Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A

Abstract

Turoctocog alfa pegol (N8-GP, Novo Nordisk, Bagsværd, Denmark), an extended half-life glycoPEGylated recombinant factor VIII (rFVIII), is being developed for prophylaxis and treatment of bleeds in haemophilia A patients. pathfinder™5 is a multinational, open-label, single-arm trial to assess safety, efficacy and pharmacokinetics of N8-GP in paediatric (<12 years), previously treated patients. Boys with severe haemophilia A (<1 % FVIII), no history of inhibitors and previously treated with FVIII products (>50 exposure days [ED] for patients aged 0-5 years [younger cohort]; >150 ED for patients aged 6-11 years [older cohort]) were included. For prophylaxis, N8-GP was dosed at 50-75 IU/kg twice weekly; bleeds were treated with 20-75 IU/kg. Half-life was estimated for the patients' previous FVIII product and for N8-GP. Sixty-eight patients received N8-GP; none developed inhibitors and no other concerns were identified. Median annualised bleeding rate was 1.95 (1.94 and 1.97 in the younger and older cohorts, respectively). Twenty-nine patients (42.6 %; 15 younger and 14 older children, respectively) did not report any bleeding while on N8-GP prophylaxis; 39 patients (57.4 %; 19 younger and 20 older children, respectively) reported 70 bleeds (all mild/moderate). N8-GP treatment was successful for 78.6 % of bleeds in all patients, 80.0 % in younger and 77.5 % in older patients. Most bleeds (80.0 %) were treated with ≤2 injections. Half-life ratio between N8-GP and the patients' previous FVIII product was 1.85. N8-GP was well tolerated and provided effective prophylaxis and treatment of bleeds in paediatric patients with severe haemophilia A.

BAY 94‐9027, a PEGylated recombinant factor VIII, exhibits a prolonged half‐life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies

“…However, indirect comparisons can also provide useful information on the possible trend in PK parameters across products. Based on available published data, BAY 94‐9027 appears to have a comparable or improved PK profile, including t ½ and AUC, in all patient age groups vs other extended‐half‐life rFVIII products by indirect comparison …”

“…Based on available published data, BAY 94-9027 appears to have a comparable or improved PK profile, including t ½ and AUC, in all patient age groups vs other extended-half-life rFVIII products by indirect comparison. 19,20,29,30 During prophylactic replacement therapy, increased time per week spent with low FVIII levels (<1%) is known to be a determinant of breakthrough bleeding risk, especially in children. 31 Similarly, time spent with FVIII levels >20%, high FVIII peak levels and AUC have been associated with reduced bleeding.…”

An overview of turoctocog alfa pegol (N8‐GP; ESPEROCT®) assay performance: Implications for postadministration monitoring

“…While these findings illustrate that PEGylation appears to influence contact activation by silica, it is important to note that there are no clinical consequences of this modification as the efficacy of N8-GP has been demonstrated in a number of studies [13][14][15]. Both PEGylated and unmodified rFVIII products exhibited a similar degree of adsorption to silica particles, suggesting that contact activation may not be blocked through specific adherence of the PEGylated molecule to the silica surface.…”

“…2,6,7 Variations in assay results appear to be related to the type of contact activator used in the APTT reagent, with some silica-based APTT reagents underestimating the activity of extended half-life rFVIII molecules. [13][14][15] N8-GP can be administered every 4th day, reducing the burden of frequent prophylactic treatment. 5 It is therefore important to identify assays that can be used to accurately monitor clinical postadministration samples and to communicate information regarding the most appropriate assays to use for monitoring to the clinical laboratories that perform these tests.…”

Extended Half-Life Factor VIII and Factor IX Preparations

“…In a pediatric cohort (68 PTPs < 12 years), N8-GP was tested in a twice weekly prophylactic regimen [34]. More than 40% of patients did not report any bleeding during trial phase and reported median ABR was 1.95 (IQR 0.00-2.79).…”