Abstract CT161: First-in-human study of ENPP1 inhibitor, SR-8541A, for the treatment of solid tumors

Abstract

Abstract Purpose: Compelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator of INterferon Genes) pathway is vital to elicit potent anti-cancer innate immune responses. STING is widely expressed and targeting it directly poses many challenges, including systemic activation of interferon. Therefore, alternative approaches to activate STING in a controlled manner may generate a better therapeutic response in cancer patients. Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) is the direct negative regulator of the STING pathway that hydrolyzes 2’3’ cGAMP, the direct activator of STING. Highest levels of 2′3′ cGAMP can be found in tumors and recent evidence suggests that 2′3′ cGAMP acts locally, as a paracrine immune transmitter. Recent studies have also reported elevated ENPP1 expression in metastatic tumors. We hypothesize that inhibiting ENPP1 with a small molecule inhibitor may produce superior outcomes by activating STING in the tumor microenvironment. We have developed SR-8541A, a highly selective and potent inhibitor of ENPP1. Our initial work to support the development of SR-8541A consisted of pharmacodynamics studies, bioanalytical development, pharmacokinetics (PK) and non-GLP toxicology studies in three species, a GLP repeat dose dog telemetry study, and 28-day GLP toxicology studies in rats and dogs including toxicokinetic (TK) analyses. Here we report initial findings from our ongoing first in human, phase I trial of SR-8541A in advanced metastatic solid tumors. Methods: This study is evaluating the safety, tolerability, and pharmacokinetics (PK) of SR-8541A administered orally as a monotherapy in subjects with solid tumors which are refractory to standard therapeutic options, or for which there are no standard therapeutic options (NCT06063681). The primary objective of the study is to characterize the safety, tolerability, DLTs, maximum tolerated dose and RP2D and schedule for future studies of SR-8541A. Secondarily, the study aims to evaluate the PK and efficacy per RECIST of SR-8541A. SR-8541A is administered orally in 28-day cycles and is following an accelerated titration dose (ATD) escalation. Blood samples are being collected for PK assessment, target engagement, and biomarker assessment. Results: Sample analysis from a subject treated with SR-8541A (5 mg) in the ATD portion of the study is ongoing. No treatment-related adverse events have been reported. No dose-limiting toxicities occurred during the 28-day DLT period. Plasma drug levels collected for the PK show cMAX concentrations in the projected therapeutic dose range. Biomarker assessment is ongoing and will be included in the presentation. The SR-8541A dose has escalated and the study is currently enrolling at the 10 mg dose. Conclusions: The first evaluated dose of SR-8541A has shown to be safe and well tolerated. Pharmacokinetic data shows strong oral bioavailability and supports escalation in the phase I trial and continued assessment of SR-8541A in the clinic. Citation Format: Alexis S. Weston, Trason Thode, Monil Shah, Amanda Seiz, Jonathan Northrup, Srinivas Kasibhatla, Mohan Kaadige, Sunil Sharma. First-in-human study of ENPP1 inhibitor, SR-8541A, for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT161.