Abstract CT180: Activation of innate and adaptive immune response with a clinical stage TLR7 agonist prodrug PRTX007

Abstract

Abstract Background. PRTX007 is an orally administered prodrug of PRX034, a toll-like receptor 7 (TLR7) agonist that elicits an unprecedented pattern of systemic immune induction in non-human primates and in humans. Notably, there is no evidence of NF-Kβ-mediated systemic inflammation at drug levels that stimulate IFN-responsive pathways and corresponding downstream cellular processes, including activation of CD8+ T cells and NK cells. We have previously reported interim results from a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study of PRTX007. PRTX007 demonstrated a favorable safety profile with no serious adverse events (SAEs) and a lack of the adverse events (AEs) historically associated with TLR7 agonists. Robust systemic immune induction was achieved, without counter-regulation or evidence of systemic inflammation, in participants receiving PRTX007 in the 300 - 500 mg MAD cohorts. This report describes new results from the 750 mg MAD cohort, the highest MAD dose level in this now-completed study. Methods. Phase 1, single-center, prospective, randomized, double-blind, placebo-controlled study of 9 SAD and 4 MAD cohorts of PRTX007 administered QOD orally to healthy adult participants. Primary objectives were safety and tolerability. Secondary objectives were evaluation of pharmacokinetics (PK) and pharmacodynamics. In total, 104 of the 130 participants in this study received study drug. Results. AEs were limited to non-dose-related mild headache, minor dose-related increases in ALT (<2X ULN) that rapidly resolved, and mild-moderate fever that were transiently observed in 1 of 8 participants. The PKs of PRTX007 and PRX034 are well-behaved with exposure increasing proportionally to PRTX007 dose without accumulation upon repeated dosing (mean PRX034 AUC (hr*ng/ml) on D1: 13,432; D13: 13,796). Coordinated expression of interferon-stimulated genes and genes known to be related to TLR7 agonism were observed in immune cells in blood in all participants. Increases in IL-1RA, MCP-1 and IP10 in plasma were also observed. IL-6, TNFα and IL- 1β remained essentially unchanged from pretreatment levels. The proportion of CD8+ T cells and NK cells, with significant expression of the proliferation marker Ki67 and activation marker CD38, increased markedly from pretreatment to end of dosing in all participants. Ki67+ expressing CD8+ T cells increased from 1.1% to 9.8% and Ki67+ expressing NK cells increased from 3.6% to 10.3% during the two-week period of drug administration. CD38+ CD8+ T cells increased from 11.8% to 21.9% and CD38+ NK cells increased from 59.4% to 80.0% during the corresponding period. Conclusion. PRTX007 demonstrated a favorable safety profile in all SAD and MAD cohorts. In the 750 mg MAD cohort, activation of the innate and adaptive immune response including important effector cell populations were observed without systemic increases in proinflammatory factors. Citation Format: Charlotte R. Lemech, Christopher Argent, Curtis L. Scribner, Andrew Sharabi, Richard Daniels, James R. Appleman. Activation of innate and adaptive immune response with a clinical stage TLR7 agonist prodrug PRTX007 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT180.