Abstract Background: Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) has emerged as a compelling therapeutic target in oncology, with data suggesting that it functions as a dual checkpoint for innate and adaptive immunity. ENPP1 directly binds to and hydrolyzes 2′3′-cyclic GMP-AMP (cGAMP), the natural ligand responsible for the activation of STING-dependent innate immunity. Additionally, ENPP1 hydrolyzes cGAMP, ATP, and nicotinamide adenine dinucleotide (NAD+) to generate adenosine, which is known to have broad immunosuppressive effects on both innate and adaptive immune responses. Elevated ENPP1 expression has been reported in advanced metastatic tumors, suggesting a mechanism of tumor-mediated immune evasion. Previously, we reported the clinical development of vizenpistat (SR-8541A), a potent oral inhibitor of ENPP1 designed to reignite anti-tumor immune response by elevating cGAMP levels and simultaneously preventing production of adenosine. Here we report initial findings from our ongoing first in human, phase I trial of vizenpistat in advanced metastatic solid tumors. Study Design: This Phase I study is evaluating the safety, tolerability, and pharmacokinetics (PK) of vizenpistat administered orally, twice daily (BID) as monotherapy in subjects with solid tumors that are refractory to standard therapeutic options or for which no standard therapies exist (NCT06063681). The primary objective of the study is to characterize the safety and tolerability of vizenpistat, identify dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD), recommended Phase II dose (RP2D), and dosing schedule for future studies. Secondary objectives include evaluation of the PK profile and antitumor efficacy of vizenpistat per RECIST criteria, as well as exploratory biomarker analyses. Vizenpistat is administered orally, BID in 28-day cycles using a standard 3+3 dose-escalation design and has successfully completed six dosing cohorts (5, 10, 15, 20, 30, and 40 mg BID). Beginning with the 15 mg cohort and following successful completion of the 28-day DLT assessment period, investigators are permitted to add anti-PD-1 therapy using standard administration protocols. No treatment-related adverse events and no dose-limiting toxicities occurred during the 28-day DLT periods. PK analysis shows a dose-dependent increase in exposure and cMAX concentrations above the projected therapeutic dose-range. Approximately 70% of patients achieved Best Overall Response (BOR) of stable disease, with near partial response in one patient. Biomarker assessment is ongoing and will be included in the presentation. Citation Format: Mohan R. Kaadige, Alexis S. Larsen, Trason Thode, Margaux Steinbach, Scott Houston, Srinivas Kasibhatla, Jonathan Northrup, Sunil Sharma. Phase I dose-escalation study of ENPP1 inhibitor, vizenpistat, for the treatment of solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT200.
Kaadige et al. (Fri,) studied this question.