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Granulocytes Stockholm, Sweden, June 13–16, 2013 Granulocytes P1024 LIPEGFILGRASTIM–A LONG-ACTING, ONCE-PER-CYCLE, GLYCOPEGY - LATED RECOMBINANT HUMAN FILGRASTIM CREATED WITH SITE-SPE - P1022 CIFIC GLYCOPEGYLATION TECHNOLOGY C Scheckermann 1,* , K Schmidt 1, A Abdolzade-Bavil 1, H Allgaier 2, U Mueller 3, IMMUNOGENICITY OF LIPEGFILGRASTIM AND PEGFILGRASTIM IN W Shen 4, P Liu 5 BREAST CANCER PATIENTS RECEIVING CHEMOTHERAPY: INTEGRAT - 1BioGeneriX GmbH, 2Merckle Biotec GmbH, 3Teva GmbH, Ulm, Germany, ED ANALYSIS FROM PHASE II AND III STUDIES 4Teva Pharmaceuticals, West Chester, 5Teva Pharmaceuticals, Washington A Abdolzade-Bavil 1,* , L Zou 2, C Sadhu 3, A Buchner 4, P Liu 3 DC, United States 1BioGeneriX GmbH, Ulm, Germany, 2Teva Pharmaceuticals, Rockville, 3Teva Biopharmaceuticals, Washington DC, United States, 4Teva ratiopharm, Ulm, Background: Lipegfilgrastim is a once-per-cycle, fixed-dose glycoPEGylated Germany granulocyte-colony stimulating factor (G-CSF) under development for the preven - tion of severe neutropenia in cancer patients receiving chemotherapy (CTx). Tra - Background: Lipegfilgrastim is a novel, long-acting, fixed-dose, glycoPEGy - ditional PEGylation of biologic molecules has been used successfully for more lated recombinant granulocyte-colony stimulating factor (rG-CSF) under review than 10 years to extend the half-life in the body, requiring less frequent dosing for neutropenia prevention in patients receiving myelosuppressive chemother - and allowing for the administration of G-CSF once per CTx cycle, making treat - apy (CTx) for cancer. Like any biological product, lipegfilgrastim could poten - ment potentially less expensive and enhancing patient compliance and safety. tially elicit an anti-drug antibody (ADA) response, which could cause adverse However, the traditional PEGylation use of chemical conjugation through reac - events (AEs) or lack of efficacy. tive groups on amino acids can result in multiple PEGylated isoforms with reduced Aims: To assess the immunogenicity of lipegfilgrastim compared with pegfil - protein activity, as well as non-uniform chemical and pharmaceutical properties. grastim using data from a Phase II and a Phase III study in patients receiving Aims: To describe a highly site-specific glycoPEGylation technology for site- CTx for breast cancer, and to correlate ADA test results with clinical events. directed PEGylation and the implications of the technology with regard to Methods: In the Phase II study, breast cancer patients undergoing CTx improved outcomes, and to summarize preclinical findings for lipegfilgrastim received a subcutaneous (s.c.) injection of lipegfilgrastim3, 4.5, or 6 mg or peg - compared with pegfilgrastim (Neulasta ®). filgrastim 6 mg on Day 2 of each of four CTx cycles. In the Phase III study, Methods: Glycosylation sequon scanning was used to identify the glycoPEGy - breast cancer patients undergoing CTx received an s.c. injection of 6 mg lipeg - lation site with the least impact on protein activity. Unlike endogenous G-CSF, filgrastim or pegfilgrastim on Day 2 of each of four cycles. In both studies, recombinant G-CSF, expressed in Escherichia coli , is not O-glycosylated. E. serum samples were taken before each cycle, at the end of the study (Day 85), coli- expressed G-CSF was selectively glycosylated at the natural O-glycosyla - and on Day 180 and Day 360 during the 360-day follow-up period. Samples tion site, and a polyethylene glycol (PEG) sialic acid derivative was attached were analyzed using multi-tiered ADA assays based on Mesoscale Discovery using a sialyltransferase (glycoPEGylation technology). Ligand binding affinity technology. Screening-reactive samples were confirmed by immunocompeti - was assessed using the BIACORE 3000 system. Biologic activity of lipegfilgras - tion. All confirmed ADA positive (ADA+) study samples were measured for titer tim was assessed in an NFS-60 cell line proliferation assay versus filgrastim and and analyzed with the NFS-60 cell proliferation assay for neutralizing activity pegfilgrastim. Pharmacokinetic (PK) and pharmacodynamic properties were against lipegfilgrastim or pegfilgrastim and endogenous G-CSF. The confirmed studied in healthy and neutropenic animal models. ADA+ samples from lipegfilgrastim-administered patients were also character - Results: The use of the naturally present glycosylation site to achieve enzy - ized for ADA specificity towards XM21 (G-CSF moiety of lipegfilgrastim) and matic coupling of an activated PEG-sugar conjugate to the filgrastim polypep - PEG moiety, as well as cross-reactivity to endogenous G-CSF by competition tide produces a glycoPEGylated, long-acting G-CSF which is similar in struc - with XM21, PEG, and glycosylated G-CSF, respectively. ture to the native glycosylated protein. Lipegfilgrastim also showed improved Results: The incidence of ADAs is summarized in the Table 1. In the Phase II in vivo PK profiles in animal models. In vitro , lipegfilgrastim had binding affini - study, only two subjects had antibodies related to lipegfilgrastim treatment. ty and specific activity comparable to pegfilgrastim, while both were slightly Among them, one subject had antibodies binding to the PEG moiety, and titer lower than non-PEGylated filgrastim. Comparable increases in leukocytes, neu - for anti-lipegfilgrastim antibodies was found to be 0.6 on Day 85 only. Another trophilic granulocytes, and monocytes were seen with lipegfilgrastim and peg - subject had antibody titer of 0 and the antibodies did not bind to either the pro - filgrastim in rats and monkeys and were consistent with the effects expected tein or PEG moiety, indicating a weak or possibly false-positive response. In for a long-lasting G-CSF. No adverse effects on organ systems were reported pegfilgrastim-treated patients, only one subject was found to have antibody after a dose 100 times higher than the recommended human dose. response to the treatment. Antibody titer and binding specificity were not inves - Summary and Conclusions: The glycoPEGylation technology platform tigated. In the Phase III study, only one subject had antibodies related to lipeg - described here is used to produce lipegfilgrastim, a novel, biologically active G- filgrastim treatment, with the titer value being 1.2 and 2.1 on Days 180 and 360, CSF with greater structural homogeneity and comparable pharmacologic prop - respectively. Antibody specificity characterization showed that the antibodies erties to conventionally PEGylated G-CSFs, thus enabling a safe and effective bind to the protein moiety of lipegfilgrastim. In pegfilgrastim-treated patients, once-per-cycle fixed dosing regimen. only one subject was found to have antibody response to the treatment. Anti - body titer and binding specificity were not investigated. ADA+ samples did not exhibit neutralizing activity against lipegfilgrastim, pegfilgrastim, or endogenous P1025 G-CSF. Unexpected AEs or lack of efficacy were not observed for patients with SAFETY AND TOLERABILITY OF LIPEGFILGRASTIM IN BREAST CAN - confirmed ADA+. CER PATIENTS RECEIVING CHEMOTHERAPY: AN INTEGRATED ANALY - SIS OF PHASE II AND III STUDIES O Gladkov 1,* , R Elsaesser 2, A Buchner 2, P Bias 2, U Mueller 2 Table 1. Incidence of confirmed anti-drug antibodies. 1Chelyabinsk Regional Clinical Oncology Center, Chelyabinsk, Russian Fed - eration, 2Teva ratiopharm, Ulm, Germany Background: Myelosuppresive chemotherapy (CTx) frequently causes neu - tropenia, leading to an increased risk of infections and delays in subsequent chemotherapy treatments. Covalent attachment of polyethylene glycol (PEG) has been shown to prolong the half-life of therapeutic proteins, allowing for less frequent dosing, improved patient compliance, and potentially lower production costs. However, traditional PEGylation methods rely on chemical conjugation through amino acid reactive groups, which may reduce protein activity and result in non-uniform chemical, pharmaceutical, and tolerability profiles. Lipegfilgrastim Summary and Conclusions: Immune response following lipegfilgrastim is a highly homogenous once-per-cycle, fixed-dose glycoPEGylated granulocyte- administration was comparable to pegfilgrastim and was not considered clini - colony stimulating factor (G-CSF) created with a highly site-specific glycoPEGy - cally significant. Serum ADA status did not appear to impact the clinical safety lation technology for site-directed PEGylation, which is under review for the pre - and efficacy of lipegfilgrastim. vention of neutropenia in cancer patients receiving CTx. Non-inferiority of lipeg - filgrastim versus pegfilgrastim (Neulasta ®) was previously demonstrated in a Phase III trial conducted in CTx-naïve breast cancer patients. 1 Aims: To report the safety and tolerability findings from an integrated analysis of two Phase II/III studies of lipegfilgrastim versus pegfilgrastim in CTx-naïve breast cancer patients. Methods: All patients who received full-dose CTx (doxorubicin 60 mg/m 2+doc - etaxel 75 mg/m 2) and either a single 6 mg subcutaneous injection of lipegfil - grastim or pegfilgrastim were included in this analysis. The incidence and sever - ity of treatment-emergent adverse events (TEAEs) and those the investigator deemed related to study drug (TEADRs) over all four cycles were compared. haematologica | 2013; 98(s1) | 421 18 th Congress of the European Hematology Association Results: TEAEs were experienced by 94.7% of patients in the lipegfilgrastim P1027 group (N=151) and 89% of patients in the pegfilgrastim group (N=155). The most common TEAEs
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