Preclinical and clinical data for tbo-filgrastim: A short-acting filgrastim

e13555 Background: Tbo-filgrastim is a G-CSF approved in the US as a biologic under the BLA 351(a) pathway, for reducing duration of severe neutropenia (DSN) in patients with non-myeloid malignancies receiving chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia (FN). Here, we summarize data from the development program (16 preclinical studies; 2 Phase I and 3 Phase III clinical studies). Methods: Preclinical: The PK, safety pharmacology, PD, and toxicology of tbo-filgrastim vs reference filgrastim were investigated in 3 in vitro studies and 13 animal model studies. Clinical: The PK/PD of tbo-filgrastim and filgrastim were compared in 2 Phase I studies in 200 healthy volunteers. The safety and efficacy of tbo-filgrastim were compared with filgrastim in 3 Phase III studies in 677 patients receiving CTx for breast cancer (BC), lung cancer (LC) and non-Hodgkin lymphoma (NHL). The BC study, in which DSN was the primary parameter, was placebo controlled. Results: Preclinical: Binding affinity to the human G-CSF receptor and growth-promoting activity were comparable between tbo-filgrastim and filgrastim in vitro. In vivo, no relevant differences were seen between tbo-filgrastim and reference filgrastim in PK, PD, safety, or tolerability in animal models. Clinical and laboratory findings, gross pathology and histopathology in animal models were similar to filgrastim. Clinical: tbo-Filgrastim was safe, effective, and comparable to filgrastim in the prevention of FN. DSN, absolute neutrophil count (ANC) nadir, and time to ANC recovery were comparable. The incidence of FN was low (mean of 12.1%, 15.0%, and 11.1% in Cycle 1 of the BC, LC, and NHL studies, respectively), with no significant differences between agents. In the BC study, in Cycle 1, DSN was 1.1 vs 3.9 days for tbo-filgrastim and placebo, respectively. The efficacy of tbo-filgrastim was independent of the myelotoxic potential of CTx. Immunogenicity and incidence of binding and neutralizing antibodies were low and comparable. Conclusions: The safety profiles of tbo-filgrastim and filgrastim were similar and characteristic of filgrastims. Tbo-filgrastim was superior to placebo and equivalent to filgrastim in reducing DSN after myelotoxic CTx. Clinical trial information: 2004-001452-36, 2004-001450-84, 2004-001449-13.