Background: Nicotinamide phosphoribosyltransferase (NAMPT) controls how cells use energy and is central to human biology. NAMPT is up-regulated in many cancers, including hematologic malignancies. Cancer cells have a heightened dependency on NAMPT-driven NAD flux that makes them particularly sensitive to NAMPT inhibitors. However, since healthy cells also require NAD for survival, previous clinical attempts at NAMPT inhibition have resulted in dose-limiting toxicities preventing their development. To circumvent this, we developed RPT1G, a first-in-class hyperbolic NAMPT inhibitor with an enhanced therapeutic window that enables therapeutically active NAD reduction in cancer cells while allowing sufficient NAD production in healthy tissues (Crimmins, ASH 2023).

Data from a first-in-human, Phase 1, randomized, double-blind, placebo-controlled, SAD and MAD study in healthy volunteers shows that oral administration of RPT1G is safe and well-tolerated with a favorable PK profile. Human target engagement results are consistent with RPT1G inhibiting NAMPT at doses predicted to be therapeutically relevant in oncology.

Study Design and Methods: RPT1G is being investigated in an international, Phase 1, multi-center, open-label clinical trial (NCT07107126) for treatment of Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) and High-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS).

The study will use a standard 3+3 design with escalating oral monotherapy doses of RPT1G, twice daily for 14-day cycles, with potential to explore other dosing schedules based on observed pharmacokinetics (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, derived from healthy volunteer study, achieves NAMPT target engagement at levels predicted to reduce tumor burden.

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. The study will enroll adults with a histological confirmation of R/R-AML as defined by the ELN 2022 criteria or HR-MDS as defined by the International Consortium for MDS 2023 criteria that have received appropriate standard of care therapy(s) in the opinion of the investigator or declined receipt of these. Adequate organ function is required. Patients will be excluded if they have ongoing AEs from prior therapies; have received radiation within 14 days of the first dose of study drug; have known active infections; or have uncontrolled cardiac issues, or other medical comorbidities that will preclude safety evaluation. Approximately 18 patients will be enrolled across 5-10 sites across the US and Australia.

RPT1G is the first NAMPT hyperbolic inhibitor to be studied for the treatment of R/R-AML and HR-MDS patients.

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2025
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