Abstract A023: Brain penetrant small molecule for the treatment of glioblastoma
Authors: Patron Lilian A. , Yeoman Helen , Wilson Sydney , Gokhale Vijay , Suzuki Teri 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is characterized as a high-grade glioma (HGG) and is the most lethal brain cancer in adults. Every year more than 12,000 people in the United States are diagnosed with GBM. The standard of care for GBM is maximally safe surgical resection, followed by concurrent radiation and temozolomide (TMZ) therapy. However, despite this treatment, GBM kills 95% of patients within five years of diagnosis, with more than half dying within the first 15 months. The existing therapies for GBM are limited, and a clinically critical issue is the inevitable development of TMZ resistance. With no new FDA approvals since 2009, there is a dearth of successful innovation providing better treatments for GBM patients. Preclinical studies by Reglagene and others have shown that tubulin-targeting therapies can be effective in treating brain cancers. Reglagene has developed a potent tubulin destabilizer RGN6024 for the treatment of GBM. One of the major challenges with GBM is that the blood-brain barrier (BBB) interferes with the delivery of therapeutic agents to the brain. RGN6024 was specifically designed to maximize BBB penetration, and achieves high concentrations in rodent brains, when given at safe dosing levels. Additionally, RGN6024 potently inhibits cell viability in vitro across a range of tumor lines. In a cell-line derived xenograft (CDX) mouse model, RGN6024 demonstrated outstanding efficacy, with significant tumor growth reduction compared to control and TMZ treatment. The development of a BBB penetrant, small molecule therapeutic with a mechanism of action that has been clinically proven in other cancers would be a major advance for the treatment of GBM and other HGGs. RGN6024 is currently in preclinical development, with a projected IND filing in mid-2024. Methods & Results: In the MDR1-MDCK (multidrug resistance protein 1, Madin-Darby canine kidney cell) in vitro model of permeability, RGN6024 has an efflux ratio of 1, indicating it is not a substrate for MDR1. RGN6024 shows excellent BBB penetration in the brains of mice (Cmax of 3530 ng/g in the brain 30 minutes after oral dosing). The potency of RGN6024 was assessed in 6 glioma/GBM cell lines with EC50 values from 30 to 150 nM. In vivo efficacy was measured using LN-18 (HGG line with an unmethylated MGMT promoter and TMZ-resistance). RGN6024 demonstrated an 80% reduction in tumor growth (vs. control and TMZ) when dosed at 7.5 mg/kg. RGN6024 did not cause significant weight loss at doses up to 30 mg/kg. Conclusions: Taken together, these results demonstrate that RGN6024 is a BBB penetrant small molecule that has striking in vitro and in vivo efficacy and shows great potential for use in the treatment of glioblastoma and other brain cancers.
Citation Format: Lilian A. Patron, Helen Yeoman, Sydney Wilson, Vijay Gokhale, Teri Suzuki. Brain penetrant small molecule for the treatment of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A023.