Safety and efficacy of KOGENATE^® Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs)

Abstract

Safety and efficacy of KOGENATE Bayer (Kogenate FS), a second-generation full-length recombinant factor VIII formulated with sucrose as stabilizer and produced without the addition of human albumin during purification and the final formulation, was assessed in a prospective, international clinical trial including 31 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe haemophilia A in home therapy and surgery. Factor VIII inhibitor development was monitored and mutation type profiles were analysed. As of 30 June 2000, the patients received a total of 2.729 infusions (mean 88; range 6-274) for bleeding episodes, surgery or prophylactic treatment. No unexpected drug-related adverse events were observed. Four patients developed an inhibitor after 3-12 exposure days (EDs). One patient successfully underwent immune tolerance treatment; inhibitors in two patients disappeared spontaneously with on-demand treatment, while the inhibitor titre remains low in one patient. Twenty-nine patients (93%) with more than 20 EDs can be regarded as at low risk for inhibitor development. In conclusion, KOGENATE Bayer is efficacious and well-tolerated for treatment of children with severe haemophilia A. The incidence of inhibitor formation is not different to that observed with other recombinant or plasma-derived products.

Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A

“…Metaanalysis of the RODIN and FranceCoag results showed a concordant and significant 60% higher risk with Product D compared with Product E for the all inhibitors and high-titer inhibitors outcomes. In contrast, in the literature only 9 (15%) of 60 PUPs and minimally treated patients enrolled in registration trials of Product D developed inhibitors, 23,24 and postmarketing studies showed even lower rates (supplemental Table 21). 25,26 One key difference with cohort studies is that patients are not selected, whereas clinical trials exclude some patients at an increased risk of inhibitor development, such as those requiring intensive initial treatment because of early severe bleeding.…”

“…This result, which represents one of the highest rates observed in an industrialized country, 27 23,24 During this period only the main genetic risk factors for inhibitor development were identified in PUPs. In our study, slightly higher proportions of patients with a high-risk F8 gene defect and a family history of inhibitors were observed among PUPs treated with Population: boys with severe HA (FVIII activity ,0.01 IU/mL) first treated with rFVIII and treated with Products A, C, D, or E within the first 75 EDs (n 5 287).…”

“…We combined HRs for Product D compared with Product E (D/E) from the RODIN study and our study using indirect log HR and variance estimation 21 BLOOD, 27 NOVEMBER 2014 x VOLUME 124, NUMBER 23 …”

Haemophilia in the first years of life

“…Older anecdotal publications suggest that the significant morbidity and mortality associated with high risk surgery may increase substantially for children who are co-afflicted with haemophilia, due to either the lack of diagnosis and/or inadequate factor replacement. Conversely, pre-and postlicensure studies of recombinant and plasma-derived factor VIII and IX concentrates, as well as the more recent anecdotal surgical literature, document that once the diagnosis is made and an appropriate prophylactic replacement strategy is implemented, complex surgery can be performed safely with a minimally increased risk of haemorrhage [3][4][5][6][7][8][9]. Minimum effective factor dosing also limits surgical haemorrhage in the developing world where resources are limited [10].…”

Haemophilia Treatment – Current and Future Challenges

“…While modern production methods for plasma-derived concentrates are fairly safe, pharmacovigilance remains of the utmost importance. Parvovirus B19 (PVB19) can exhibit resistance to the heat treatment and solvent/detergent treatment used for viral inactivation or elimination in the manufacture of plasma-derived products, 8 10 In spite of the aforementioned issues with prophylaxis, the primary concern for physicians nowadays is undeniably the development of inhibitors. Much research has focused on this aspect; studies have shown that although there are elements that can increase the risk of inhibitor development, 9,11 there is a notable benefit for prophylaxis, where the risk of inhibitor development is 60% lower compared with that seen with on-demand treatment.…”