Next-Generation NAMPT Inhibitors Aim to Revive a Stalled Target in AML and MDS

Next-generation NAMPT inhibitors may build on the prior efficacy seen with earlier-generation agents in this class evaluated for the treatment of patients with solid tumors and improve upon their toxicity profile to make this target a feasible and safe therapeutic strategy in hematologic malignancies.

NAMPT is an enzyme that controls intracellular concentrations of NAD, which contributes to many enzymatic reactions and cellular pathways, and is consumed by key enzymes that are over-activated or over-expressed in cancer cells.¹ NAMPT expression is elevated in several cancers, including hematologic malignancies.^1,2 This has formed the hypothesis for targeting NAMPT in oncology and spurred preclinical and clinical research evaluating several compounds directed at this target.¹

However, since NAD is also a key component of healthy cell survival, NAMPT inhibitor monotherapy has been associated with dose-limiting toxicities (DLTs), including hematologic adverse effects (AEs) like thrombocytopenia, as well as the potential for retinal and cardiac toxicities.^1,2

“For a long time, people thought this was an important target but wasn’t going to be feasible to target,” Aaron D. Goldberg, MD. PhD, said in an interview with OncLive^®. “However, now there have been important developments in the ability to potentially target NAMPT in a safe way.”

Goldberg is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

Novel NAMPT inhibitors, such as RPT1G, may circumvent the limited tolerability of previously studied agents by allowing for therapeutically effective NAD depletion to occur in cancer cells without hindering sufficient NAD levels in normal cells.

What have been the benefits and limitations of previously developed NAMPT inhibitors?

Earlier clinical research into NAMPT inhibition was built on a foundation of preclinical data showing that NAMPT targeting had potent clinical activity. However, translating these outcomes to patients has proved more challenging. For instance, in a phase 1 study (NCT00003979), the NAMPT inhibitor CHS 828 was investigated in patients with solid tumors that were refractory to standard therapies (n = 16).³ Although the hematologic toxicities associated with the agent were reported to be mild, the DLTs included thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. Additionally, no tumor responses were reported, although 7 patients achieved stable disease (SD).

Another first-in-human study evaluated the NAMPT inhibitor FK866 in a similar patient population (n = 24).⁴ Thrombocytopenia was again reported as a DLT, although no other severe hematologic AEs were noted. Mild fatigue and nausea were also reported. Again, no patients responded to treatment with this agent, although 4 patients achieved SD.

What makes RPT1G unique among NAMPT inhibitors?

RPT1G is an investigational, first-in-class hyperbolic NAMPT inhibitor that has been previously investigated in hematologic cancer models.⁵

“It can never completely turn off the enzyme; it can only turn it off to a certain level,” Goldberg explained. “In the laboratory and in animal models, and even in a healthy volunteer study in people, it is still a NAMPT inhibitor. It affects metabolism and the cofactors in a way that [shows that it] is active as an NAMPT inhibitor, but it’s not completely active, so it’s not going to completely deplete all NAMPT.”

A first-in-human, phase 1 trial (NCT06667765) administered RPT1G to healthy participants in Australia (n = 56) and showed no grade 3 or higher treatment-emergent AEs (TEAEs), no serious AEs, and no TEAEs that led to treatment discontinuation. The most frequently reported TEAEs, nausea and vomiting, only occurred following the first dose, and their incidence was not correlated with dose increases. Notably, no cytopenias were reported at any dose level of the agent, and the drug had a favorable pharmacokinetic profile.

“We don’t really know yet for sure beyond that healthy volunteer study, but it was enough to say that we are inhibiting NAMPT at a level where you would expect to see activity in cancer cells, so it makes sense to try this in people,” according to Goldberg. “There are some specific cell types and cancer cells that we thought would be the most susceptible [to NAMPT inhibition], and that’s where our work in leukemia comes in.”

What is the rationale for investigating RPT1G in patients with select hematologic malignancies?

“There have been a number of effective therapies that have been developed in the past 10 or 15 years, which have revolutionized the management of acute myeloid leukemia [AML], and we have made a ton of progress, but we’re still not where I’d like us to be,” Goldberg contextualized. “The reason that [NAMPT inhibition is] potentially going to work here, and the reason that it works in the laboratory, is that the gene for NAMPT is on 7q, the long arm of chromosome 7 that is deleted in many patients with myelodysplastic syndrome [MDS] and in a subset of patients with AML and therapy-related AML.”

Based on this hypothesis, Goldberg and colleagues designed an ongoing phase 1 trial (NCT07107126) evaluating escalating doses of RPT1G in patients with relapsed/refractory AML and higher-risk MDS.² The primary aims of this trial include determining the safety and tolerability of the agent, identifying the recommended phase 2 dose, and assessing pharmacokinetics and preliminary efficacy. This is the first study to evaluate a NAMPT hyperbolic inhibitor in this patient population.

“Relapsed/refractory AML is an enormous problem, and we need therapies that are truly going to be disease-modifying, that are going to get rid of the leukemia cells, and [are going to] achieve deeper and more durable remissions,” Goldberg emphasized. “The hope is that this NAMPT inhibitor RPT1G may be able to do so. In the laboratory, that’s the case, but we need to see this in the clinic.”

What are the next steps for evaluating NAMPT inhibition in AML?

The phase 1 trial of RPT1G in patients with AML/MDS is currently enrolling patients at least 18 years of age with an ECOG performance status of 0 to 2 and adequate organ function.⁶

Beyond this monotherapy trial, Goldberg noted that NAMPT inhibitors have the potential to synergize with many different classes of drugs, including ones that are already used in patients with hematologic malignancies, such as the BCL-2 inhibitor venetoclax (Venclexta).

“By stressing the cell by inhibiting this NAD salvage pathway, you’re priming that cell for apoptosis,” he described. “When you give that in combination with a BCL-2 inhibitor, the cells are selectively dying. There have been preclinical data [showing the potential to] overcome resistance even to venetoclax by adding a NAMPT inhibitor, so that’s why we’re particularly excited.”

He stressed that this synergy also appears to extend beyond BCL-2 inhibition, encompassing activity with PARP inhibitors and RAS pathway inhibitors, of which daraxonrasib (Rasonque) was FDA approved in August 2026 for the treatment of patients with metastatic pancreatic ductal adenocarcinoma.⁷

“[NAMPT inhibitors] synergize with RAS inhibitors in the lab,” he concluded. “Now we have to see how this works in people, and then hopefully get this as monotherapy [and] combinations to people as soon as we can.”

References

1. Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA. Recent advances in NAMPT inhibitors: a novel immunotherapic strategy. Front Pharmacol. 2020;11:656. doi:10.3389/fphar.2020.00656
2. de Jesús-Díaz DA, Goldberg A, Abella S, Robb CM, Schelle M, Crimmins G. Phase 1, open-label, multi-center trial of RPT1G in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes/neoplasms. Presented at: 2026 AACR Annual Meeting; San Diego, California; April 17-22, 2026. Abstract CT267/1.
3. Hovstadius P, Larsson R, Jonsson E, et al. A phase I study of CHS 828 in patients with solid tumor malignancy. Clin Cancer Res. 2002;8(9):2843-50
4. Holen K, Saltz LB, Hollywood E, Burk K, Hanauske AR. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest New Drugs. 2008;26(1):45-51. doi:10.1007/s10637-007-9083-2
5. Crimmins G, Polasek T, Robb C, et al. 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. Blood. 2025;146(suppl 1):5044. doi:10.1182/blood-2025-5044
6. Safety and proof-of-concept study of RPT1G in adults with acute myeloid leukemia and high-risk myelodysplastic syndromes. ClinicalTrials.gov. Updated March 25, 2026. Accessed October 8, 2026. https://clinicaltrials.gov/study/NCT07107126
7. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed October 8, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery