ONM-501, a dual-activating polyvalent STING agonist, enhances tumor retention and demonstrates favorable preclinical safety profile
Introduction
The STING (STimulator of INterferon Genes) pathway plays a crucial role in the innate immune response against infection and cancer. Previous STING agonist development compounds have showed limited therapeutic efficacy (for intratumoral compounds) and/or a prohibitive safety profile (for IV STING agonists) in clinical trials for oncology applications. ONM-501 is a dual-activating STING agonist: the endogenous STING agonist 2’,3’-cGAMP is encapsulated within a micelle of PC7A, a synthetic polymer that induces polyvalent STING condensation and prolongs innate immune activation. This combined approach should result in both “burst”’ and “sustained” STING activation. Here we report in vivo efficacy and pharmacodynamic analysis of ONM-501 as monotherapy and in combination with anti-PD1 in pre-clinical tumor models. Furthermore, we present the safety evaluation, pharmacokinetic and biodistribution analysis of ONM-501 in mice and safety evaluations in non-clinical models from multiple species.
Methods
Anti-tumor efficacy was evaluated by tumor growth inhibition and survival in tumor-bearing mice. Immune activation and tumor microenvironment changes were evaluated by FACS analysis in tumor and draining lymph nodes and cytokine analysis in peripheral blood; STING activation was evaluated by downstream gene expression. To characterize the pharmacokinetics and biodistribution of ONM-501, a fluorescent labeled ONM-501 was used in intratumoral (IT) or subcutaneous (SC) administration. Plasma and multiple organ samples were collected; whole tissue specimens were first imaged ex vivo. ONM-501 was quantified against standard curves. PK parameters were calculated using non-compartmental methods. Safety and tolerability were evaluated in mice, rats, and primates by single- and multiple-dose subcutaneous injections in naïve animals up to the highest feasible dose.
Results
Anti-tumor efficacy was demonstrated both as ONM-501 monotherapy and in combination with anti-PD1 in syngeneic B16F10 tumor model. FACS analysis showed significantly increased number of tumor-infiltrating T-cells after ONM-501 monotherapy and anti-PD1 combo therapy. ONM-501 upregulated PD-L1 expression in tumor tissue which may sensitize it to anti-PD1. STING activation was observed by increased IRF7 and CXCL10 mRNA levels in tumor lymph nodes. The biodistribution pattern of ONM-501was similar for IT and SC administrations. The highest concentrations of ONM-501 were observed at the injection site and draining lymph nodes at all timepoints for both routes of administration. The concentrations in the injection site were much lower following SC than following IT administration. Systemic exposure to ONM‑501 was higher after SC than IT administration. Tumor concentrations were substantially higher than those in plasma as were the values for Cmax and AUC; intratumoral t½ of ONM-501 was 25.2 hours. In the single-dose studies, ONM-501 was well tolerated in mice, rats, and cynomolgus monkeys without severe or irreversible systemic toxicities up to the maximum feasible doses. In the 4-week repeat-dose studies, the HNSTD in rats was 30mg/kg and in monkey, 7.5mg/kg.
Conclusion
ONM-501 demonstrated marked anti-tumor efficacy as a monotherapy or in combination with anti-PD1 in murine syngeneic tumor models. The in vivo PD analysis confirmed STING activation, enhanced tumor T-cell infiltration and PD-L1 upregulation by ONM-501. Toxicology studies of ONM-501 in rats and non-human primates demonstrated a strong safety profile and large therapeutic window. Systemic exposure to ONM-501 was higher after SC than IT administration, demonstrating enhanced ONM-501 retention in tumors. Preclinical toxicology studies indicated a favorable tolerability and safety profile that supports its continued development in cancer patients. Based on these pre-clinical results, ONM-501 has entered a first-in-human Ph1 trial of monotherapy and combination with an anti-PD-1 monoclonal antibody.