Potent and Durable Neutrophil Stimulation and Progenitor Stem Cell Mobilization by Maxy-G34 a Next Generation G-CSF.

Introduction: Maxy-G34 is a PEGylated, recombinant human G-CSF that has been modified to reduce both renal and G-CSF receptor-mediated clearance, thereby enabling superior neutrophil stimulating activity compared to benchmark competitors in pre-clinical models of chemotherapy-induced neutropenia. It is anticipated that Maxy-G34 will provide improved supportive care in a broad variety of cancers and chemotherapy regimens. This report represents the first investigation of Maxy-G34 in humans.

Objective: To investigate the safety and tolerability of Maxy-G34 in healthy volunteers

Methods: 47 healthy volunteers were administered a single dose of one of the following: 5μg/kg, 10 μg/kg, 30 μg/kg, 60 μg/kg, 100 μg/kg, 150 μg/kg of Maxy-G34 or placebo in a randomized, double-blind, dose escalation fashion. At each dose-level 6 subjects received Maxy-G34 and 2 subjects received placebo except for the 5μg/kg dose-level where six subjects received 5 μg/kg Maxy-G34 and one subject received placebo. Serial blood samples were collected through 30 days following administration of Maxy-G34 for determination of Maxy-G34 serum concentrations, evaluation of the absolute neutrophil count (ANC) and CD34+ progenitor cell counts and immunogenicity. An additional immunogenicity sample was collected at 90 days.

Results: Single dose administration of a Maxy-G34 was safe and well tolerated across the dose range studied. No serious adverse events were reported. As expected with G-CSF compounds, bone pain was the most frequent adverse event reported in 39% of the subjects receiving Maxy-G34, with moderate pain being observed in only 2 subjects. Maxy-G34 administrations resulted in a potent stimulation of neutrophils and mobilization of stem cells. Dose-dependent increases in mean peak absolute neutrophil count (ANC) were observed with increasing doses of Maxy-G34 and ranged from 16 ± 5.5 to 40.3 ± 5.8 (1000/mm³) relative to a mean peak ANC of 5.1 ± 1.1 (1000/mm³) for placebo. Stimulation of neutrophils resulted in a durable response evident by ANC levels remaining above the upper limit of normal for a duration of 10.8 ± 1.2 to 20.8 ± 8.4 days across the Maxy-G34 dose range, relative to a duration of 0 days for placebo. The mean time to peak ANC ranged from 63 – 82 hours following administration. Mobilization of progenitor stem cell CD34+ also demonstrated a potent response with mean peak CD34+ ranging from 41 – 87 cells/mm³ relative to a mean peak CD34+ of 6.2 cells/mm³ for placebo. Mean time to peak CD34+ ranged from 96 – 164 hours post-dose. Plasma concentration vs. time profile for Maxy-G34 revealed similar terminal half-lives across all doses with mean terminal half-lives of 105 – 141.2 hours across the dose-range studied. No anti-G-CSF antibodies (binding or neutralizing) were noted over a period of 90 days post-administration.

Conclusion: Maxy-G34, a next generation G-CSF, is a potent and durable stimulator of neutrophils and progenitor stem cells in normal healthy volunteers. Maxy-G34 was safe and well tolerated across the dose range of 5 μg/kg – 150 μg/kg following administration as a single dose. The observed potency and durability of response are anticipated to confer important benefits in the setting of chemotherapy-induced neutropenia and is the subject of ongoing investigations.