AST-008, a TLR9 agonist spherical nucleic acid, activated NK cells, T cells, and cytokines in healthy subjects in a Phase I clinical trial

Background Exicure develops spherical nucleic acid (SNA) constructs, which are 3-dimensional arrangements of oligonucleotides where the nucleic acids are densely packed and radially oriented around a nanoparticle. SNAs have properties that are distinct from the “linear” nucleic acids (i.e., nucleic acids not arranged in the SNA format), which include, most importantly, increased cellular uptake compared to linear nucleic acids. AST-008 is an SNA configuration of a toll-like receptor 9 (TLR9) agonist oligonucleotide, designed to trigger anti-tumor immune responses in patients with cancer. AST-008 is intended to be administered intratumorally in combination with checkpoint inhibitors for the treatment of solid tumors. AST-008 has potent antitumor activity as a monotherapy and synergizes with anti-PD-1 antibody therapy in several preclinical tumor models. Materials and Methods AST-008 has been evaluated in a Phase 1 study (Protocol number: AST-008-101). The safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending doses of AST-008 were studied in healthy volunteers. Four dose levels of AST-008 were evaluated in four cohorts. Results The results indicated that AST-008 was safe and well tolerated after single subcutaneous injections. No serious adverse events or dose limiting toxicity were reported. The most common adverse events observed were flu-like symptoms, injection site reactions, and reversible, short-lived leukopenia and neutropenia. AST-008 induced an innate immune response after administration to healthy volunteers. Cytokine and chemokine analysis indicated that a Th1-type immune response was elicited. IL-12 (p40), IL-1RA, IL-6, IP-10, and MCP-1 were consistently induced across all doses. AST-008 elicited 9.5 fold and 3.5 fold increases in the fraction of activated T cells and natural killer cells, respectively, compared to baseline at the highest dose tested. These results suggest that the cytokines and immune cell activation elicited by AST-008 will initiate and propagate the cancer immunity cycle in the presence or absence of checkpoint inhibitors. Pharmacokinetic analysis revealed that the concentration of AST-008 in plasma peaked 2 hours after dosing and was dose proportional. Conclusions AST-008 elicited no serious adverse events or dose limiting toxicity at the doses tested. AST-008 is a potent innate immune activator and exhibits pharmacodynamic properties that are expected to result in anti-tumor effects in patients with cancer. A Phase 1b/2 study of AST-008 in combination with pembrolizumab in cancer patients is ongoing. Citation Format: Weston L. Daniel, Ulrike Lorch, Simon Coates, Alice S. Bexon, Scott Mix. AST-008, a TLR9 agonist spherical nucleic acid, activated NK cells, T cells, and cytokines in healthy subjects in a Phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT044.