Comparison of Pharmacokinetics and Pharmacodynamics of Two Anti-CD20 Monoclonal Antibodies (Candidate Biosimilar DRL-Rituximab and Innovator Reference Product Rituximab (Mabthera®) in a Randomised, Multi-Centre, Double-Blind, Parallel Group Study of CHOP with Rituximab Chemotherapy in Patients with CD20-Positive Diffuse Large B-Cell Lymphoma

Abstract Background: DRL-Rituximab (T) is a proposed biosimilar of rituximab. The similarity of DRL-Rituximab andtheinnovator reference products(USA: Rituxan®; European Union: Mabthera® [R]) has been demonstrated in physicochemical analyses and nonclinical studies. This study was undertaken to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T with R sourced from the European Union. Methods: Multiple-center, randomized, double-blind, two-arm, parallel-group study conducted in patients of both genders, aged 18-60 with a centrally confirmed newly diagnosed CD20 positive diffuse large-B-cell lymphoma (DLBCL) in their first line of treatment. Patients were randomized to receive 6 cycles of 21 days either T or R at an initial dose of 375 mg/m2 along with chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone (CHOP). The primary objective of this study was to compare the PK of T and R. One of the secondary objectives was to establish the similarity of T and R in the pharmacodynamic parameters - as B-cell depletion and repletion in peripheral blood using counts of CD19+ positive cells determined by flow cytometry. The PK similarity criterion was that the 90% confidence intervals (CI) of the geometric mean ratios of AUC0-21days, and Cmax in Cycle 1 were within 80.00% - 125.00%. Cycle 1 PK, PD and summary safety results are reported here. Other PK parameters were evaluated as secondary endpoints. Results: A total of 151 patients were randomized to the study (76 to T, 75 to R). After exclusion of 2 patients with very low exposure (results confirmed to be outliers by a z-score higher than 3 and currently under further investigation), both products met the preset Cycle 1 PK similarity criterion (Table 1), with these 2 patients included the Cmax criterion was met, but for AUC the lower limit of the CI was 78.36% (Table 2). PK parameter values were generally comparable (Table 3). For PD both products appear comparable regarding both B-cell depletion and B-cell repletion, both in terms of proportion of patients as well as median time to depletion/repletion. (Table 4 & Figures 1A and 1B) Safety was also comparable between both products. Grade 3/4 Adverse Events (AEs) showed a similar trend in incidence across the two treatment arms [overall: 121 (80.1%); T: 57 (75.0%); R: 64 (85.3%)]. Neutropenia was the most frequently reported of the grade 3/4 AEs, followed by febrile neutropenia, leukopenia, and anaemia. The most commonly reported TEAEs related to the study drug were neutropenia [overall: 48 (31.8%); T: 29 (38.2%); R: 19 (25.3%)] and leukopenia [overall: 24 (15.9%); T: 16 (21.1%); R: 8 (10.7%)]. A total of 5 deaths are reported in the study amounting to 3.3% fatality rate. Conclusion: DRL-rituximab has equivalent PK profile to Mabthera in Cycle 1 when given in combination with standard CHOP chemotherapy for the treatment of CD20 positive DLBCL. PD and safety results are also similar. While awaiting results of further PK/PD data as well as outcomes from this trial, these results are highly encouraging and provide further impetus to development of DRL-rituximab as a candidate rituximab biosimilar. Acknowledgment: We thank all the Principal Investigators for their participation in conducting this study: Dr. Randeep Singh, Dr. Chiramana Haritha, Dr. Asis Mukhopadhyay, Dr. Anup Majumdar, Dr. Shailesh Bondarde, Dr. Rajnish Vasant Nagarkar, Dr. Vijay Ramanan, Dr. Chetan Dilip Deshmukh, Dr. MVT Krishna Mohan, Dr. SVSS Prasad, Dr. Nalini Kilara, Dr. Poonam Patil, Dr. Shekhar Patil, Dr. Neelesh Reddy, Dr. Suresh Sudalaiandi, Dr. Krishnan Srinivasan, Dr. Sundar Subramanian, Dr. VP Gangadharan, Dr. Auro Viswabandya, Dr. Alok Srivastava, Dr. Sharat Damodar, Dr. Rajesh Grover, Dr. Reena Nair, Dr. Bhausaheb Bagal, Dr. Kasi Viswanathan, Dr. Minish Jain, Dr. Jitendra Singh, Dr. Dipti Samanta, Dr. Sudha Sinha, Dr. Lakshmaiah Kuntegowdanahalli, Dr. Rajendersingh Arora, Dr. Sandip Shah, Dr. Shashikant Janardhan Apte, Dr. Mukul Goyal, and Dr. Prasanth Ganeshan. Disclosures Batra: Dr. Reddy's Labs: Employment, Equity Ownership. Lazaro:Dr. Reddy's Labs: Employment, Equity Ownership. Kankanwadi:Dr. Reddy's Labs: Employment, Equity Ownership.

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