First-in-human randomized placebo-controlled Phase 1 study of RPT1G, a novel hyperbolic NAMPT inhibitor for use in acute leukemias: Safety, pharmacokinetics, and pharmacodynamics in healthy volunteers

Abstract Background. Nicotinamide phosphoribosyltransferase (NAMPT) is a well-known and extensively studied target in oncology. NAMPT catalyzes the rate limiting step in NAD recycling and is up-regulated in many hematological malignancies and other cancers. NAD is a required co-factor for cellular metabolism and is consumed during DNA damage repair, gene regulation, and cell signaling. Cancer cells are heavily reliant on NAD flux through the NAMPT pathway due to increased activity of NAD-consuming processes. However, healthy tissues also require NAD for survival and NAMPT knockouts are embryonic lethal. Four previous clinical development programs targeting NAMPT were halted due to dose-limiting on-target toxicities, mainly thrombocytopenia and lymphopenia. RPT1G is a first-in-class hyperbolic NAMPT inhibitor that eliminates NAD in cancer cells while allowing NAD production in healthy tissues (Crimmins, ASH 2023). The safety profile of RPT1G was evaluated in rats and non-human primates in a consecutive 28-day dosing regimen without the on-target toxicities seen in the clinic with previous NAMPT inhibitors, while efficacy has been validated in multiple hematological cancer models (Crimmins, ASH 2024). Here, we demonstrate the safety, tolerability, and meaningful NAMPT target engagement of RPT1G in a first-in-human Phase 1 study. These results provide the foundation for an ongoing Phase 1 trial in acute leukemias. Methods. We conducted a first-in-human, Phase 1, single-center, randomized, double-blind, placebo-controlled, single (SAD) and multiple (MAD) ascending dose study of RPT1G administered orally to healthy adult participants in Australia (NCT06667765). Safety and tolerability were the primary objectives, with additional objectives assessing pharmacokinetics (PK, secondary) and NAMPT target engagement (PD, exploratory). The study consisted of seven cohorts of 8 subjects randomized 3:1, RPT1G:placebo. Participants received a single dose of RPT1G (20, 60, 120, 240mg) or multiple doses of RPT1G (30, 60, 120mg) administered BID for 5 consecutive days. Results. A total of 56 participants were enrolled in the study with 42 receiving RPT1G. The median age was 30 years (range 18 to 55 years) and 53% were female. All participants completed treatment as planned. There were no reports of treatment emergent adverse events (TEAE) above Grade 2, no serious adverse events, and no TEAE leading to drug discontinuation. The most common TEAEs were nausea and vomiting, which occurred only after the first dose, did not show a dose-related increase in incidence, and resolved untreated or with a single dose of antiemetic. No safety concerns were identified in clinical laboratory parameters, physical examinations, vital signs, ECGs, and ophthalmologic examinations. In sharp contrast to previous clinical NAMPT programs, no cytopenias were observed at any dose level of RPT1G. RPT1G showed a favorable PK profile with exposure increasing proportionally to dose and a T1/2 of ~6 hours. No drug accumulation was seen after 5-day BID dosing. NAMPT target engagement was assessed in plasma by measuring the substrate of NAMPT, nicotinamide (NAM), and a NAM breakdown product, 1-methylnicotinamide (1-MNA). In preclinical xenograft studies, a 3.5-fold induction of NAM correlates with reduced tumor burden. In humans, the RPT1G-driven NAM and 1-MNA induction is 4-fold at 120mg and 5-fold at the 240mg dose levels, greater than the induction needed for preclinical efficacy. Both NAM and 1-MNA responses were dose-proportional.Conclusions. RPT1G was safe and well-tolerated in healthy volunteers at single and multiple (5-days BID) ascending dose levels, with favorable, dose-proportional PK, and no drug accumulation after 5-day BID dosing. RPT1G showed meaningful NAMPT inhibition with dose-proportional increases in NAM and 1-MNA up to 5-fold versus placebo. The magnitude of target engagement in humans is greater than the response in xenograft mouse models at effective doses, indicating a therapeutic level of NAMPT inhibition. Together, the Phase 1 safety, PK, and PD data show that RPT1G is the first drug capable of inhibiting NAMPT at clinically meaningful levels without significant on-target toxicity. A Phase 1 study evaluating RPT1G in relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes/neoplasms is underway (NCT07107126).