Progress in the development of investigational gene therapies for hemophilia has generated much buzz in recent years, and for good reason — safe and effective gene therapy may provide patients with a new treatment option that could potentially improve their clinical outcomes and quality of life.1 Still, several challenges and important questions remain.1
Bruce Ewenstein, M.D., Ph.D., Vice President and Head of Clinical Sciences for Hematology at Takeda, has spent decades researching and practicing hemophilia care. His current research includes studying gene therapy for hemophilia, and he recently discussed some of the outstanding questions and considerations surrounding hemophilia gene therapies.
Question: To start, can you please explain to us how adeno-associated virus (AAV) gene therapy for hemophilia is hypothesized to work?
BE: To develop and deliver a gene therapy to a hemophilia patient, a normal copy of the gene missing in these patients – either the factor VIII gene (F8) or factor IX gene (F9) – is packaged into a delivery vehicle called a vector.2 Recombinant AAV, particularly AAV5 and AAV8 serotypes, serves as the vector in most of the ongoing hemophilia studies.3 The AAV vector carrying the normal gene is administered to the patient, generally using an IV infusion, for ultimate delivery to the patient’s liver cells.1 These cells, which are now equipped with the normal F8 or F9 gene, may now potentially produce the necessary coagulation factor VIII or factor IX protein to allow the patient’s blood to clot normally.1
Question: It’s known that pre-existing immunity to AAV vectors can exclude hemophilia patients from gene therapy trials.3 What’s the latest research on pre-existing immunity, as well as potential solutions?
BE: AAV is a common, harmless virus in our environment, resulting in many people having already been exposed to it.4,5 Because of this, a rather large proportion of the general population is known to have measurable anti-AAV antibodies as well as capsid-specific memory cells, which results in B cell and T cell immunity to AAV.3 This pre-existing immunity neutralizes the AAV vector’s ability to enter the liver cells and deliver the gene therapy.3 At Takeda, we recently conducted a study to better understand the co-prevalence of pre-existing immunity to common AAV vectors and found that approximately 50% of adult hemophilia patients have pre-existent neutralizing antibodies to AAV2, AAV5 or AAV8, and 40% have co-prevalence to all three.3 Similar percentages of patients showed a positive cellular response to AAV8 antigens.3
To develop a new strategy for evading pre-existing immunity to AAV8 vectors, which are utilized in Takeda’s investigational gene therapies for hemophilia, we are also developing an AAV8-specific immune adsorption column (IAC) to remove anti-AAV8 antibodies.6 The hope is that this approach will enable hemophilia patients with pre-existing immunity to AAV8 vectors to participate in future gene therapy trials and be eligible to receive gene therapy once the products are licensed.6
Question: It’s also known that investigational gene therapies are not a “cure” for hemophilia.1 What are the potential benefits of these therapies, and how long may they be effective?
BE: The bar has been set high for hemophilia gene therapies, as there are already highly effective and well tolerated treatments available for hemophilia patients with and without inhibitors.7 Still, even the longest-acting factor concentrates and mimetics require ongoing administration.8 With gene therapy, patients would ideally achieve sustained factor levels over multiple years, which would potentially eliminate spontaneous bleeds and the need for frequent factor infusions.9,10
Question: How do investigational gene therapies compare to factor replacement therapy?
BE: With factor therapy, the goal is to maintain a high-enough level of factor to protect a patient from bleeds, but there will always be peaks and troughs to a patient’s factor levels.11 With gene therapy, the goal is to maintain a prolonged, sufficient level of factor that doesn’t go through peaks and troughs.12 That said, not every patient is eligible or ideally suited for gene therapy, and thus, factor replacement therapy will continue to be a valued and necessary treatment option in hemophilia care in the foreseeable future.1
Question: What other major considerations should physicians and their hemophilia patients be aware of when it comes to gene therapy?
BE: The recent advances in gene therapy for hemophilia are incredibly exciting, but we’re still at the beginning of a journey.1 Uncertainly persists around the variability in hemophilia patients’ responses to investigational gene therapies, as well as the therapies’ durability.1 It also remains to be determined whether the therapies currently in clinical trials can be used with certain patient populations, such as the very young and those living with co-morbidities.1 Despite these challenges, I see far more reasons to be optimistic than not.