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Dr. Pierce began with a brief history and overview. “We have gone from treatment on demand to 24/7 coverage, but curative therapy is the ultimate goal,” he said. “It’s the dream of every affected person to have a cure and it’s been out of reach until now.” He proposed that the definition of a cure is “being free of bleeding and use of any coagulant therapies. We need to take that definition and think about, would an injection every five years, one year, three months, or one week also qualify as a cure if the person was bleed-free between times?”
He described different types of gene therapy, starting with adeno-associated virus (AAV) vector mechanisms. AAV manufacturing has progressed and now is made in 20,000-liter stainless steel bioreactors so all lots are similar, and manufacturing is well controlled. “But we as individuals all have different metabolic parameters,” Dr. Pierce said. “The amount that enters the liver is different in all of us, which leaves much variability. Once in the nucleus, it de-coats and eventually leaves the nucleus and gets into the cytoplasm. We are dealing with a huge inefficiency in delivery.”
Next, Dr. Pierce updated attendees on FVIII transgene modifications. “We are afraid to put this therapy into the clinic because of inhibitors; so much is still untested. It is difficult to make it and transport it, but ET3 is being tested.”
Regarding non-AAV delivery, Dr. Pierce said that lipid nanoparticles can be used as they don’t induce an immune response. “Transposons can deliver FVIII and then transposases can deliver it into the cell,” he said. “Another benefit is that repeat dosing can be done to continue to deliver more FVIII until dose is as the level needed.”
Finally, gene editing is a type of gene therapy where the gene is knocked out, repaired, or a new gene is integrated into the DNA sequence. “Initial work has been done in vivo and is moving toward the clinic,” Dr. Pierce said. “A couple of companies are looking at using B lymphocytes instead of hepatocytes for delivery. Gene therapy is moving fast. A product in the clinic may be eclipsed by tomorrow’s discovery that makes it safer, better and cheaper.”
Dr. Kaczmarek said that the need for better protection from bleeding is driving us to keep pursuing new treatments. “Most individuals in the hemophilia A studies showed liver enzyme elevations in AAV GT clinical trials. There is a highly variable therapeutic response and there is still much we do not know in AAV gene therapy. The advance of gene therapies toward commercialization has outpaced our fundamental biological understanding of AAV gene transfer in humans. The field would benefit from more data sharing and transparency,” he said.
Dr. Reiss focused on the impact of gene therapy for hemophilia on care delivery in the HTC. Two gene therapy products have been approved in the U.S.: etranacogene dezaparvovec-drlb (brand name Hemgenix) for hemophilia B and valoctocogene roxaparvovec (brand name Roctavian) for hemophilia A, she said.
Guidelines, SOPs and open communication with stakeholders will direct HTCs in how to expand comprehensive care within the HTC care model for offering AAV-mediated gene therapy. “The person with hemophilia (PWH) is at the center of the decision-making process on receiving gene therapy. Education and guidance for the whole cohort and the individual PWH is important,” she said.
Dr. Reiss said the HTC team needs to know as much as possible. She referenced the MASAC Document 277 as one place to start. “Things to consider for HTC infrastructure and staffing include having a gene therapy program coordinator; employing a dedicated pharmacist; reference laboratory; diagnostic imaging; interdepartmental and extra-institutional communications and collaborations; the physical location; and short- and long-term monitoring,” she said. “Other considerations surrounding the actual vector product include handling, storage, reconstitution and waste management. These are product-specific.”
“Gene therapy impact on the HTC requires expanding knowledge, care pathways and expanding existing care services,” Dr. Reiss said.
