Doctor Center for Bleeding Disorders and Coagulation, Careggi University Hospital Florence, Italy
WHAT IS THE OPTIMAL TREATMENT FOR HEMOPHILIA B: GENE THERAPY Giancarlo Castaman – Center for Bleeding Disorders and Coagulation, Department of Heart, Lung and Vessels, Careggi University Hospital, Florence, Italy
The use of extended half-life (EHL) factor products has led to higher trough levels and reduced the number of intravenous infusions, while maintaining low bleed rates. These products have also enabled the individualization of treatment depending on the patient’s lifestyle, including optimizing factor trough levels or reducing the number of infusions required to minimize treatment burden. Due to the longer half-life of FIX compared to FVIII, there are more options for flexibility of dosing with EHL-FIX replacement products, compared with EHL-FVIII products. Patients with hemophilia B are able to dose once every 7–14 days with EHL-FIX products; selected adult patients also have the option to extend dosing intervals up to 21 days. Despite the positive clinical outcomes with prophylaxis, there remain several unmet needs for patients with hemophilia. Prophylactic treatment is often associated with a high treatment burden because of the requirement for life-long, repeated intravenous injections and adherence issues. Furthermore, this approach also results in fluctuating factor levels with the possibility of breakthrough bleeds when FIX is falling below minimum levels. Repeated breakthrough bleeds can lead to the development of arthropathy, which can impact a patient’s mobility and ultimately their quality of life. Gene therapy appears to be a feasible option for adults with severe and moderately severe hemophilia B. Etranacogene dezaparvovec is an AAV serotype 5 (AAV5) expressing the hyperactive factor IX Padua (FIXPadua) variant. The phase 3 trial enrolled 54 adult patients with FIX level ≤ 2% and showed a promising multi-years’ therapeutic response after a single AAV5-FIXPadua injection, even in individuals with antibodies against AAV5. At year 4 post-treatment, 46/47† (98%) evaluable participants have FIX activity levels ≥5% and 16/47 (34%) evaluable participants have FIX activity levels ≥40% and 96% of patients remained free of FIX prophylaxis. Differently, Fidanacogene elaparvovec, an engineered AAV serotype Rh74 (AAVRh74) to deliver the FIXPadua transgene, has been used only in patients who were negative for neutralizing antibodies against AAVRh74. The phase 3 trial enrolled 45 adult patients with FIX level ≤ 2% and after 15 months of follow-up the mean FIX activity was 26.9% (median, 22.9%), with 64% of patients having zero bleeding. Remarkably however, 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) compared with 17% only of those enrolled in the trial with Etranacogene dezaparvovec. However, with this approach there remain still open issues to address, including high variability in expression, the potential loss of transgene expression over time and the restriction to adults only due to the “dilution” of the non-replicative episomal vector in a growing liver. However, long-term data are required to ascertain the durability of FIX levels achieved and safety. The cost-effectiveness and adoption of innovative payment models for reimbursement are key in choosing gene therapy over existing treatments.
