Gene therapy for hemophilia is starting to come of age and promises to transform the way patients with this rare blood disease are treated.
“The concept of gene therapy has sort of been at the root of where we’ve been heading in the treatment of hemophilia from the very beginning,” Steven Pipe, MD, of the University of Michigan in Ann Arbor, told MedPage Today.
Usually an inherited disorder, hemophilia patients have a defective gene that causes them to lack proteins necessary for blood clotting — factor VIII in the case of patients with hemophilia A, or factor IX in the case of hemophilia B, Pipe pointed out.
“In the recombinant DNA era, we’ve been taking a good copy of the factor VIII and IX gene and putting it in cells, and making recombinant copies of factor VIII or IX replacement protein that patients have been infusing,” he said. “That kind of replacement therapy has been the foundation for how we’ve treated hemophilia now for several decades.”
With gene therapy, the concept remains the same, Pipe explained: “If we can get a good copy of the factor VIII or IX gene to the patients’ own cells, then they could make their own factor VIII or IX and also maintain steady-state levels. And that really has been an aspirational goal — to see this happen in hemophilia.”
From a safety and efficacy standpoint, the gene therapy platform that is clearly the most promising is the adeno-associated viral (AAV) vector.
In a landmark study presented at the 2011 American Society of Hematology (ASH) meeting and published in the New England Journal of Medicine, Nathwani and colleagues reported that a one-time infusion of AAV vector-expressing factor IX led to sustained increases in factor IX production in six patients with severe hemophilia B.
This approach “gives us an opportunity to do the gene delivery in a targeted fashion to the liver,” said Pipe. “And the clinical trial results in the past 10 years have shown we can do this safely, and we can achieve [factor activity] levels that are transformational for patients from a phenotype perspective.”
What became clear, Pipe added, was that the success of gene therapy would come out of a partnership between bioengineered molecules and a gene therapy delivery platform such as AAV.
Pipe is the principle investigator of uniQure’s phase III HOPE-B pivotal study of AMT-061, an investigational AAV-based gene therapy incorporating the factor IX-Padua variant for the treatment of patients with severe and moderately severe hemophilia B.
The company’s ongoing phase I/II trial of its first-generation AAV-based gene therapy, AMT-160, consists of an AAV5 vector carrying gene cassette with the standard wild-type factor IX gene.
While that earlier trial has been successful, Pipe noted that by substituting the bioengineered Padua variant — which generates a hyperactive form of factor IX — for the wild-type factor IX gene, investigators have been able to achieve factor IX levels of 25% to 50% of normal with AMT-061, compared with levels of 5% to 10% with AMT-060.
Another gene therapy for hemophilia B, SPK-9001, is being developed by Spark Therapeutics and Pfizer and is based on the Padua variant. The therapy has proven to be effective in reducing bleeding and factor IX infusions in phase I/II and is now in phase III testing.
“We had sustained expression of factor IX — an average of 35% for 15 hemophilia B patients,” said principal investigator Lindsey George, MD, of Children’s Hospital of Philadelphia. “From a safety standpoint there were no major safety concerns, and no adverse events.”
“We know with hemophilia that the clinical phenotype is closely correlated with what your factor activity is, so with mean factor levels of 35% we weren’t surprised to see a dramatic alteration of the phenotype in patients,” she told MedPage Today, noting that there was almost a complete resolution of bleeding, with one patient having a bleeding event that was remarkably reduced from his baseline.
“And then along those same lines there has been virtual elimination of the requirement of factor use, which is the traditional standard of care for hemophilia,” George said. “So, the efficacy has been particularly striking.”
“This partnership between these bioengineered molecules and the AAV platform is proving to be very successful,” said Pipe. “And we are seeing the same thing happen with factor VIII.”
George is also the principle investigator for Spark’s SPK-8011 phase I/II trial for hemophilia A, for which preliminary data was reported at the 2018 ASH meeting.
She noted that no safety concerns have emerged in the trial and that from the preliminary efficacy data, even the expression of a modest amount of factor results is a “really impressive improvement in the clinical phenotype,” similar to what has been seen in the hemophilia B study.
With these advances in gene therapy, is it too early to talk about a cure for hemophilia?
“It always makes me nervous to say ‘clinical cure,'” said George, who pointed out that investigators still don’t have information about the duration of expression in patients treated with these therapies. But she added that the men from the first successful hemophilia B trial have had stable expression for about 10 years, and this duration of expression has also been observed in large animal models.
“It’s reasonable to predict you would have some sustained expression from the therapy throughout your adult lifetime, but guaranteeing your factor level would be X percent throughout your lifetime is where the question mark is,” she said.
However, she noted that the men in that hemophilia trial haven’t had bleeding events and haven’t had to use factor. “From a clinical standpoint they really haven’t had any manifestations of their hemophilia, so I guess you could characterize that as a phenotypic cure,” she said. “But, I think we need more time before we can say that with complete confidence.”
Pipe also noted that researchers are working on different iterations of AAV, “which will give us some needed choice related to the eligibility of patients.”
Eligibility for gene therapy is a potential barrier for hemophilia patients because AAVs are viruses that can produce an immune response in patients — perhaps in as many as half of patients.
“With some additional engineering some companies have been able to reduce the screen failures for clinical trials — getting it downwards to 25% to 30%,” said Pipe. “That’s still a disappointing impairment for enrollment in clinical trials. That’s why we are excited to see multiple capsid platforms being developed in the research community, because we anticipate we are going to need multiple versions of these AAV vectors to maximize the eligibility for patients.”
As for the eventual commercialization of a gene therapy product, George predicted there is likely to be a licensed product available within 2 to 5 years. “My guess is there will be quite a few licensed products for hemophilia A and B that over time will really have the potential to alter the paradigm of how we treat hemophilia patients,” she said.
Pipe disclosed relationships with Bayer, BioMarin Pharmaceutical, Bioverativ, CSL Behring, Novo Nordisk, Pfizer, Roche, Spark, Shire, and uniQure N.V.
George reported relationships with Spark Therapeutics and Pfizer.