Abstract

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.

Author notes

Disclosure: Employment: Drs. Vetticaden, Apt and Chitour are employees of Maxygen, Inc or its affiliate Maxygen, ApS, sponsor of this trial. Dr. Goldwater is an employee of PAREXEL International the contract organization that conducted this trial on behalf of Maxygen. Ownership Interests:; Dr. Vetticaden, Apt and Chitour own stock options of Maxygen, the sponsor of this trial.