ST7-S – an oral small-molecule drug for mitigation of Acute Radiation Syndrome
Phoenicia BioSciences, Inc. and Boston University School of Medicine
Exposure to ionizing radiation (IR) as the result of nuclear terrorism or accidental exposure, such as occurred following the earthquake and tsunami in Japan in 2011, has become an increasing threat and concern. In New England, a large population over a wide geographic area is at risk of exposure in a nuclear plant accident in the aging facilities. A recent interagency workshop on the radiobiology of nuclear terrorism has concluded that, in such an event, many victims may receive moderate doses of IR in the range of 1 to 10 Gy. Exposure to these doses of IR will cause significant civilian casualties due to IR-induced damage to normal tissues and subsequent complications. Without treatment, approximately half of all people exposed to a dose of more than 350 rad (3.5 Gy) will die within 60 days from complications of low blood cells, such as infection and bleeding, and gastrointestinal damage. In this context, new radioprotective agents that can be used as mitigating agents or treatments for post-radiation rescue therapy are needed.
The hematopoietic (bone marrow) and GI (gastrointestinal) components of the Acute Radiation Syndrome (ARS) are very important issues in the field of radiation countermeasures since there are no approved drugs for the treatment of ARS. Even assuming the availability of cytokines, growth factors, supplies for injection, and full medical support, there is still an urgent need to identify new treatments that will increase survival during ARS. There is a need to expand the repertoire of countermeasures to include agents that do not require clinical support and physician supervision, as such support has been shown to be problematic in realistic analyses of mass casualty scenarios. An ideal therapeutic would require a small, highly-stable molecule, preferably orally-active, with low toxicity and suitably stable for stockpiling in national and regional sites.
Phoenicia BioSciences has a molecule in preclinical development (designated ST7-S) which meets these requirements and has passed critical go-no go safety tests. In extensive preclinical studies, we have found that:
- ST7-S increases hematopoietic stem cell proliferation in multiple distinct murine and human assays
- In irradiated mice, ST7-S given 24 hr later profoundly accelerates marrow recovery of all hematopoietic lineages (red and white blood cells and platelets). White blood cells (neutrophils) are particularly needed to avoid fatal infection.
- In lethally-irradiated mice, oral ST7-S treatment for 4 days post-irradiation significantly increases survival (suggesting mitigating effects on both the Hematopoietic and the GI components of ARS).
- In baboons and dogs, ST7-S increases absolute neutrophil counts and platelets, cells that make the blood clot and prevent bleeding
- In anemic baboons and mice, ST7 increases red blood cells
Advantages of ST7-S over recombinant peptide growth factors include:
- Oral bioavailability (parenteral injection not required)
- Stability at ambient and elevated temperature (easily stored/shipped and stockpiled; refrigeration not required)
- Once-daily dosing predicted at (tolerable) human equivalent doses (HED) of between 350 and 1500 mg for an average 70 kg adult And teaspoon or single tablet doses from children
Potential uses of ST7-S thus include:
- Provision to first responders, military, or other personnel at risk of exposure to radiation (e,g., nuclear plant employees), for immediate use, if exposed.
- Treatment of large civilian or military populations after accidental or intentional radiation exposure, to prevent the life-threatening risks of bone marrow suppression
Next steps in the development of ST7-S as a mitigator of ARS, to define other beneficial effects and make this therapeutic available for clinical use, include:
- Demonstrate mitigating effects of ST7-S on the GI component of ARS
- Determine protective actions of ST7-S on the late central nervous system component of ARS
- Establish methods for upscaling synthesis of ST7-S for IND enabling studies and large-scale production
- Conduct IND-enabling toxicology studies of ST7-S and prepare an IND
- Further, characterize effects on stem cells
- Prepare a Medicinal Formulation of ST7-S for clinical trials
- Submit an IND for human Phase I safety testing under the Animal Efficacy Law for radiation exposures, or standard phased clinical testing to accelerate marrow recovery in another condition such as transplant, as an alternate use to facilitate application in radiation accidents.
Susan P. Perrine MD (firstname.lastname@example.org)
Douglas V. Faller PhD, MD (email@example.com)