Abstract 582: Selection of a novel toll-like receptor 7 (TLR7) agonist PRX034 for immunotherapy of cancer

Abstract

Abstract At Primmune, we believe that maximal therapeutic benefit in cancer immunotherapy will be achieved by maintaining sustained, systemic immune pressure involving both innate and adaptive immunity. We have therefore chosen PRX034, an orally administered TLR7 small molecule agonist, for clinical development. This candidate will ultimately be used in combination with immune checkpoint inhibitors (ICPIs) for the treatment of cancer. This TLR7 agonist preferentially activates plasmacytoid dendritic cells, the master coordinator of innate and adaptive immunity. Further, PRX034 and related analogs preferentially induce cellular production of Type I interferons while minimizing production of proinflammatory cytokines through the NFκβ pathway in vitro and in vivo. We have previously reported values for a series of unusual properties that must be matched for any drug candidate successfully targeting TLR7 and intended for chronic and systemic administration (1). During lead optimization, each compound was evaluated in the following assays in order to assess whether requirements had been met: cellular assays (TLR reporter cells, human and monkey peripheral blood mononuclear cells), pharmacokinetic assays (IV administration of active agonist and PO administration of corresponding prodrug in cynomolgus monkeys), and pharmacodynamic response in cynomolgus monkeys. The declaration of PRX034 as a clinical candidate was ultimately dependent upon successfully meeting pre-selected targets for compound potency and reproducibility of induced immune response in a repeat dose study in cynomolgus monkeys. Specifically, PRX034 was administered orally as a prodrug on a QOD schedule for two weeks at two dose levels selected in a previous dose range-finding study. TLR7 agonist pharmacokinetics and the kinetics and dynamics of immune induction following each administered dose were constant within targeted levels throughout the study. Consequently, PRX034 has progressed into IND-enabling studies. Based upon our previous experience with TLR7 agonists meeting our profile, we expect safety in pivotal repeat-dose toxicology studies to be sufficient to enable PRX034 to be evaluated in healthy volunteers (HVs). This clinical study will include SAD cohorts followed by two MD cohorts, the latter including two dosing schedules. Feasibility and utility of this HV study require both appropriate preclinical safety findings and relevant pharmacodynamic markers that can be readily measured in volunteers. This study will ensure that subsequent cancer patients receive only pharmacologically active doses and that evaluation in combination with ICPIs is facilitated. (1) Appleman J, Webber, S. Discovery of a series of novel toll-like receptor 7 agonists for systemic immunotherapy of cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2019. Mar 29 - Apr 3; Atlanta, GA. Abstract # 3262. Citation Format: James Richard Appleman, Stephen E. Webber. Selection of a novel toll-like receptor 7 (TLR7) agonist PRX034 for immunotherapy of cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 582.