Posted June 10, 2020

Michael Kaytor, Ph.D., Humanetics Corporation

Protecting the health of U.S. military personnel during their performance of duty is essential in all environments, especially those known to contain chemical, biological, radiological, or nuclear (CBRN) hazards. Radiation sources can range from major radioactive materials, such as leaked nuclear fuel seen in the Fukushima Daiichi nuclear disaster, to common X‑ray machines. Exposure to ionizing radiation can lead to cellular DNA damage that can cause health issues such as cancer, diabetes, heart disease, lung fibrosis, liver fibrosis, kidney fibrosis, and acute radiation syndrome (ARS), which affects the hematopoietic and gastrointestinal systems. Building on their Fiscal Year 2016 (FY16) Technology/Therapeutic Development Award from the Peer Reviewed Medical Research Program (PRMRP), a team of researchers led by Dr. Michael Kaytor obtained funding through the FY18 Joint Warfighter Medical Research Program (JWMRP) Military Medical Research and Development Award to expand development of BIO 301 (also termed BIO 300 Oral Powder) as a radiation medical countermeasure that provides pre-exposure prophylaxis against the damaging effects of ionizing radiation. 

The active ingredient in BIO 300 Oral Powder, genistein, has shown promise for radioprotection but has eluded drug developers for decades due to its poor solubility and low bioavailability. Genistein acts as a highly selective agonist of estrogen receptor-beta (ERβ), a transcription factor found throughout the body that regulates genes controlling the cell cycle, DNA damage repair, and inflammation. Regulation of ERβ-mediated gene expression by genistein dictates the extent, severity, and response to DNA damage from ionizing radiation, which confer a radioresistant state to healthy cells. ERβ is also a tumor suppressor, and higher ERβ expression is prognostic for better patient outcomes following solid tumor radiotherapy. Previously, the Armed Forces Radiobiology Research Institute (AFRRI) and Humanetics Corporation developed BIO 300 Oral Suspension a patented formulation containing synthetic genistein nanoparticles. BIO 300 Oral Suspension is being developed as a supportive care agent for cancer patients undergoing radiation therapy via self-administration with pre-loaded oral syringes, and is currently being evaluated in a Phase 1b/2a clinical trial (NCT02567799).

The BIO 300 Oral Suspension formulation does not lend itself to use by Warfighters in field operations. Thus, supported by their FY16 PRMRP award, Dr. Kaytor’s team designed a new formulation, BIO 300 Oral Powder, which is amenable to a solid dosing form (tablet, capsule, etc.) to better suit the needs of deployed Warfighters. The researchers rapidly developed and screened over 100 formulations, one of which (an amorphous dispersion) exhibited vastly improved oral bioavailability compared to BIO 300 Oral Suspension in animal studies and was sufficiently stable for further development efforts. This formulation can be either encapsulated or tableted to create the oral dosage form desired for field operability. Further, because the active pharmaceutical ingredient in BIO 300 Oral Powder matches that of BIO 300 Oral Suspension, the researchers are able to use the Oral Suspension data to support the rapid development and regulatory approval of BIO 300 Oral Powder. 

The current FY18 JWMRP award supports non-clinical and clinical studies to advance the development of BIO 300 Oral Powder, including dosing and safety studies in mice, non-human primates (NHPs), and healthy human volunteers, as well as efficacy studies in NHPs. The non-clinical studies will be completed in collaboration with Dr. Vijay K. Singh (Uniformed Services University of the Health Sciences/AFRRI). The studies will also evaluate BIO 300 Oral Powder in combination with Neupogen®, an FDA-approved drug for the treatment of hematopoietic subsyndrome of acute radiation syndrome (H-ARS). Human efficacy studies to evaluate radiation medical countermeasures are not ethical, thus these studies are designed to meet the FDA’s guidance for approval under the Animal Rule. Currently, the researchers have secured a subcontract for the NHP studies and are awaiting additional data from the FY16 PRMRP studies before beginning dose-scheduling experiments in mice. Once deemed safe and effective by the FDA, BIO 300 Oral Powder will substantially enhance operational preparedness efforts in radiological or nuclear threat scenarios, and its use could be expanded to protect other populations at risk for radiation exposure (e.g., astronauts and first responders).

Link:

Public and Technical Abstracts: Development of BIO 301 to Prevent Acute Radiation Syndrome and Mitigate the Delayed Effects of Acute Radiation Exposure

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