Phase 1, open-label, multi-center trial of RPT1G in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes/neoplasms

Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in the NAD salvage pathway, regulates cellular energy metabolism and plays a key role in human biology. NAMPT expression is elevated in many cancers, particularly hematologic malignancies. Cancer cells exhibit an increased reliance on NAD-flux, which renders them especially vulnerable to NAMPT inhibitors. Yet, because normal cells also require NAD for survival, earlier clinical trials involving NAMPT inhibition resulted in dose-limiting toxicities that hindered their advancement. We developed RPT1G, a first-in-class hyperbolic inhibitor with an improved therapeutic window. RPT1G's novel mechanism of action, allows therapeutically effective NAD depletion in malignant cells while maintaining sufficient NAD synthesis in normal tissues (Crimmins, ASH 2023). A first-in-human, Phase 1, randomized, double-blind, placebo-controlled, SAD and MAD study in healthy volunteers of RPT1G showed that oral administration of RPT1G is safe and well-tolerated with a favorable pharmacokinetics (PK) profile. Target engagement results are consistent with RPT1G inhibiting NAMPT at doses predicted to be therapeutically relevant. Study Design and Methods: RPT1G is being investigated in a Phase 1, multi-center, open-label clinical trial (NCT07107126) for treatment of Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS). The study uses a standard 3+3 design with escalating oral doses of RPT1G, twice daily for 28-day cycles. Other dosing schedules will be explored based on observed PK parameters, PK/pharmacodynamic (PD) relationships, safety, and tolerability data to identify the maximum tolerated dose (MTD) or presumptive biologically effective dose (BED) and select the recommended phase 2 dose (RP2D). The starting dose of 120 mg BID is pharmacologically active in humans and predicted to result in early signs of efficacy. Primary objectives include: 1) defining safety and tolerability; 2) determining the RP2D, optimal schedule and/or BED. Key secondary objectives include: 1) evaluating PK; 2) assessing preliminary efficacy by European LeukemiaNet (ELN) 2022, including overall response rate (ORR), duration of response (DoR), and hematologic improvement (HI), and clinical benefit by transfusion independence and the International Working Group 2023 HR-MDS response criteria. Enrollment for this study includes adults > 18 years old, with a histological confirmation of R/R-AML (ELN 2022 criteria) or HR-MDS (International Consortium for MDS 2023 criteria) that have received appropriate standard of care therapy(s) or declined receipt of these. Adequate organ function is required. Patients are excluded if they have ongoing AEs from prior therapies; received radiation < 14 days from the first RPT1G dose; known active infections; or have uncontrolled cardiac issues, or other medical comorbidities that will preclude safety evaluation. The trial is continuing as planned and the next data analyses will be taking place in summer 2026. RPT1G is the first NAMPT hyperbolic inhibitor to be studied for the treatment of R/R-AML and HR-MDS patients.