Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura

Abstract INTRODUCTION Immune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by immunoglobulin G (IgG) antibodies. These antibodies target the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which is vital for cleavage of von Willebrand factor. The resulting ADAMTS13 deficiency leads to microthrombi through platelet aggregation to Ultra-Large von Willebrand factor. If untreated the mortality rate in iTTP is in excess of 90%, but the use of plasma exchange (PEX) and immunosuppression has significantly reduced this (to between 10%-20%). Rituximab (a humanised anti-CD20 antibody, MabThera; Roche Pharmaceuticals), is now used routinely in iTTP in relapsed/refractory patients, but also acutely to prolong disease free-survival. The pre-emptive administration of rituximab in patients with a low ADAMTS13 has been shown to be effective in preventing clinical relapse. In 2013 the patent for rituximab expired in Europe and will expire in 2018 in the United States. The European Medicine Agency has now approved two Rituximab biosimilars for use in Europe. Biosimilar products are designed to have no meaningful differences from the reference/originator product. Truxima (CT-P10, a rituximab biosimilar) is approved for the treatment of RA, CLL and NHL in Europe, and we began using Truxima in iTTP in May 2017. Many other rituximab biosimilars exist and are in development. METHODOLOGY Here we report a retrospective cohort study of our patients with iTTP. Data from 84 patients was examined from a two-year time period May 2016-and May 2018, based on our pharmacy registry (having switched to the rituximab biosimilar in May 2017). 45 patients were treated with MabThera and 39 with the rituximab biosimilar Truxima. Laboratory parameters recorded included the patient's platelet counts, ADAMTS13 activity, and CD19 levels at D1, D28 and 3months following treatment. In addition, adverse reactions, and infective complications following treatment were also recorded. Statistical analysis was performed and means +/- 90% confidence interval calculated, with clinical equivalency compared based on clinically significant values. RESULTS Following MabThera/Truxima administration on D1, at 28 days the mean platelet count (+/- SEM, x10^9/L) was 263.3 (+/-10.69) in patient treated with MabThera and 263.8 (+/-11.81) with Truxima (90% CI -24.95 to 27.91), and remained similar at 3months at 275.8 (+/- 10.05) and 275.9 (+/- 12.2) respectively (90% CI -25.96 to 26.2). The ADAMTS13 (+/- SEM) at 28 days was 50.87 iu/dL (+/-4.899) in patients treated with MabThera and 50.88 iu/dL (+/- 4.371) for Truxima (90% CI 11.01-11.03), rising to 85.4 iu/dL (+/- 5.237) and 81.35 iu/dL (+/- 4.549) respectively at 3 months (90% CI 15.84-7.71). CD19 levels at 28 days in patients treated with MabThera had fallen to 0.00259 (x10^9/L)(+/- 0.00049) and 0.02151 (+/- 001161) with Truxima (90% CI 0.00073 to 0.037120), and were 0.01782 (+/- 0.01033) and 0.02098 (+/- 0.01042) respectively at 3 months (90% CI -0.02139 to 0.02771), all demonstrating a marked reduction from baseline means of 0.3247(+/-0.05721) and 0.2456 (+/-0.03016) respectively. The median number of infusions in both groups was 4 (range 1-8). Infusion reactions were comparable between both groups, with infusion reactions occurring in 33% of the MabThera treated patients, and 40% in the Truxima group. Infective complications (principally urinary tract infections) were comparable between both groups, 15% in the MabThera group and 18% in the truxima cohort. The mean saving per patient per treatment course cost was >£4000. DISCUSSION Rituximab is now off patent in Europe, and the EMA approval of Biosimilars offers an opportunity for significant cost savings as demonstrated here. Rituximab has been well established in iTTP, and rituximab biosimilars have demonstrated equivalence to the originator in rheumatoid arthritis and follicular lymphoma. Here we report the first published series of the rituximab biosimilar Truxima in iTTP, and demonstrate equivalence in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at 28days and 3 months post administration, in addition to showing comparable infusion and infective complications. Disclosures Cheesman: Celltrion: Other: Speaker Fee; Roche: Other: Advisory board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau.