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Originally published by 2 Minute Medicine® (view original article). Reused on AccessPediatrics with permission.

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1. A one-time infusion of a recombinant viral vector with a highly expressed factor IX gene resulted in sustained endogenous factor IX coagulant activity among patients with hemophilia B.

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2. Transient and asymptomatic increases in alanine aminotransferase (ALT) were observed in study participants.

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Evidence Rating Level: 4 (Below Average)

Study Rundown:

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Hemophilia B is characterized by a deficiency in clotting factor IX and commonly manifests with hemarthrosis. Current treatment includes regularly administered exogenous factor IX, which requires numerous clinical visits and is not always effective for bleeding prevention. This phase 1-2a study assessed the recombinant adeno-associated virus (AAV) vector SPK-9001, which included a gain-of-function variant gene of factor IX (factor-IX-R338L). The primary objective was evaluation of adverse events, with secondary objectives to evaluate factor IX activity. Of 10 patients treated 40 total adverse events were observed, with the most serious being a transient increase in ALT in 1 patient. Factor IX analysis indicated a one-time infusion of SPK-9001 resulted in sustained endogenous factor IX activity, a reduced need for exogenous hemophilia injections, reduced factor IX consumption, and decreased annualized bleeding rates over the cumulative 52 week follow-up period. These results indicate few adverse effects associated with the viral vector used and suggest a useful hemophilia B therapy. Being a phase 1-2a study, a larger follow-up trial is needed to better monitor the safety profile and long-term efficacy of the SPK-9001 vector.

In-Depth [case series]:

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This multicenter, nonrandomized, open-label phase 1-2 trial recruited 14 men aged 18 to 53 with hemophilia B and less than 2% of normal factor IX activity. Of those enrolled, 10 men ultimately received a one-time intravenous infusion of the AAV SPK-9001 vector with variant factor-IX-R338L gene. Patients were followed for 492 weeks cumulatively after infusion (mean follow-up time 49±13.4 weeks, range 28 to 78 weeks). There were 40 adverse events reported; none were regarded as serious. A transient elevation in ALT over 2.5 times the upper limit of normal was observed in one patient. Another participant also exhibited increased ALT levels though within the normal range. Other adverse events included upper respiratory infections, gastroesophageal reflux, allergic rhinitis, and arthritis, however these were all deemed to be independent to the study intervention.

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Mean (± standard deviation) vector-derived factor IX activity was 33.7±18.5% (range, 14-81) of normal at 52 weeks follow-up. The annualized bleeding rate decreased significantly after vector infusion (mean rate 11.1 events per year before vector infusion [range 0-48 events] vs. 0.4 events per year after administration [range 0-4 events]; p = 0.02). Consumption of factor IX was significantly reduced post-treatment (mean 2908 IU/kg pre-treatment [range 0-8090 IU/kg] vs. 49.3 IU/kg post-treatment [range 0-378 IU/kg]; p = 0.004). Patients required fewer factor IX transfusions after treatment (mean 67.5 [range 0-159] pre-treatment vs. 1.2 [range 0-10] post-treatment; p = 0.004). Collectively, researchers estimated that this experimental therapy led to a savings of $3.6 million in treatment costs that would have otherwise been incurred with exogenous factor IX concentrate administration.

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