Abstract 4076: A novel prodrug of indoximod with enhanced pharmacokinetic properties
Authors: Mautino Mario R. , Kumar Sanjeev , Zhuang Hong , Waldo Jesse , Jaipuri Firoz , Potturi Hima , Brincks Erik , Adams James , Marcinowicz Agnieszka , Allen Clarissa Van , Vahanian Nicholas , Link Charles J. 
Published: July 2017

Abstract
IDO1 catalyzes degradation of tryptophan (Trp) into kynurenines, which plays an important role in the regulation of immune responses by triggering anergy on reactive effector T cells and by modulating differentiation and activation of regulatory T cells (Treg). Indoximod has been demonstrated to relieve IDO-mediated immunosuppression in vitro and in vivo, by creation of an artificial Trp-sufficiency signal that bypasses activation of GCN2 and inhibition of mTOR in conditions of Trp deprivation. Inhibition of the IDO pathway by indoximod in combination with immune-stimulatory treatments leads to increased T cell proliferation, Treg reprogramming and antitumor effect. Indoximod has demonstrated an excellent safety profile in human clinical trials and is being dosed orally at 1200 mg bid. Increases in doses above this level do not generally result in increased plasma concentration or drug exposure due to limiting dose-dependent oral bioavailability. Animal models suggest that increased therapeutic benefit could be achieved at higher levels of exposure. For this reason, we synthesized and tested the pharmacokinetic profile of several indoximod prodrugs in mice, rat and monkeys in both liquid and capsule formulations. We selected clinical development drug candidate NLG802, which increases indoximod exposure and plasma concentration ~ 2-fold in rats and ~ 5-fold in monkeys dosed with capsules of comparable formulation to that being used in clinical trials. NLG802 is rapidly absorbed and metabolized in vivo to indoximod. NLG802 DMPK profile and GLP toxicology studies have been carried out in rats and monkeys suggesting a safe toxicological profile at predicted therapeutic doses. In a preclinical tumor model of mice bearing established B16F10 tumors, administration of NLG802 markedly enhanced the anti-tumor responses of naïve, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. In this tumor model, NLG802 plus pmel-1/vaccine produced significant tumor size reduction within 4 days of vaccination. Moreover, the tumor response was achieved at lower doses than equivalent molar doses of indoximod. In conclusion, NLG802 is a prodrug of indoximod predicted to increase clinical drug exposure to indoximod above the current achievable levels and will soon enter Phase 1 safety testing in oncology clinical trials.
Citation Format: Mario R. Mautino, Sanjeev Kumar, Hong Zhuang, Jesse Waldo, Firoz Jaipuri, Hima Potturi, Erik Brincks, James Adams, Agnieszka Marcinowicz, Clarissa Van Allen, Nicholas Vahanian, Charles J. Link. A novel prodrug of indoximod with enhanced pharmacokinetic properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4076. doi:10.1158/1538-7445.AM2017-4076