Background: The SIPPET study investigated inhibitor development in 251 previously untreated patients (PUPs) treated with either plasma-derived FVIII products containing von Willebrand factor (pdFVIII/VWF; n = 125), or recombinant FVIII (rFVIII; n = 126) from hamster cell lines. Amongst PUPs with non-null F8 mutations, none developed inhibitors when treated with pdFVIII/VWF while the cumulative inhibitor incidence was 43% in those treated with hamster-cell-derived rFVIII. In patients with null F8 mutations, the cumulative inhibitor incidences were 31% and 47% in patients treated with pdFVIII/VWF and rFVIII, respectively. In patients with null mutations the cumulative incidences of high-titre inhibitors were 22% and 30% with pdFVIII/VWF and rFVIII, respectively. Aim: To investigate the relationship between inhibitor development and F8 mutation type in PUPs with severe hemophilia A treated with either a rFVIII from a human cell line (Nuwiq®; simoctocog alfa) or either of two pdFVIII/VWF products, one with a VWF/FVIII ratio of 0.4 (octanate®) the other with a VWF/FVIII ratio of 1.0 (wilate®). Materials and Methods: Data from completed multicenter, prospective trials with octanate® and wilate® and interim data from the NuProtect study with Nuwiq® were analyzed. Data on F8 mutation type were available for 50/51, 27/28 and 58/66 patients in each of the studies. All patients in the three studies had no previous treatment with FVIII concentrates or other blood products containing FVIII. Results: In the three studies, 18% (9/50), 7.4% (2/27) and 19%.0% (11/58) of patients had non-null mutations. None of the patients with non-null mutations developed inhibitors with octanate®, wilate® or Nuwiq®. In patients with null mutations, 9.8% (4/41), 12.0% (3/25), and 17.0% (8/47) developed high-titre inhibitors. Conclusions: PUPs with non-null F8 mutations did not develop inhibitors when treated with octanate®, wilate® or Nuwiq®. Whilst the different studies are not directly comparable, the findings with these products, two pdFVIII/VWF and a rFVIII from a human cell line, show similar behavior to the SIPPET trial where no patients with non-null mutations treated with pdFVIII/VWF products developed inhibitors. Disclosures Liesner: Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Roche: Research Funding; Sobi: Speakers Bureau; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Versteden:Octapharma AG: Employment. Lowndes:Octapharma AG: Employment. Belyanskaya:Octapharma AG: Employment. Oldenburg:Grifols: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Shire: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria.
Introduction/Objective: The development of FVIII inhibitors remains the greatest challenge to the treatment of previously untreated patients (PUPs) with haemophilia A. Uncontrolled studies in PUPs have suggested that immunogenicity of FVIII concentrates varies between different products. In the SIPPET study, the first and only large randomised controlled study to examine the impact of FVIII product type on immunogenicity, the cumulative incidence of high-titre inhibitors in PUPs and minimally treated patients (MTPs) treated with hamster cell-derived recombinant FVIII (rFVIII) products was 28.4%, compared with 18.6% for plasma-derived FVIII/von Willebrand factor (pdFVIII/VWF) products [1]. However, SIPPET did not include all currently available FVIII products, limiting the applicability of its conclusions to the current haemophilia treatment landscape. In previous clinical studies of true PUPs treated with the pdFVIII/VWF concentrates octanate® [2] and wilate®, the cumulative incidences of high-titre inhibitors were 8.0% and 11.3%, respectively. For the human-cell derived rFVIII Nuwiq®, the cumulative incidence of high-titre inhibitors was 12.8% (data from a preplanned interim analysis) [3]. These incidences suggest a favourable immunogenicity profile compared to products in the SIPPET study. However, there is a need for more real-life data on treatment effectiveness and safety in PUPs and MTPs. The ongoing, non-interventional, multi-centre Protect-NOW study is a prospective and retrospective study evaluating real-life treatment patterns, effectiveness and safety, including inhibitor development, in PUPs and MTPs with severe haemophilia A who are treated with Octapharma's pdFVIII or rFVIII products. Methods: One hundred and forty PUPs (no previous treatment) and MTPs (<5 previous EDs with other FVIII products) with severe haemophilia A of all ages and ethnicities will be studied for 100 EDs or up to 3 years. Treatment effectiveness will be evaluated for regular prophylaxis, treatment of bleeding episodes, and surgical prophylaxis. Optional sub-studies, including epitope mapping, detection of non-neutralising inhibitors, and gene mutation analysis, will assess factors potentially associated with inhibitor development and eradication in patients with severe haemophilia A. Optional sub-studies will be carried out at the central laboratory at the Institute of Experimental Haematology in Bonn. Protect-NOW is planned to include around 17 countries and 50 centres worldwide. In the US, the Protect-NOW will be performed as part of the ATHN-8 study. Results: Recruitment is ongoing, with seven patients recruited at two German centres to date. The study has been approved by central and/or local ethics committees in Germany, US, UK, Spain and Russia, and is under ethical review in Canada. Final data collection is expected in 2022. Conclusions: Protect-NOW will collect real-life clinical experience with Octapharma's FVIII products in PUPs and MTPs. This study will contribute real-world data to the current debate on the relevance of FVIII concentrate type in inhibitor induction. ReferencesPeyvandi F et al. N Engl J Med 2016; 374:2054-64.Klukowska A et al. Haemophilia 2018; 24:221-28.Liesner R et al. Haemophilia 2018; 24: 211-20. Disclosures Oldenburg: Novo Nordisk: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Pavlova:Octapharma: Honoraria; Novo Nordisk: Honoraria. Halimeh:Bayer healthcare, Baxalta Innovations, Biotest, CSL Behring, Novartis, Novo Nordisk, Octapharma, LFB, Pfizer: Honoraria; Bayer Healthcare, Baxalta Innovations, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer: Research Funding. Klamroth:Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Research Funding; Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Consultancy. Versteden:Octapharma AG: Employment. Jansen:Octapharma: Employment. Belyanskaya:Octapharma AG: Employment.
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