Bolder Biotechnology Inc

Novel Drug Combinations for Improving Survival From Acute Radiation Syndrome When Administered 48 Hours Post- Irradiation - Abstract. Bone Marrow Is One of the Most Radiation-sensitive Tissues, and Patients Acutely Exposed to Total Body Irradiation (TBI) Doses > 2 Gy Develop Severe Neutropenia, Thrombocytopenia, Anemia, and Lymphopenia Within Days to Weeks of Exposure, Often Dying From Infections (due to a Lack of Neutrophils) and Uncontrolled Bleeding (insufficient Platelets) (referred to as the Hematopoietic Acute Radiation Syndrome, or H-ars). the Few Drugs That Have Received Fda Approval to Treat H-ars Increase Survival When Administered Within 24H of Radiation Exposure, But Do Not Increase Survival When Administered at Later Times Such as 48H Post-irradiation in Animal H-ars Models. in a Radiological/nuclear Emergency, Hundreds of Thousands of People Potentially Will Be Exposed to > 2 Gy Radiation and It Is Extremely Unlikely That They All Can Be Treated Within the First 24 Hours of Radiation Exposure. Thus, There Is a Critical Unmet Medical Need for Drugs Capable of Increasing Survival From H-ars When Administered 48H or Later Post-irradiation. We Demonstrated That a Novel Drug (peg IL-11) and 3 Drug Combination Including Peg IL-11 Significantly Improve 30D and 180D Survival of LD70/30 Irradiated Mice When Administered Once 48H Post-tbi. This Is the Only Drug/drug Combination We Are Aware of Capable of Increasing Survival When Dosing Is Delayed Until 48H Post-tbi in Mice. When Dosed Once 24H or 48H Post-tbi, the 3 Proteins Interact Positively With Each Other to Increase Survival More Than the Individual Proteins, Most Evident at High Tbi Doses. the 3 Protein Combination and Peg IL-11 Show Sex-specific Survival Effects, Up to 100% Survival at LD95/30 Tbi Doses, When Combined With a 4TH Radiation Mitigator, an Angiotensin Converting Enzyme Inhibitor (acei), an Unprecedented Survival Rate. Most H-ars Studies to Date Have Used Inbred Young Adult Mice. Since Mouse Strains and Different Age Mice Show Different Radiation Sensitivities, the Phase 2 Grant Will Evaluate Whether These Exciting Findings Extend to Pediatric Mice and Outbred Mice to Determine Whether the Survival Efficacy and Sex-specific Effects of the Proteins (+/- Acei) Are Universal or Mouse Strain / Age Specific. We Will Evaluate Whether (1) Peg IL-11 and the 3 Protein Combination (+/- the Acei) Increase Survival of Pediatric and Outbred Mice Exposed to LD70/30 Radiation Doses When the Proteins Are Administered 24 and 48H Post-tbi; (2) Whether Increased 30D Survival Correlates With Accelerated Peripheral Blood Cell Recovery (neutrophils, Platelets) and More Rapid Increases in Hematopoietic Stem and Progenitor Cell Numbers Early After Irradiation; and (3) Whether Drug Treatment and Increased Survival Correlate With Specific Plasma Biomarker Changes. We Will Evaluate Safety of Different Doses of Peg IL-1 in a Mouse GLP Toxicology Study to Identify Safe Doses of the Drug for Use in Humans, and Manufacture a GMP Lot of the Protein, Both of Which Are Required for Filing an Ind to Begin Testing the Protein in Humans. Peg IL-11 and TC Are Potential Life-saving Treatment Options for a Heretofore Untreatable H-ars Population – Patients Who Cannot Be Treated Until 48H or Later Post-tbi.