DDEL-15. EnTrega CSF circulation and drug delivery system improves drug distribution in brain parenchyma

Abstract BACKGROUND Central nervous system metastases are difficult to treat with standard systemically administered drugs due to the blood-brain barrier (BBB) and blood cerebrospinal fluid (CSF) barrier. Intrathecal administration of chemotherapy can enhance drug delivery to the CSF but does not penetrate or distribute throughout the brain parenchyma. EnClear Therapies created the EnTrega device, a technology that uses the access to CSF and drives CSF circulation to improve drug delivery and enable easy sampling of CSF. METHODS We treated 8 healthy sheep with the EnTrega system using two different flow paths. Group 1 had catheters in the right and left lateral ventricle and Group 2 had a catheter in one lateral ventricle and the lumbar thecal sac. Administration of methotrexate was followed by an extracorporeal pump to control the speed and direction of CSF. Sensors continuously monitored pressure, respiration, and heart rate. Injection of Omnipaque dye determined the best parameters for controlling CSF flow. Methotrexate levels in CSF, blood, brain, spinal cord, kidney, and liver were measured with LC/MS. RESULTS Dye studies confirmed that CSF flow can be controlled using the EnTrega system as we observed dye moving from one ventricle to the other and back again. EnTrega’s sensor array continuously monitors intracranial pressure, heart and respiratory rate which were found to stay within safe limits during controlled CSF circulation. Good bilateral distribution of methotrexate in the brain was observed with penetration into the parenchyma that exceeded therapeutic levels (>1 ug/mg) including deep structures such as the striatum. CONCLUSIONS This presentation demonstrates the safety and feasibility of optimal drug delivery using the novel EnTrega system and demonstrates both CSF and brain parenchymal drug distribution with CSF drug administration in a large animal model. We plan to test this technology in a first-in-human study planned to open Q2 2026.