Riboscience, LLC announced successful completion of the Phase 1a dose escalation portion of its clinical trial evaluating RBS2418, marking a significant milestone for the first ENPP1 inhibitor to enter clinical development. The data, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting by Dr. Thomas U. Marron from Mount Sinai, demonstrates promising safety and target-dependent efficacy in heavily pretreated cancer patients.
Study Design and Patient Population
The Phase 1a/b clinical trial (NCT05270213) enrolled adult patients with advanced, unresectable, recurrent or metastatic solid tumors who had progressed on or were ineligible for standard therapies. The dose escalation phase followed a 3+3 design, testing increasing doses of RBS2418 (100, 200, 400, 800 mg) administered orally as monotherapy or in combination with pembrolizumab.
The study population represented significant treatment challenges, with 24 patients across 13 different cancer types and 83% having failed three or more lines of prior treatment. This heavily pretreated population underscores the potential value of RBS2418 for patients with limited therapeutic options.
Safety Profile and Pharmacokinetics
RBS2418 demonstrated an exceptional safety profile across all dose levels tested. No dose-limiting toxicities (DLTs), treatment-related serious adverse events (SAEs), or treatment-related adverse events above grade 2 were observed. The drug's tolerability is further evidenced by one patient continuing daily 800 mg twice-daily monotherapy for more than 17 months, confirming long-term safety and immune control.
Pharmacokinetic analysis revealed dose-proportional increases in median plasma maximum concentration (Cmax) and trough levels (Ctrough) of RBS2418. Importantly, drug concentrations in both plasma and tumor samples exceeded the human serum EC90 for ENPP1 inhibition across all patients and dose levels, indicating effective target engagement.
Target-Dependent Clinical Benefit
The study revealed a critical biomarker-driven efficacy signal. Patients were stratified based on baseline tumor expression of ENPP1 and cGAS proteins, defining EG+ and EG- phenotypes. Progression-free survival was significantly increased in EG+ versus EG- phenotypes (p=0.001), demonstrating clear target-inhibition dependent clinical benefit.
This biomarker correlation extended to immune activation patterns, with baseline cold tumor phenotype showing immune activation and tumor infiltration of CD4 and CD8 T cells on treatment, specifically correlating with ENPP1 and cGAS protein expression in baseline tumor samples.
Mechanism and Clinical Development
RBS2418 functions through ENPP1 inhibition and cGAMP stabilization, achieved at all dose levels tested. This mechanism represents a novel approach to cancer immunotherapy, targeting the cGAS-STING pathway to enhance anti-tumor immune responses.
Based on these encouraging Phase 1a results, Riboscience has advanced RBS2418 into Phase 2 development. The first Phase 2 study focusing on advanced metastatic colorectal cancer began enrolling participants in February 2025 (NCT06824064), representing a significant step forward for this first-in-class immunotherapy agent.
The successful completion of Phase 1a dose escalation positions RBS2418 as a potentially transformative treatment option for cancer patients, particularly those with tumors expressing the target biomarkers. The combination of excellent tolerability, clear target engagement, and biomarker-driven efficacy provides a strong foundation for continued clinical development of this novel immunotherapy approach.
