Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study

Abstract

For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate(®) is a plasma-derived, human, von Willebrand factor-stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate(®) in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate(®) dose change. All inhibitors developed under on-demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate(®). Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22-inversions or large deletions. Octanate(®) was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate(®) in prophylaxis and treatment of bleeding were generally rated as 'excellent', and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (± 0.6) % IU(-1) kg(-1) . These interim results indicate Octanate(®) to be an efficacious, well-tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.

The role of previously untreated patient studies in understanding the development of FVIII inhibitors

“…PUP inhibitor rates from these studies range from 10 to 33%, but numbers are not directly comparable. Baseline risk factors (ethnicity, family history of inhibitors and severity of disease) for inhibitor development have differed substantially across these studies (Table A) . After controlling for ethnicity and family history, inhibitor rates in subjects with low‐risk genetic profiles (caucasians with negative family history of inhibitors) were generally similar across the evaluated studies (8–11%; Table ).…”

Searching for the role of primary prophylaxis in preventing inhibitor development in hemophilia A

“…Of them, 24 were further excluded because the relevant data were unavailable or because analyzed patients were included in other published studies or because the study design did not permit a pooled analysis of the data. Finally, 27 studies with usable information (15 prospective, 11 retrospective and one retrospective/prospective), published between 1996 and 2011, were included in this systematic review [8,10,12,14–37], as reported in Table 1. Statistical analysis was performed using the chi‐square test.…”

Hemophilia Inhibitors Prevalence, Causes and Diagnosis

“…The studies of patients treated with a single plasma-derived high purity antihemophilic factor concentrate containing vWF (Alphanate ® , Humate-P ® , Koate ® -HP) showed the incidence of inhibitors in the range from 0% to 12.4% (45,46 47, 48 ,49). Most of the current high purity pd-FVIII products carry almost 0% risk of inhibitor formation (50,51). There is data supporting the protective effect of vWF, a carrier protein of FVIII which is present in a large amount in most pd-FVIII products but not in rFVIII, on inhibitor formation by reducing the immunogenicity of FVIII through preventing its entry into professional antigen presenting cells (52).…”