DDEL-16. DELIVERY OF OT-101 - TGF-Β ANTISENSE- FOR THE TREATMENT OF GLIOBLASTOMA

Abstract

Abstract OT-101 - a TGF-beta antisense- is active against recurrent glioblastoma in G004- a phase 2 clinical trial [Uckun FM, Qazi S, Hwang L, Trieu VN. Recurrent or refractory high grade gliomas treated by convection enhanced delivery of a TGF-beta2 targeting RNA therapeutic: a post-hoc analysis with long-term follow up. Cancers. 2019, 11:1892]. OT-101 was delivered intratumorally by Convection Enhanced Delivery (CED). To further expand the application of OT-101, we explored the intrathecal delivery of tritiated OT-101 into Sprague-Dawley CD (albino) rats. Throughout the studies, there were no sex differences. After 1 hr intracerebral infusion in rats, OT-101 was limited to the infusion site. Whereas for the 1 hr itravesicular infusion, OT-101 was more widespread with 35X, 19X, 12X higher concentration found in cerebellum, remaining cerebrum, cerebrospinal fluid (CSF), respectively. OT-101 concentration was stable for the first 4 hours post infusion and decayed biexponentially with a slow terminal half life for tissue but not for CSF, suggestive of rapid penetration of the underlying tissue away from the CSF compartment. Minimum amount of OT-101 was detected in the plasma compartment. Intrathecal bolus administration of 0.1mL of OT-101 at 14, 30, 200, 300, and 500 uM into cynomolgus monkies did not result in any single dose toxicity. Histopathology examination revealed no substance-related histomorphological lesions in the cavum subarachnoideale of the lumbar region. No changes were noted in the grey and white matter of the spinal cord, the nerve trunk, and nerve cells did not show any abnormalities. These data suggest that intrathecal administration of OT-101 is a potentially effective delivery route for antisense therapeutics such as OT-101 to the midline ie. for Diffuse Midline Glioma (DMG). A phase 1b/2 clinical trial evaluating OT-101 against DMG is proposed and the trial design will be presented