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1 Corr.2*, July 2011. 12. mean ratio (T/R) of AUEC0\last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%\111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one STK3 after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study KRP-203 confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg. Keywords: biosimilars, filgrastim, highly similar, myelosuppressive chemotherapy, neutropenia, oncology, pegfilgrastim, supportive care AbbreviationsADAanti\drug antibodyAEsadverse eventsANCabsolute neutrophil countAUECarea under the effect curveBMIbody mass indexCVcoefficient of variationECLelectroluminescenceELISAenzyme\linked immunosorbent assayEMAEuropean Medicines AgencyG\CSFgranulocyte colony\stimulating factorIVDin vitro diagnosticPDpharmacodynamicsPEGpolyethylene glycolPKpharmacokineticPTspreferred KRP-203 termsQCquality controlSAEsserious adverse eventsSOCSystem Organ ClassTMBtetramethylbenzidine 1.?INTRODUCTION Chemotherapy impacts rapidly dividing cells by directly causing cell death and slowing or stopping proliferation. Due to these effects, many chemotherapy regimens are associated with myelosuppression, resulting in reduced production of neutrophils (and also other blood cells like erythrocytes and thrombocytes). Often such hematological toxicities limit the delivery of the planned dose and intensity of chemotherapy, which is crucial for tumor control and patient survival. In clinical practice, neutropenia is the main limiting factor for the applicability of chemotherapy.1 Thereby, both the duration of Grade 4 neutropenia (defined as absolute neutrophil count [ANC] of <0.5??109/L) and the depth of the nadir after chemotherapy are correlated with the development of infectious complications.2 Thus, an important goal in oncological practice is the prevention of neutropenia when administering chemotherapy. Filgrastim is a recombinant human granulocyte colony\stimulating factor (G\CSF), which stimulates the production of neutrophil precursors, enhances the function of mature neutrophils, and ameliorates neutropenia and its complications.3 Pegfilgrastim is a pegylated form of filgrastim, developed to increase its half\life. Pegfilgrastim retains the same biological activity as filgrastim and binds the same G\CSF receptor. A once\per\chemotherapy\cycle administration of pegfilgrastim was shown to be sufficient KRP-203 to reduce the duration of severe neutropenia as effectively as daily treatment with filgrastim.4 The efficacy and safety of pegfilgrastim (Neulasta) for prevention of chemotherapy\induced neutropenia was demonstrated in two pivotal Phase 3 studies,2, 5 leading to regulatory approval of Neulasta in the US and the EU. Pelmeg (development code KRP-203 "type":"entrez-nucleotide","attrs":"text":"B12019","term_id":"2093139","term_text":"B12019"B12019) was developed as a biosimilar to Neulasta. A comprehensive analytical, functional, and preclinical comparability program has demonstrated KRP-203 a high degree of similarity of Pelmeg to Neulasta.6 In the clinical development program, two comparative studies have been conducted to investigate differences between Pelmeg and Neulasta. The first and pivotal study (“type”:”entrez-nucleotide”,”attrs”:”text”:”B12019″,”term_id”:”2093139″,”term_text”:”B12019″B12019\101) has demonstrated pharmacokinetic (PK) and pharmacodynamic (PD) comparability to Neulasta while using the clinical dose of 6?mg (study B12019\101; manuscript submitted for publication). The second and supportive study (“type”:”entrez-nucleotide”,”attrs”:”text”:”B12019″,”term_id”:”2093139″,”term_text”:”B12019″B12019\102) mainly aimed to confirm PD similarity between Pelmeg and Neulasta at a more sensitive dose, and to investigate any potential differences in immunogenicity, which is considered as a general safety concern common to all therapeutically applied proteins. Various factors were considered when designing this study. The study was conducted in healthy subjects. Compared to cancer patients receiving chemotherapy, healthy subjects lack comorbidities and comedications, and are not immunosuppressed. Thus, they represent the most sensitive study population for conducting the PD comparison. The use of a sensitive population is recommended by the Guideline on similar biological medicinal products containing biotechnology\derived proteins as active substance: nonclinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 Rev 1). Also, regarding the assessment of potential immunogenicity of pegfilgrastim, healthy subjects are considered more sensitive than cancer patients, as the latter have a compromised immune system. In both healthy and patient populations, the mechanism of action of pegfilgrastim is the same, whereby pegfilgrastim elicits its effects on hematopoietic cells by binding to specific cell surface receptors stimulating proliferation and differentiation of committed progenitor cells of the granulocyte\neutrophil lineage into functionally mature neutrophils. Because the bone marrow in a healthy subject population is functionally unimpaired (in comparison with patients undergoing myelosuppressive chemotherapy), the bone marrow of this subject population is expected to be more responsive to stimulation with G\CSF.7 The primary PD parameter ANC is an accepted surrogate marker and can be related to patient outcome to the extent that demonstration of similar effect on the PD marker will ensure a similar effect on the clinical outcome (Guideline on similar biological medicinal products containing biotechnology\derived proteins as active substance: nonclinical and clinical issues, EMEA/CHMP/BMWP/42832/2005 Rev 1). The 3?mg dose was chosen as it was shown to be in the ascending part of the.