Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model

Abstract

Background

High dose ionizing radiation exposure is associated with myelo-depression leading to pancytopenia and the expected clinical manifestations of acute radiation syndrome (ARS). Herein, we evaluated the efficacy of sargramostim (Leukine^®, yeast-derived rhu GM-CSF), with regimens delivered at 48, 72, 96, or 120 h after radiation exposure.

Methods

A randomized and blinded nonhuman primate (NHP) study was conducted to assess the effects of sargramostim treatment on ARS. NHPs were exposed to total body radiation (LD_83/60 or lethal dose 83% by Day 60) and were randomized to groups receiving daily subcutaneous dosing of sargramostim starting from either 48, 72, 96, or 120 h post-irradiation. Additionally, separate groups receiving sargramostim treatment at 48 h post-irradiation also received prophylactic treatment with azithromycin. Sargramostim treatment of each animal continued until the preliminary absolute neutrophil count (ANC) returned to ≥1000/μL post-nadir for three consecutive days or the preliminary ANC exceeded 10,000/μL, which amounted to be an average of 15.95 days for all treatment groups. Prophylactic administration of enrofloxacin was included in the supportive care given to all animals in all groups. All animals were monitored for 60 days post-irradiation for mortality, hematological parameters, and sepsis.

Results

Delayed sargramostim treatment at 48 h post-irradiation significantly reduced mortality (p = .0032) and improved hematological parameters including neutrophil but also lymphocyte and platelet counts. Additional delays in sargramostim administration at 72, 96, and 120 h post-irradiation were also similarly effective at enhancing the recovery of lymphocyte, neutrophil, and platelet counts compared to control. Sargramostim treatment also improved the survival of the animals when administered at up to 96 h post-irradiation. While sargramostim treatment at 48 h significantly reduced mortality associated with sepsis (p ≤ .01), the additional prophylactic treatment with azithromycin did not have clinically significant effects.

Conclusion

In a NHP ARS model, sargramostim administered starting at 48 h post-radiation was effective to improve survival, while beneficial hematological effects were observed with sargramostim initiated up to 120 h post exposure.

Keywords:

• NHP-ARS
• MCM
• sargramostim
• delayed treatment
• antibiotherapy

Acknowledgements

The authors would like to thank the staff at BARDA (Biomedical Advanced Research and Development Authority, DC, USA) for their contribution to the design and analysis of the study.

Disclosure statement

None of the authors have any conflicts of interest, other than their employment in commercial pharmaceutical companies or contract research organizations.

Additional information

Funding

This work was supported by the ‘Biomedical Advanced Research and Development Authority’ (HHSO100201300005I).

Notes on contributors

Yifei Zhong

Yifei Zhong is a study director at Citoxlab, a Charles River company. She holds a B.Sc. in Microbiology and Immunology and a HBA from the University of Western Ontario, and a Ph.D. in Pharmacology and Therapeutics from McGill University.

Mylene Pouliot

Mylene Pouliot is a study director at Citoxlab North America. She holds a B.Sc. and a Ph.D. in Physiology from Universite de Montreal and is a Diplomate of Safety Pharmacology (DSP).

Anne-Marie Downey

Anne-Marie Downey is a research fellow and study director at Citoxlab, a Charles River company. She holds a B.Sc. in Biopharmaceutical Sciences (medicinal chemistry) from the University of Ottawa and a Ph.D. in Pharmacology and Therapeutics from McGill University.

Colleen Mockbee

Colleen Mockbee is the chief development officer and head of regulatory and quality at Partner Therapeutics. She graduated from Butler University with degrees in chemistry and pharmacy in 1990 and 1994, and received her MBA from Purdue’s Krannert School of Business in 2016.

Debasish Roychowdhury

Debasish Roychowdhury is a hematologist/oncologist and the co-founder of Partner Therapeutics and serves as its chief medical officer. He graduated from India and competed his fellowship from UCSF and practiced in Cincinnati before joining the pharmaceutical industry. He served in various leadership roles in Lilly, GSK and Sanofi and since 2013 has been a serial enterpreneur.

Wieslaw Wierzbicki

Wieslaw Wierzbicki is a certified radiophysicist with a Ph.D. in biophysics from Universite de Montreal and a post-doctoral fellowship from McGill University.

Simon Authier

Simon Authier is senior director of scientific operations and veterinary science at Citoxlab, a Charles River company. He holds a DVM from Universite de Montreal, an MBA from HEC and a Ph.D. in Pharmacology. He is a Diplomate of Safety Pharmacology (DSP).