Preclinical Evaluation of RGN6024: A Promising Tubulin-Targeting Therapy for Brain Cancer
Introduction
The development of innovative therapies for brain cancer has been challenging due to the difficulty of delivering drugs to the brain. Targeting tubulin has shown promise in preclinical studies for treating primary and secondary brain tumors. However, clinical studies have faced repeated failures due to the blood-brain barrier. Reglagene is currently developing RGN6024, a novel orally administered tubulin destabilizing agent. Animal studies have shown promising results, indicating RGN6024's excellent safety profile in vivo and its ability to penetrate the brain. RGN6024 is currently in the preclinical development stage, undergoing safety studies in dogs and rodents. An IND filing is planned for mid-2024, followed by human clinical studies.
Methods
The objective of this research was to evaluate the efficacy of RGN6024 at three different dosing levels compared to Temozolomide (TMZ) and a vehicle in CB17 SCID mice bearing LN-18 tumors. Mice were inoculated with tumor cells subcutaneously and treatments began on day 4 when the average tumor volume reached approximately 92 mm3. The vehicle used was 30% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in saline. TMZ was formulated with 0.5% hydroxypropyl methylcellulose (HPMC) and dosed at 25 mg/kg on a 5 days on/2 days off schedule. RGN6024 was administered orally and daily in the vehicle at 7.5 mg/kg and 15 mg/kg, with an additional 25 mg/kg dose given on a 5 days on/2 days off schedule. Daily observations were made on tumor growth, normal behavior, body weight, eye/hair matting, and other abnormalities. Tumor sizes were measured three times a week, and samples were collected on day 15 for pharmacokinetic (PK) analysis.
Results
Mice in the RGN6024 cohorts showed comparable body weight and appearance to those receiving the vehicle. RGN6024 significantly reduced tumor growth rates compared to the vehicle, while TMZ had a similar impact to the vehicle. PK analysis revealed high concentrations of RGN6024 in plasma (up to 17 uM), tumor (up to 7.5 uM), and brain (up to 7.7 uM). The reduction in tumor growth was consistent across all three RGN6024 dose levels.
Conclusion
This preclinical study demonstrated the potential of RGN6024 as a promising therapy for brain cancer. The results showed excellent oral bioavailability, safety, brain penetration, and efficacy of RGN6024 in a drug-resistant glioblastoma animal model. Moreover, RGN6024 achieved high concentrations in plasma, tumor, and brain, making it a particularly promising candidate for further development. These findings provide hope for the development of an effective treatment for glioblastoma and support the continued investigation of RGN6024 as a potential therapy for this challenging form of brain cancer.