Oncology Frontier: Could you please introduce the concept of gene therapy in hemophilia and specifically for hemophilia B?
Prof. Steven Pipe: The idea of gene therapy research is to develop a one-time treatment that can lead to a steady-state expression of the clotting factors in the blood. To do this, we use an adeno-associated virus vector as the delivery vehicle for a functional copy of the factor gene - the transgene. The vectors naturally home to the liver and the particles are taken up by individual hepatocytes. The vector then delivers this functional copy of the factor gene to the nucleus of the cell. There, the transgene forms circular DNA elements that we call episomes. They persist in the cell and use the normal machinery of the hepatocyte to start to synthesize the factor protein. The cell then secretes that factor into the blood plasma and it reaches up to a steady-state level, and that is what produces the lasting effect for the patient.
Hemophilia B is an inherited bleeding disorder where patients are missing clotting factor IX. This is a critical blood clotting protein. Patients with a severe deficiency of this are at risk for traumatic and spontaneous bleeds, primarily into their joints. With repeated bleeding into their joints, this leads to inflammatory and degenerative changes in the joints that eventually leads to a debilitating arthropathy that can really be crippling and impacts on quality of life. To try to prevent this, patients beginning as young as infants are placed on regular IV infusions of clotting factor IX concentrates. Because of the short half-life of these concentrates, patients need to infuse once or twice a week on average. Prophylaxis needs to be continued lifelong in order to prevent bleeding events and protect joint health over the lifespan. So this is a tremendous burden on the patient and their caregivers. We know even with regular prophylaxis that joint bleeds can still occur and arthropathy can still ensue. We think this is because the blood levels often reach critical low levels just before the next IV infusion. The challenge that gene therapy aims to overcome here is by delivering a functional copy of the factor IX gene into the patient’s own liver. We allow the patient’s liver to make a continuous supply of factor IX that will be delivered in the blood stream. This leads to a steady-state expression of factor IX with levels we hope are close to the normal range, and then patients would no longer be subject to bleeding events and would not require prophylaxis any longer. The real hope from gene therapy is that a one-time treatment would produce a durable and functionally curative level of factor IX in the plasma.
Oncology Frontier: Could you share the study design and result for HOPE-B Gene Therapy Trial and the indication in clinical practice?
Prof. Steven Pipe: The gene therapy etranacogene dezaparvovec uses an adeno-associated virus vector, serotype 5, as the delivery vehicle vector. This has had the viral genes replaced by a functional copy of the human factor IX gene. This transgene has been enhanced by a naturally occurring point mutation that codes for a hyperactive form of factor IX. This is called the Padua variant. This boosts the effective activity of factor IX in the blood plasma 6-8 fold above natural factor IX. This vector is delivered by a single IV infusion in the outpatient setting. What we see within a couple of weeks is that factor IX expression is sufficient to protect patients from bleeding. The subjects in this trial have achieved a mean factor IX activity of 37% at 26 weeks following dosing. The non-hemophilic range starts at about 40%. These levels have remained stable over the course of the study, and the longest follow-up period now has been 18 months. These levels have allowed patients who achieve transduction to cease prophylaxis for the duration of the follow-up period, and the number of treated bleeds fell by 91% compared to a six-month lead-in period when all the patients were on their regular factor IX infusions. There are two additional takeaways from this trial that I think are important. First of all, this study is the first phase III study to report findings on their entire cohort of subjects given gene therapy for hemophilia. It is also the largest cohort of subjects who have received gene therapy for hemophilia to report to-date. The other point is that all AAV5-mediated liver direct gene therapy trials to-date have excluded patients who had pre-existing neutralizing antibodies to the AAV5 vector. Preceding phase I and II studies suggested that pre-existing antibodies to AAV5 would not impact transduction. All the subjects in this trial were tested. They received the dose anyway. Over 42% of the subjects had pre-existing neutralizing antibodies and these had no correlation with any safety or efficacy parameters. The results actually show that we saw effective transduction in patients who had antibody titres as high as 678. These are encouraging results because the ability to treat in the presence of these pre-existing antibodies is going to maximize eligibility for patients.
Oncology Frontier: Could you please introduce the phase II study of Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia A or B, with or without Inhibitors?
Prof. Steven Pipe: The core defect in hemophilia is ineffective clot formation due to insufficient thrombin generation. Fitusiran is a small interfering RNA (siRNA) that is designed to lower antithrombin to then improve thrombin generation and promote hemostasis in people who have hemophilia A or B with or without inhibitors to factor VIII or factor IX. In a completed phase I study, monthly subcutaneous administration of fitusiran was generally well tolerated and it lowered antithrombin in a dose dependent manner resulting in increased thrombin generation and decreased bleeding frequency. The safety, tolerability, pharmacokinetics and pharmacodynamics as well as dosage setting were explored in that phase I program, but then a phase II open label extension study was designed to evaluate the long-term efficacy and safety of fitusiran. This included adult subjects with moderate or severe hemophilia A or B with or without inhibitors. They were on continuous monthly subcutaneous prophylactic dosing at two doses of fitusiran. We have had a total of 34 subjects now who have been followed for a median of 3.1 years on fitusiran dosing , but a maximum of five years. It includes subjects from all the eligible groups - hemophilia A, B, with and without inhibitors. What we see is that antithrombin lowering occurs quickly upon dosing reaching a nadir beyond two-weeks post-dose where there are sustained levels at or below 20% as long as they remain on the subcutaneous prophylaxis. Accordingly, thrombin generation in these individuals is approaching overlapping with normal individuals. Not surprisingly, subjects achieved overall median annualized bleeding rates that are essentially zero for treated bleeds during the treatment period. This was similar for hemophilia A and B, and similar with and without inhibitors. We did analyze the treated bleeds patients had over the course of the observation period, and in general, any breakthrough bleeds were mostly located in joints, mild in severity, and tended to be spontaneous in those patients with inhibitors. What is interesting in this study is that fitusiran improves thrombin generation but it doesn’t treat a patient if the patient has a breakthrough bleed for some reason. The breakthrough bleeds still have to be managed with factor replacement therapy or bypassing agents if they have an inhibitor. Because of the substantially improved thrombin generation, we have to instruct the patients to use modified breakthrough bleed management guidelines that substantially reduces the dose of factor replacement or bypassing agent so they can avoid complications from excessive clotting. Overall, the safety of the patients in the trial have been evaluated. The most common adverse events were elevations in liver transaminases, then headache, as well as injection site erythema. There have been some reported serious adverse events with this therapy however. There was an individual who had an atrial thrombosis, and a death occurred in 2017 due to a cerebral venous sinus thrombosis (initially diagnosed as a subarachnoid hemorrhage where the patient was getting a lot of procoagulant treatment for that but later determined to be a clot). It was actually that case that triggered the revised breakthrough bleeding management guidelines that patients have followed since then. So fitusiran is an investigational siRNA therapeutic that has the potential to be used as a prophylactic treatment for people with hemophilia A and B with and without inhibitors. This monthly fitusiran prophylaxis provides sustained antithrombin lowering in people with hemophilia A and B with or without inhibitors. It results in a low annualized bleeding rate. Patients have now been followed to a maximum of five years. Breakthrough bleeds were generally mild and managed in accordance with the revised bleeding management guideline. Fitusiran is now being evaluated in the ongoing global phase III ATLAS program.