688 A phase 1 multi-center, open-label, dose escalation study to evaluate the safety and pharmacokinetics of oral SR-8541A, an ENPP1 inhibitor, in patients with advanced solid tumors

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Background Cancer cells have evolved multiple mechanisms to evade anti-tumor immune response. One mechanism involves upregulation of ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1), a protein that sits at a crossroad and regulates both innate and adaptive immunity. ENPP1 suppresses innate immunity by hydrolyzing 2’3’-cGAMP, which is an essential ligand for stimulation of STING (STimulator of INterferon Genes) activity. It also hydrolyzes ATP to AMP and plays a major role in the production of adenosine, a molecule associated with suppression of adaptive immunity and promotion of cancer cell migration and metastasis. TCGA data shows that ENPP1 is expressed in many tumor types and those with high ENPP1 expression are associated with immune suppression, cancer metastasis, and poor patient outcomes. Therefore, ENPP1 is an ideal target to challenge immune evasion caused by impaired STING-interferon signaling and adenosine-induced immune suppression in the tumor microenvironment. We have developed SR-8541A, a highly selective and potent inhibitor of ENPP1, which is now in Phase 1 clinical trials assessing its safety and pharmacokinetics (PK) in patients with advanced metastatic disease. This presentation reports preliminary safety, PK, and biomarker evaluation data from three dose cohorts. Methods The Phase 1 study is evaluating the safety, tolerability, and PK of SR–8541A administered orally as a monotherapy in patients with solid tumors 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, dose limiting toxicities (DLTs), and establish the recommended Phase 2 dose of SR-8541A. Secondarily, the study aims to evaluate the PK and preliminary efficacy of SR-8541A. SR-8541A is administered orally twice daily (BID) in 28-day cycles. Blood samples are being collected for PK assessment, target engagement, and biomarker assessment. Results Sample analysis from patients treated with SR-8541A (5, 10, or 15 mg BID) in the dose escalation portion of the study is ongoing. No serious adverse events (SAEs) or DLTs have been reported. All drug related adverse events (AEs) reported have been Grade 1 or 2. Plasma drug levels collected for the PK show consistent concentrations in the projected therapeutic dose range over a 24-hour period in all cohorts. Biomarker assessment is ongoing and will be included in the presentation. Conclusions All evaluated doses of SR-8541A appear to be generally safe and well tolerated. Pharmacokinetic data shows strong oral bioavailability and immune activation signatures. This data supports continued assessment of SR-8541A in the clinic. Trial Registration The trial has been registered and the unique identifier is: NCT06063681. Ethics Approval This study obtained the appropriate ethics committee, in Australia: Bellberry Human Research Ethics Committee, approval is 2023-08-953 Monash Health Human Research Ethics Committee, approval is 102763.

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