A Double-blind Randomized Comparative Phase I Study to Assess Biosimilarity and Immunogenicity of "Trastuzumab" (LLC "Mabscale", Russia) and Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland) in Healthy Volunteers

Abstract

Introduction. Trastuzumab is the first drug based on the monoclonal antibodies’ technology targeted to the neu oncogene expression product discovered in the middle 80-s – human epidermal growth receptor, HER2. After being approved trastuzumab had become the drug of choice for combine therapy of metastatic breast cancer (BC). This therapy had also allowed to improve patients’ 5-year survival rate dramatically, almost up to 90 % in some cases. Despite the fact that more than 10 biosimilars of trastuzumab are now in the pipeline around the world, including Russia, the development and registration of trastuzumab biosimilars still remain relevant.Aim. Aim of the study was to conduct the analytical part of the double-blind randomized comparative clinical trial for trastuzumab pharmacokinetics and safety assessment in healthy volunteers with subsequent biosimilarity evaluation of "Trastuzumab" (LLC "Mabscale", Russia) and Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland).Materials and methods. 92 healthy volunteers, who fulfilled the inclusion/exclusion criteria, were enrolled to the study. Trastuzumab quantitation and anti-trastuzumab antibodies detection was performed using ELISA method with photometric detection. To support the clinical trial two different independent bioanalytical methods were validated.Results and discussion. Trastuzumab quantitation method in human blood serum was validated for selectivity, calibration curve and regression model, sensitivity (LLOQ), accuracy and precision, MRD, dilution linearity and stability. The method for anti-trastuzumab antibodies detection, that was previously described by the authors, was validated for cut-point, selectivity, sensitivity, prozone effect, drug tolerance, precision and stability (short-term and long-term). The validated methods were successfully applied to the study samples assay to perform the analytical part of the comparative study for trastuzumab pharmacokinetics and immunogenicity assessment. The obtained drug concentrations were used for PK-parameters and confidence interval calculations to estimate the biosimilarity of test and reference drug.Conclusion. The study results showed that test and reference drug are biosimilar, and moreover immunogenicity assessment showed no anti-trastuzumab antibodies in any samples of healthy volunteers.