Veledimex racemate, the racemic form of veledimex, is an orally available, small-molecule ligand that activates the RheoSwitch Therapeutic System.

Interleukin 12 (IL-12) is a pro-inflammatory cytokine essential for stimulating anti-cancer immune responses. Ad-RTS-IL-12 is an adenovirus vector designed to express hIL-12. Veledimex, an orally active small molecule diacylhydrazine, controls the expression of target genes, with gene product levels and duration of action dependent on veledimex dose and administration timing.

In murine models of melanoma, breast cancer, and glioma, the combined intratumoral injection of Ad-RTS-mIL-12 and oral dose of veledimex has shown to produce a dose-dependent antitumor effect. This response is associated with increased veledimex levels in plasma and tumor tissues. Notably, this combination therapy leads to a dose-responsive activation of IL-12 mRNA (switch on) and subsequent elevations of IL-12p70 within the tumor, while only minimally increasing its levels in the serum. Enhanced tumor levels of IL-12 are linked with an upsurge in CD8+ cytotoxic T cells and a reduction in regulatory T cells within the tumor microenvironment. Consequently, this regimen achieves dose-dependent reductions in tumor growth rates without significantly affecting body weight in both breast and melanoma syngeneic mouse models. Veledimex exhibits moderate to low oral bioavailability (-56% in mice and up to 17.4% in cynomolgus monkeys), alongside relatively low plasma clearance (1399 mL/h/kg in mice and 1170 mL/h/kg in monkeys), a high volume of distribution (20271 mL/kg in mice and 9180 mL/kg in monkeys), and prolonged terminal half-lives (-10 hours in mice and -30 hours in monkeys), following single oral or intravenous administrations.