Genotype Analysis of Patients with Hereditary Factor X Deficiency Enrolled in 2 Phase 3 Studies of Pdfx, a New High-Purity Factor X Concentrate

Abstract

Introduction: Hereditary factor X (FX) deficiency is a rare, autosomal recessive bleeding disorder of variable severity, with an estimated prevalence of 1:500,000 to 1:1,000,000. Like hemophilia A and B, patients with severe FX deficiency commonly present with bleeding into joints, muscles, or mucous membranes. However, unlike the X-linked disorders of hemophilia A and B, hereditary FX deficiency occurs equally in both sexes due to the location of the FX gene (F10) on chromosome 13q34. A novel, high-purity, high-potency, plasma-derived FX concentrate (pdFX) has been developed for replacement therapy in patients with hereditary FX deficiency. This analysis examines the genotypic and phenotypic characteristics of subjects with hereditary FX deficiency enrolled in 2 prospective, open-label, multicenter phase 3 studies of pdFX. Methods: In study 1, subjects aged ≥12 years with moderate or severe FX deficiency (basal plasma FX activity [FX:C] of ≥1 and Results: Study 1 enrolled 16 subjects (aged 12-58 years [mean 27.1 years], 62.5% female) from the United Kingdom (n=3), Spain (n=4), the United States (n=2), Turkey (n=6), and Germany (n=1); two patients had moderate and 14 had severe FX deficiency. Among the 16 subjects, 13 separate mutations were identified, of which 6 were novel. Nine mutations were missense mutations, 2 were deletions, 1 was a nonsense mutation, and 1 was a splice-site mutation. Consistent with the low FX:C of Study 2 enrolled 2 male subjects (ages 55 years [United States] and 59 years [United Kingdom], respectively), both with mild FX deficiency (basal FX:C of 6 and 8 IU/dL, respectively) and compound heterozygous mutations. Of the 4 mutations identified in these 2 patients, 3 were novel. Of the subjects with moderate or severe FX deficiency (study 1), all 6 Turkish subjects had homozygous mutations resulting in an identical amino acid substitution (p.Gly262Asp). Two subjects in Spain and 1 each in the United States and Germany had mutations resulting in an identical amino acid substitution (p.Gly21Arg); one of these Spanish subjects was a compound heterozygote, with an additional missense mutation of p.Cys246Arg, while the other 3 subjects9 mutations were homozygous. Two UK subjects were each homozygous for 2 different missense mutations (p.Phe71Ser and p.Ile451Phe, respectively), and the remaining 4 subjects each had unique compound heterozygous mutations (p.Val298Met and p.Tyr384Leufs*57 [United Kingdom], p.Glu350Lys and p.Gly450Arg [Spain], p.Cys57Phe and c.70+4A>G splice site mutation [Spain], and p.Gln411* and exon 2 deletion [United States], respectively). The basal level of expressed FX protein (FX:Ag) in 1 patient (87 U/dL) was within the normal range (73-127 U/dL), whereas FX:Ag levels in all other patients (range, Each subject with mild FX deficiency (study 2) had unique compound heterozygous mutations (p.Tyr319His and c.71-1G>C splice site mutation [United Kingdom] and p.Cys90Arg and p.Gln416Leu [United States]). Basal FX:Ag levels in these patients (55 and 48 U/dL, respectively) were close to the normal range. Conclusions: In this analysis, 17 separate F10 mutations were identified in 18 subjects with mild to severe hereditary FX deficiency. Of the mutations identified, 9 are novel and have not previously been characterized. Support: Bio Products Laboratory Ltd. Disclosures Mitchell:Viapath: Employment, Other: employee of Viapath, which received funding from Bio Products Laboratory to perform genetic analysis. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Norton:Bio Products Laboratory: Employment. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Off Label Use: ALN-AT3 is an investigational drug for potential treatment of hemophilia. The data represent phase 1 data..