with different neutralizing antibodies are in the works, too, he added.

Long-term safety is a question, George acknowledged, because the larger number of treated patients have really only accrued in the last 5 years.

A trial had been put on hold due to hepatocellular carcinoma, which was subsequently confirmed to have arisen independently of the gene therapy, Pipe noted.

The AAV does not integrate into the hepatocyte DNA but rather forms circular DNA episomes in the nucleus. Liver biopsy data have shown that there is a very low rate of integration into the genome -- 0.027% -- which given the large number of particles administered, could still mean possibly millions of integration events in liver cells, Pipe said. Still, the areas that they tend to integrate into are not ones expected to lead to leukemia or other cancers, as had been the case with retrovirus vectors, he pointed out.

While the risk appears to be low, patients will be followed for a minimum of 5 to 15 years in the trials and then until the end of their lives afterward through registries, he added. Patients who receive the commercial products, if they are approved, should also be followed in registries, Pipe emphasized.

Gene therapy likely isn't going to be the right choice for every potentially eligible candidate, George said.

Patients appear to get only one shot at gene therapy for hemophilia, with the technology as it currently is, and the second generation of vectors might be better and more durable, she pointed out.

"It looks really great, it's not perfect. At this point, I think we need to answer some more questions before I would say we should blanket treat all the hemophilia A patients, for example, with this therapy," George said.

"I feel like it's a discussion with patients, what is your risk tolerance?" she added. "Does everyone have a response? Are the levels durable and stable over time? There's variability in the level of expression. What is the role of these neutralizing antibodies? We basically have to have a real conversation with patients ... It's really important they understand what we know and what we don't know to avoid a so-called buyer's remorse."

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