F-627 (BINEUTATM, benegrastim)
Introduction
F-627 (benegrastim) is under development for the treatment of chemotherapy-induced neutropenia (CIN) in cancer patients. F-627 is a recombinant fusion protein containing human granulocyte colony-stimulating factor (G-CSF) and human IgG2-Fc and is expressed in Chinese Hamster Ovary (CHO) cells. F-627 has an immunoglobulin-like structure. It consists of two G-CSF molecules at the N-terminal of Fc fragments (a G-CSF dimer). G-CSF is a growth factor acting on the neutrophilic lineage in the hematopoietic system. G-CSF binds to specific G-CSF receptors (G-CSFR) on the cell surface and stimulates differentiation, proliferation, and activation of neutrophilic granulocytes.

The rhG-CSFs for CIN
The first generation (short-acting) of rhG-CSFs, filgrastim and lenograstim, was approved in 1990s to treat CIN. Filgrastim and lenograstim require daily dosing due to their short half-life. The second generation (long-acting) of rhG-CSF, pegfilgrastim, received FDA approval in 2002. Pegfilgrastim was made by PEGylating filgrastim thus extending its half-life to a once per chemotherapy cycle dosing schedule, however with reduced bioactivity due to the addition of polyethylene glycol (PEG). F-627 is a third generation (long- and strong-acting) rhG-CSF. The extended half-life (long-acting) with Fc fusion technology provides patients with convenience, a once per chemotherapy cycle dosing schedule. The rhG-CSF dimer on the F-627 molecule mediates strong G-CSFR activation signals (strong-acting), thus F-627 may fulfil the unmet medical need to manage severe neutropenia and febrile neutropenia, especially in patients with liquid tumors.

CIN Market
CIN occurs commonly during current cancer treatments. In the US alone, it is estimated that approximately 1.7 million cancer patients receive chemotherapy treatment, which amounts to a total of 7.5 million chemotherapy cycles performed annually with approximately 5.0 million chemotherapy cycles involving CIN. The global CIN market is estimated to be at $7.0 billion with about >85% of patients still on first-generation of rhG-CSFs, and less than 15% of patients using second-generation rhG-CSFs. F-627 has a unique potential to compete in the CIN global market, due to its novel design with enhanced bioactivity, new mode of G-CSF activation, robust manufacturing process and clinical safety profile.

Clinical Development Status
Seven clinical studies have been completed for F-627 including two Phase I studies in healthy men, and three Phase IB and two Phase II studies in women with breast cancer receiving various chemotherapies.

Pivotal Phase III studies for F-627 have been initiated in the US, Europe and China. Generon has reached an agreement in 2017 with the U.S. Food and Drug Administration (FDA) under a Special Protocol Assessment (SPA) regarding the second pivotal global Phase III study design of F-627. The SPA provides a binding agreement with the FDA¨s review division that the Phase III trial can adequately address objectives in support of a U.S. regulatory submission for approval of F-627 for the treatment of cancer patients with CIN. F-627 drug substance for Phase III clinical development is manufactured in a Generon¨s cGMP facility. F-627 drug product is manufactured in a cGMP facility located in the US.


      F-627: Mechanism of Action             Structure of F-627