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Potential improvements in quality of life for hemophilia patients using adeno-associated virus mediated gene transfer

Preliminary data from an ongoing Phase I/II trial suggest that patients with hemophilia B, who are born unable to produce the blood-clotting protein factor IX (FIX), began producing FIX at sufficient levels after receiving a single infusion of an investigational gene therapy product called SPK-9001. The results show the highest and most consistent levels of FIX production of any gene therapy tested to date. The levels of FIX:C achieved by SPK-9001 permitted termination of prophylaxis, prevention of bleeding, and nearly complete cessation of factor use. Despite the heterogeneity in subjects with respect to presence and extent of hemophilic arthropathy, age, and co-morbidities, consistency of transgene expression and clinical outcomes have been observed in all participants studied to date.

FIX is crucial to the formation of blood clots and to the prevention of life-threatening uncontrolled bleeding. Earlier data demonstrated long-term expression of factor IX following AAV8-mediated gene transfer at 2 x 1012 vg/kg in hemophilia B. While the clinical improvement imparted by stable FIX levels is clear, these levels of expression fall short of trough values obtained by long-acting FIX prophylaxis and of natural history data suggesting that levels of approximately 12% are required to prevent minor, chronic bleeding in the joints, a common cause of disability in patients with hemophilia. Unfortunately, achieving higher levels of FIX:C with dose escalation has not been possible without eliciting a dose-dependent, capsid-specific immune response that may prevent sustained expression and efficacy. In this light, researchers sought to develop a highly efficient vector capsid and expression cassette that could be administered at low doses to achieve hemostatic FIX expression without the need for immunosuppression.

SPK-9001 uses an inactive virus to deliver into a patient’s cells a small section of DNA that, when stabilized in the patient’s own liver cells, allows the body to produce FIX. Current standard of care for hemophilia B requires patients to self-administer intravenous infusions of laboratory-produced FIX at regular intervals, typically one to two times a week. A key downside of this standard regimen is that it causes FIX levels to fluctuate widely, and patients may need to limit their activities to avoid breakthrough bleeding when their FIX levels are low.

The presented ongoing study enrolled nine, previously treated, adult patients with a baseline FIX level of less than 2%. As of the November 30, 2016, data cut off, seven of the nine patients who have progressed to at least 12 weeks post-vector administration showed FIX levels in the range of 12 to 46% with a mean steady-state level greater than 28%, a range the researchers say is close enough to normal (at least 50% in healthy adults).

The FIX levels achieved with SPK-9001 to date in this study have been sufficient to allow patients to engage in normal daily activities without the need for FIX infusions. Two participants recently suffered an autoimmune response and were put on corticosteroids. Despite the immune response and decline in FIX activity level, these two participants have not had any bleeds or required replacement FIX. Eight of the infused patients did not require factor IX concentrates to prevent or control bleeding events since the day after vector administration. One participant with severe joint disease self-administrated a precautionary infusion two days after administration of SPK-9001 for a suspected ankle bleed and again at week 35 post the data cut-off date and despite a factor IX activity level of 36, for a suspected knee bleed. In total, 6 patients reported an increased physical activity and an improved quality of life. The 4 subjects previously maintained on prophylaxis were able to safely stop this treatment, without breakthrough bleeding.

In summary, preliminary data suggest SPK-9001 safely and consistently produces sustained elevation in FIX levels sufficient to prevent spontaneous hemarthroses, without the need for factor consumption or immunosuppression. At the factor IX levels seen in this study, most normal activities of daily living should be open to people with hemophilia.


George L, Sullivan S, Giermasz A, et al. SPK-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B Achieves Sustained Mean Factor IX Activity Levels of >30% without Immunosuppression. Presented at ASH2016; Abstract 3.


Speaker Lindsey George


Lindsey A. George, MD,
Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania and Division of Hematology, The Children's Hospital of Philadelphia,, Philadelphia, PA, USA.


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