Opaganib as a Medical Countermeasure for Gastrointestinal Acute Radiation Syndrome

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PROJECT ABSTRACT The Radiation Countermeasures Program of the NIAID is seeking medical countermeasures (MCMs) to prevent acute tissue damage and chronic pathologies resulting from exposure to ionizing radiation from an accidental or terroristic event. Radiation induces inflammatory cytokines that promote tissue damage including Gastrointestinal Acute Radiation Syndrome (GI-ARS). Because there are no approved drugs to prevent GI-ARS, there is an intense need for new drugs for therapy following exposure to radiation. Sphingolipids, particularly ceramides and sphingosine 1-phosphate (S1P), regulate GI epithelial cell survival, the DNA damage response, and responses to inflammatory cytokines. Synthesis of S1P is dependent on sphingosine kinase (SK1 and SK2) activity, and so SKs are rational new molecular targets to mitigate GI-ARS. Apogee has developed the first-in- class Investigational New Drug opaganib (previously called ABC294640). Opaganib is the only clinical-stage inhibitor of SK2 and has broad anticancer and anti-inflammatory efficacy in preclinical models. Phase 1 clinical trials of orally-administered opaganib to patients with advanced solid tumors or multiple myeloma are complete, and Phase 2 clinical trials of opaganib in patients with prostate cancer or cholangiocarcinoma are in progress. Additionally, opaganib improved clinical outcome for highly compromised patients with severe Covid-19. To date, opaganib has been administered to >470 patients with a favorable safety profile. Because GI-ARS is mediated by epithelial cell apoptosis and excessive inflammation, processes regulated by sphingolipids, we hypothesized that opaganib will decrease GI damage from radiation exposure leading to mitigation of GI-ARS and improved survival. In Proof-of-Concept studies supported by the Biomedical Advanced Research and Development Authority and the Department of Defense, we demonstrated that oral opaganib provides highly significant protection against mortality from GI-ARS in mice following irradiation in a 5% bone marrow-shielded model. Opaganib increased survival when administered either prior to radiation or 24 hr after radiation exposure and was efficacious at levels that have been demonstrate safe in human trials. In a pre-IND meeting, the FDA encouraged the continue development of opaganib as an MCM for GI-ARS under the Animal Rule for regulatory approval. Specific requirements for approval were identified, and are addressed in the following Specific Aims for this Phase 2 SBIR project: 1. Definition of the biochemical mechanism(s) for protection against radiation-induced cell death and inflammation in intestinal epithelial cells; 2. Definition of the effect of radiation exposure on the pharmacokinetics (PKs) of orally-administered opaganib; and 3. Identification of assessable pharmacodynamic (PD) biomarkers for opaganib for future pivotal animal studies and human clinical trials. The studies proposed herein follow FDA guidance for approval under the Animal Rule and will enable continued advancement of opaganib as an MCM for GI-ARS.