Opportunities and challenges with animal models for acute radiation syndrome drug discovery

Figures & data

Figure 1. Steps involved in countermeasure development following FDA animal rule. Such countermeasures under development may receive pre-emergency use authorization (pre-EUA) prior to full approval for human use by FDA. BLA, biologics license applications; IND, investigational new drug; NDA, new drug application.

Table 1. U.S. FDA-approved biologics for H-ARS following animal rule and available in SNS/VMI.

Biologics	Mechanism	Animal models of radiation injury used	FDA-approved indication	Remarks	References*
Neupogen/filgrastim/G-CSF	Stimulates proliferation, differentiation, commitment, maturation, and function of neutrophils	Effective in murine, canines, swine (minipigs), and NHP models as a radiomitigator for H-ARS	H-ARS, Adult patients – March 2015	Available in SNS/VMI, effective with full supportive care, administration can be delayed up until 24 h after total-body radiation exposure	[18,19]
Neulasta/pegfilgrastim/Pegylated G-CSF	Stimulates proliferation, differentiation, commitment, maturation, and function of neutrophils	Effective in murine and NHP models as a radiomitigator for H-ARS	H-ARS, Adult and Pediatric patients – November 2015	Available in SNS/VMI, effective with full supportive care, administration can be delayed up until 24 h after total-body radiation exposure	[21,22]
Leukine/Sargramostim/GM-CSF	Supports survival, clonal expansion, commitment, and differentiation of hematopoietic progenitors in the granulocyte-macrophage pathways (neutrophils, monocytes/macrophages and derived dendritic cells)	Effective in murine, canines, and NHP models as a radiomitigator for H-ARS	H-ARS, Adult and Pediatric patients – March 2018	Available in SNS/VMI, effective with minimal supportive care, administration can be delayed up until 48 h after total-body radiation exposure	[17,20]

DRF values for G-CSF in mice are 1.06 – 1.20 depending on dose, route of administration, and treatment schedule. In the Beagle canine model, DRF is 1.34 without supportive care and 1.73 with supportive care. G-CSF: Granulocyte colony-stimulating factor;

GM-CSF: Granulocyte-macrophage colony-stimulating factor; H-ARS: hematopoietic-acute radiation syndrome; SNS: Strategic national stockpile; US FDA: United States Food and Drug Administration; VMI: vendor-managed inventory

* Since there is a limit of total references in editorial article, it was not possible to cite an original reference for each countermeasure.

Table 2. Radiation countermeasures under development following the FDA animal rule criteria for ARS with U.S. FDA IND status.

Biologics	Mechanism	Animal models of radiation injury used	FDA approval status	Remarks	References*
Entolimod/CBLB502/(truncated flagellin – TLR-5 ligand)	NF-κB activator, stimulates G-CSF and IL-6 production, immunomodulator, free radical scavenger	Radioprotective and radiomitigative efficacy in murine and NHP models, also canine for biomarker study	IND, Pre-EAU application pending with FDA	Found safe in clinical investigation	[23]
HemaMax/NMIL12-1/rhuIL-12	T cell-activating factor, promotes Th1 maturation, possibly NF-κB activator, promotes hematopoietic and GI recovery	Effective in mice and NHPs as a radioprotector and radiomitigator	IND	Safe and well-tolerated in clinical study	[23]
Ex-RAD/ON01210.Na/Recilisib	Upregulates PI3-kinase/AKT pathways in cells, appears to potentiate DNA repair	Studied in mice (oral and sc) and NHPs (sc) as radioprotector and radiomitigator	IND	Safe and well-tolerated in clinical study	[23]
5-Androstenediol/HE2100/Neumune (a natural steroid)	Stimulates hematopoiesis, ameliorates neutropenia, activates immune cells, and induces cytokine expression	Effective in mice and NHPs as a radioprotector and radiomitigator, respectively	IND	Safe and well-tolerated in clinical study	[23]
Genistein/BIO 300 (nano suspension) – soy isoflavone	Antioxidant, anti-proliferation, anti-cancer	Radioprotective and radiomitigative efficacy in mice, NHP study in progress	IND	Safe and well-tolerated in clinical study	[23]
Myeloid progenitors/CLT-008	Produce functional granulocytes, red blood cells, and platelets	Radiomitigative efficacy in different strains of mice	IND	Completed phase 1 safety testing in a total of 75 patients receiving treatment for a hematologic malignancy	[23]
PLX-R18/Placenta-derived, mesenchymal stromal cells	Releases cytokines, chemokines, and growth factors, which facilitate healing of damaged tissue by stimulating the body’s own regenerative mechanisms	Radiomitigation efficacy in mice and NHPs	IND	Clinical study has not yet been reported	[23]
AEOL 10150/Meso-porphyrin mimetic	Neutralizes reactive oxygen and nitrogen spices, which helps in reducing oxidative stress, reduces inflammation as well as tissue damage	Radiomitigative efficacy for DEARE in mice and NHPs	IND	Clinical study in progress	[23]
OrbeShield/BDP (corticosteroid)	Modulates local inflammation and epithelial cellular apoptosis in GI	Radiomitigative efficacy observed in canine	IND	Clinical study has not yet been reported	[23]

AKT: a serine/threonine protein kinase; ARS: Acute radiation syndrome; BDP: Beclamethasone 17,21-dipropionate; DEARE: Delayed effect of acute radiation syndrome; EAU: Emergency use authorization; G-CSF: Granulocyte colony-stimulating factor; GI: Gastrointestinal; IL-6: Interleukin-6; IND: Investigational new drug; NF-κB: Nuclear factor kappa B; NHP: Nonhuman primate; rhuIL-12: recombinant human interleukin-12; PI3K: Phosphoinositide 3-kinase; sc: subcutaneous; Th1: T helper cell-1; U.S. FDA: United States Food and Drug Administration

* Since there is a limit of total references in editorial article, it was not possible to cite an original reference for each countermeasure.

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U.S. Food and Drug Administration. FDA approves Neupogen for treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident. 2015. Available at: http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/AboutMCMi/ucm443245.htm [Last accessed 2016 Jul 6]

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Hankey KG, Farese AM, Blaauw EC, et al. Pegfilgrastim improves survival of lethally irradiated nonhuman primates. Radiat Res. 2015;183:643–655.

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National Institute of Allergic and Infectious Diseases. Pegfilgrastim approved for treating acute radiation syndrome. 2015. Available at: https://www.niaid.nih.gov/topics/radnuc/Pages/pegfilgrastim.aspx [Last accessed Aug 18, 2016]

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U.S. Food and drug Administration. FDA approves Leukine for acute radiation syndrome. 2018. Available at: https://www.fda.gov/downloads/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/AboutMCMi/UCM603226.pdf [Last accessed 2018 Apr 01]

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Clayton NP, Charpentier EJJ, LaCasse ER, et al. Sargramostim significantly improved the mortality rate at Day 60 in a non-human primate model of hematopoietic acute radiation syndrome with minimal supportive care when administered 48 h after total body irradiation. 42nd Conference of the European Radiation Reasearch Society. Amsterdam, Netherlands 2016:190

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U.S. Food and Drug Administration. Investigational New Drug (IND) Application. 2017. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm [Last accessed 2017 Dec 23]

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