BIO 300: a promising radiation countermeasure under advanced development for acute radiation syndrome and the delayed effects of acute radiation exposure

Figures & data

Figure 1. Molecular structure of genistein, C₁₅H₁₀O₅, molecular weight: 270.24 Da.

Figure 2. Molecular structure of 17β-estradiol, molecular weight: 272.4 Da.

Table 1. List of genistein-related product details.

Drug Substances and Formulations	Manufacturer	Description
Genistein	DSM Nutritional Products	A naturally occurring soy isoflavone that is commonly delivered in a standardized isoflavone mixture derived by extraction.
Bonistein®	DSM Nutritional Products	Pharmaceutical grade synthetic genistein present in all BIO 300 drug product formulations and manufactured by DSM Nutritional Products
geniVida®	DSM Nutritional Products	Nutraceutical grade synthetic genistein manufactured by DSM Nutritional Products and available commercially.
BIO 300 capsules	Humanetics Corporation	Bonistein®capsule without excipients (particle size median diameter 8 microns)
BIO 300 injectable formulation	Pharmaceutics International, Inc.	Bonistein® nanoparticles in a sterile aqueous suspension (particle size d(50) ≤ 0.2 microns). Has been used in both parenteral and oral nonclinical studies. The route of administration for each study mentioned in this manuscript is explicitly stated.
BIO 300 oral formulation	Pharmaceutics International, Inc.	Bonistein® nanoparticles in an aqueous suspension with preservatives (particle size d(50) ≤ 0.2 microns).
BIO 300 oral formulation (powder)	Lonza Group AG	Bonistein® solid formulation

Table 2. Summarized nonclinical ARS efficacy studies.

Species	Formulation	Route	Study	Doses	Duration	Comments	Reference
Mouse	Genistein in PEG 400	sc	Efficacy	400, 200, 100, 50, 25, 12.5, 6.25, 3.12 mg/kg	Single dose 1 h and 24 h before 9.5 Gy TBI	Doses of at least 25 mg/kg showed significant improvements in survival when administered 24 h before TBI	[61]
Mouse	Bonistein® in PEG 400	sc	Efficacy	200 mg/kg	Single dose 24, 8, 4, 2, 1 and 0.5 h before 8.75 Gy TBI	24 h prior to TBI treatment group had improvement in 30-day survival relative to vehicle	Landauer MR et al. - Unpublished
Mouse	Genistein in PEG 400	sc	Efficacy, hematol.	200 mg/kg	Single dose 24 h prior to 8.75 Gy TBI	Significant improvement in CBC and accelerated hematologic recovery in irradiated mice	[62]
Mouse	Bonistein® in PEG 300/castor oil, PEG 300/cottonseed oil or PEG 300/sesame oil	sc	Efficacy with different excipients	200 mg/kg	24 h prior to 8.75 Gy	All Bonistein® groups showed significant increases in survival	Landauer MR et al. - Unpublished
Mouse	Bonistein® in PEG 400 or BIO 300 injectable suspension (IS)	sc	Efficacy	200 mg/kg (Bonistein®) 150 mg/kg (IS)	Single dose 24 h prior to 8.75 Gy, 9.0 Gy or 9.25 Gy TBI	Both formulations had similar efficacy	Landauer MR et al. - Unpublished
Mouse	BIO 300 IS	sc	Efficacy	200 mg/kg	Single dose 24 h prior to 9.0 Gy TBI	Significant improvement in survival	Landauer MR et al. - Unpublished
Mouse	Genistein in PEG 400	sc	Efficacy	200 mg/kg	Single dose 24 h before 7.75 Gy TBI	Significant improvement in survival	[66]
Mouse	Genistein in PEG 400	po	Efficacy	100 and 400 mg/kg	QD 4 d prior to 9.5 Gy TBI	Improved survival only at 400 mg/kg	[59]
Mouse	Bonistein® in PEG 400	po	Efficacy	400 mg/kg	Once daily for 4, 7, 14, and 21 days prior to 8.75 Gy TBI	Daily dosing for 7, 14 or 21 d improved survival	Landauer MR et al. - Unpublished
Mouse	Bonistein® in PEG 400	po	Efficacy	200 mg/kg twice daily (BID) or 400 mg/kg QD	2, 4 or 6 days prior to 8.75 Gy TBI	Optimal treatment regime was 200 mg/kg BID for 6 days prior to TBI	[58]
Mouse	Bonistein® in PEG 400	po	Efficacy and DRF	200 mg/kg BID	BID for 6 days prior to 8.75–10.25 Gy TBI	Estimated DRF 1.11 with 95% confidence intervals of [1.09–1.14]	Landauer MR et al. - Unpublished
Mouse	Bonistein® in PEG 400	po	Efficacy	133.3 mg/kg thrice daily (TID) or 200 mg/kg BID	TID for 1,2,4,6 days prior to 9.0 Gy TBI and 6 d for BID prior to TBI	No improvement with TID over BID dosing	Landauer MR et al. - Unpublished
Mouse	Bonistein® in PEG 400	po	Efficacy	400 mg/kg	QD 1,2,4,6 d prior to 8.75 Gy TBI	Survival similar to sc dosing	Landauer MR et al. - Unpublished
Mouse	Bonistein® in PEG 400 or BIO 300 Oral Suspension (OS)	po	Efficacy	200 mg/kg BID	6 days prior to 9.25 Gy TBI	Both formulations had similar survival	Landauer MR et al. - Unpublished
Mouse	BIO 300 OS	po	Efficacy	200 mg/kg	BID 6 days prior to 8.75 Gy to TBI	6 d prior to irradiation, po efficacy equivalent to im dosing	Landauer MR et al. - Unpublished
Mouse	BIO 300 Oral Powder	po	Efficacy	200 mg/kg	BID 6 and 3 days prior to 9.2 Gy TBI	Significant improvement in survival when administered for 6 days prior or 3 days prior	Unpublished – manuscript under preparation
Mouse	Bonistein® in PEG 400 or BIO 300 IS	im	Efficacy	200 mg/kg Bonistein® 150 mg/kg IS	Single dose 24 h prior to 9.25 Gy TBI	Similar survival results with both formulations	Landauer MR et al. - Unpublished
Mouse	BIO 300 IS	im	Efficacy	150 mg/kg	Single dose 24 h prior to 9.5, 9.75, 10 and 10.25 Gy TBI	LD50 is between 10 and 10.25 Gy	[45]
Mouse	BIO 300 IS	im	DRF	150 mg/kg	Single dose 24 h prior to 9.5, 9.75, 10, 10.25, 10.5, 10.75, 11 Gy TBI	DRF of 1.16	[45]
Mouse	BIO 300 IS	im	Efficacy	200 mg/kg	QD 24 h prior to 9.2 Gy TBI	Significant improvement in survival	Unpublished – manuscript under preparation
Mouse	BIO 300 IS	im	Efficacy	150 mg/kg	QD 1, 2, 3, 4 or 5 days prior to 9.25 Gy TBI	Single dose provides radioprotection for up to 48 h prior to TBI	[45]
Mouse	BIO 300 IS	im	Efficacy	150 mg/kg	QD 24 h prior to 9.0 Gy TBI	BIO 300 IS efficacy is dependent on ER-binding	[45]
Mouse	BIO 300 IS	im	Efficacy	150, 75, 37.5, 18.75, 9.375 mg/kg	Single dose 24 h prior to 9.25 Gy TBI	Significant improvement in survival down to 37.5 mg/kg	[63]
Canine	Bonistein® in PEG 400	sc	Efficacy	370 mg/kg	Single dose prior to 2.6 Gy TBI	Significant improvement in survival, amelioration of leukopenia, neutropenia, and thrombocytopenia	[68]

Summary of published and unpublished efficacy studies with genistein, Bonistein® and various formulations of BIO 300 using murine and canine models. DRF, dose reduction factor; im; intramuscular; sc, subcutaneous; po, oral; TBI, total-body irradiation.

Box 1. Drug summary

Drug name	BIO 300
Phase	Phase 1 (safety), Phase 1b/2a (oncology indication)
Indication	Acute radiation syndrome and the delayed effects of acute radiation exposure, Protection against normal tissue toxicities resulting from cancer radiotherapy
Pharmacology/mechanism of action	Ligand for estrogen receptor-β, Controls hematopoietic progenitor cell depletion and lung damage after irradiation by increasing expression of cell cycle checkpoint proteins, DNA repair enzymes, and reducing expression of pro-inflammatory proteins
Routes of administration	Oral, intramuscular, intravenous, subcutaneous
Chemical structure
Pivotal trials	Phase 1 (ClinicalTrials.gov Identifier: NCT00504335) Phase 1b/2a (ClinicalTrials.gov Identifier: NCT02567799) in non-small cell lung cancer (NSCLC) patients receiving chemoradiotherapy

Landauer MR, Srinivasan V, Seed TM. Genistein treatment protects mice from ionizing radiation injury. J Appl Toxicol. 2003;23:379–385.

 PubMed Web of Science ®Google Scholar

Davis TA, Clarke TK, Mog SR, et al. Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival. Int J Radiat Biol. 2007;83(3):141–151.

 PubMed Web of Science ®Google Scholar

Day RM, Barshishat-Kupper M, Mog SR, et al. Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat Res. 2008;49:361–372.

 PubMed Web of Science ®Google Scholar

Landauer M. Radioprotection by the Soy Isoflavone Genistein. In: Arora R, editor. Herbal radiomodulators: applications in medicine, Homeland defense and space. Wallingford, England: CABI Publishing; 2008. p. 163–173.

 Google Scholar

Landauer, M.R. et al. Radioprotection by oral administration of genistein in mice receiving total body irradiation. 48th Annual Meeting and ToxExpo; March 15–19; Baltimore, MD. 2009.

 Google Scholar

Landauer MR, Harvey AJ, Kaytor MD, et al. Mechanism and therapeutic window of a genistein nanosuspension to protect against hematopoietic-acute radiation syndrome. J Radiat Res. 2019;60:308–317.

 PubMed Web of Science ®Google Scholar

Ha CT, Li XH, Fu D, et al. Genistein nanoparticles protect mouse hematopoietic system and prevent proinflammatory factors after gamma irradiation. Radiat Res. 2013;180:316–325.

 PubMed Web of Science ®Google Scholar

Dykstra JC, Harvey AJ, Ingram MAC, et al. Development of BIO 300 as a Medical Countermeasure for H-ARS and DEARE-lung. In Policies and Regulatory Pathways to FDA Licensure: Radiation Countermeasures and Biodosimetry Devices. Rockville, MD, USA: RNCP, NIAID; 2018

 Google Scholar