Hereditary factor X (FX) deficiency (FXD) is a rare autosomal recessive bleeding disorder with an estimated prevalence of 1:500 000-1:1 000 000. The bleeding patterns of FXD are broadly similar to those seen in haemophilia A and B: spontaneous joint and muscle bleeds are common, as are mucocutaneous bleeding (eg, nose, oral cavity and gastrointestinal tract), and there is a significant risk of intracranial haemorrhage. Bleeding can also occur spontaneously, after minor trauma or during surgical interventions. Unlike haemophilia A and B, however, FXD occurs equally among both sexes and affected women and girls also experience menorrhagia. In general, FX activity (FX:C) levels of 10-20 IU/dL are regarded as sufficient to maintain haemostasis, but some individuals may experience significant bleeding despite having FX:C levels above 20 IU/dL.
Until recently, treatment options for factor replacement to treat bleeds in FXD were restricted to fresh-frozen plasma (FFP) and prothrombin-complex concentrates (PCCs), which contain factors II, VII and IX, as well as FX. However, because none of these treatments are specific for FX, they can lead to inconsistent dosing and variable elevations in plasma levels of both FX and other coagulation factors.
Plasma-derived factor X (pdFX) is a novel, high-purity, high-potency FX concentrate approved in the United States for on-demand treatment of hereditary FXD in adults and children (aged 12 years and above) and in the European Union for the prophylactic and/or on-demand treatment of hereditary FXD. The safety and efficacy of pdFX as short-term prophylactic and on-demand treatment for subjects ≥12 years old with moderate and severe FXD has been established,11-13 but data in children <12 years are limited to 3 children who received pdFX on a compassionate use basis. This study was therefore conducted to investigate the efficacy, safety and pharmacokinetics of pdFX in the prophylactic and on-demand treatment of moderate or severe hereditary FXD in children <12 years.
Up to 12 subjects were enrolled to obtain a minimum of 8 evaluable subjects. Children aged <12 years were enrolled if they had a diagnosis of moderate or severe hereditary FXD based on basal plasma FX:C < 5 IU/dL on the lowest recorded FX:C assessment.
In addition, subjects were required to have either a history of severe bleeding or an F10 gene mutation known to cause a severe bleeding phenotype. Subjects were excluded from the study if they had a history of FX inhibitor development, thrombocytopenia or clinically significant renal or liver disease.
Following 6 months of prophylactic treatment, investigators assessed the efficacy of pdFX in preventing or reducing bleeds as “excellent” for each of the 9 subjects, meaning that either the subject experienced no major or minor bleeds or that the frequency of bleeds was lower than expected given the subject’s medical and treatment history. Of the 10 bleeds reported by 3 subjects, 3 were minor traumatic bleeds, 4 were menorrhagic bleeds and 3 were spontaneous nosebleeds, which are common in children even without bleeding disorders.
Across 665 exposure days, no AEs occurred during this trial that were judged by investigators to be related to pdFX treatment. All reported AEs were mild or moderate in severity, and the 2 serious AEs that occurred in 1 subject (mild influenza and moderate lower respiratory tract infection) resolved. During extended prophylactic use of pdFX in subjects who had previously received treatment with other clotting factors—including 3 subjects who had received pdFX for compassionate use prior to study entry—no evidence was seen in this study population for the development of FX inhibitors.
In this study in children aged <12 years with moderate to severe hereditary FXD, pdFX given as routine prophylaxis for 6 months was rated excellent at reducing or preventing bleeding episodes. pdFX efficacy was also rated as excellent for on-demand treatment of both major and minor bleeds. Prophylactic dosing in children <12 years old should therefore be implemented cautiously and closely monitored to achieve the desired trough FX:C level. In summary, consistent with previous findings in subjects aged ≥12 years, these results demonstrate that pdFX was well tolerated, safe and effective among subjects <12 years old.
Haemophilia 2018
Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high-purity plasma-derived factor X (pdFX) concentrate
Liesner R, Akanezi C, Norton M,Payne J.
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