Abstract CT189: PRTX007, an optimized TLR7 agonist for systemic immunotherapy of cancers: Interim analysis of phase I study in healthy volunteers (2022)

Abstract Background. Toll-like receptor 7 (TLR7) agonists have long been recognized as potential systemic anti-cancer immunotherapy agents. However, clinical development has been limited by complex target-mediated pharmacology including those associated with elevated levels of proinflammatory factors, which also limit the ability to combine with immune checkpoint inhibitors (CPI). PRTX007 is an orally administered prodrug of PRX034, a novel TLR7 agonist that elicits IFN-mediated immune induction without inducing inflammation via the NF-κβ pathway. QOD dosing in primates maintains a stable immune response without immune exhaustion or toxicity. Efficacy, safety, and compatibility with immune CPI were demonstrated in a CT26 syngeneic rodent tumor model. Methods. We conducted a phase 1, single-center, prospective, randomized, double-blind placebo-controlled study of 8 single-ascending dose (SAD) and 4 multiple-ascending dose (MAD) cohorts of PRTX007 administered orally to healthy adult participants. Primary objectives were safety and tolerability. Secondary objectives were evaluation of pharmacokinetics (PK) and pharmacodynamics. This interim analysis focuses on the 8 SAD (50-600 mg) and 2 MAD (300-400 mg) cohorts, with 64 of the 84 participants in the study receiving drug. Results. Treatment-related adverse events include non-dose‒related mild headache, and minor dose-related increases in ALT (&amp;lt;2X ULN) that rapidly resolved. The PKs of PRTX007 and PRX034 are well-behaved eg, exposure increasing proportionally with PRTX007 dose. Consistent with studies in human cells in vitro and non-human primates in vivo, oral administration of PRTX007 elicits systemic TLR7-mediated immune induction without engaging NF-κβ─mediated biosynthesis of IL-6, TNFα and IL-1β in humans. A single dose of PRTX007 (300-600 mg) elicits coordinated expression of IFN-stimulated genes (ISGs) in blood without quantifiable increases in circulating IFNs. At 500 and 600 mg doses, IP-10, IL-1RA, MCP-1 and TRAIL but not IL-6, TNFα or IL-1β increase in plasma (maximal response = 4020, 1460, 650 and 360 pg/ml, respectively). When PRTX007 is administered for 2 weeks on a QOD schedule at 400 mg/dose, the degree of ISG expression progressively increases when compared to the first-dose response, (eg, ISG15 increases 2.1-fold [geometric mean] following Dose 1 vs pretreatment baseline, rising to 12.2-fold following Dose 7). This is accompanied by modest activation of circulating NK, B, and CD4+ and CD8+ T cells as measured by cell-surface markers. IL-6, TNFα and IL-1β remain unchanged from pretreatment levels. Conclusion. At the interim analysis, PRTX007 demonstrated a favorable safety profile when administered orally to all tested SAD and MAD cohorts. Dose-dependent systemic exposure was observed, as well as activation of the innate immune response, without production of proinflammatory factors. Citation Format: Charlotte Lemech, Christopher Argent, Curtis Scribner, Richard Daniels, James Richard Appleman. PRTX007, an optimized TLR7 agonist for systemic immunotherapy of cancers: Interim analysis of phase I study in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT189.