What NAMPT inhibitors are in clinical trials currently?

Introduction to NAMPT and Its Role

Function of NAMPT in Cellular Metabolism

Nicotinamide phosphoribosyltransferase (NAMPT) is a critical enzyme that regulates NAD⁺ biosynthesis in mammalian cells by catalyzing the rate‐limiting step in the salvage pathway from nicotinamide (NAM) to nicotinamide mononucleotide (NMN). NAD⁺ is not only essential for the production of ATP via cellular respiration but also serves as an essential co-factor for a range of enzymes – including sirtuins, poly(ADP‐ribose) polymerases (PARPs), and other NAD⁺‐dependent deacetylases – that regulate genomic stability, cell survival, and metabolic adaptation. As such, the intracellular levels of NAD⁺, maintained predominantly by NAMPT, are crucial in modulating energy homeostasis, redox balance, and the cellular capacity to respond to metabolic stress. Importantly, because NAD⁺ plays a central role in both glycolysis and mitochondrial oxidative phosphorylation, the activity of NAMPT directly influences multiple aspects of cellular metabolism, which in turn affect proliferation, apoptosis, and other survival pathways.

Importance of Targeting NAMPT in Cancer Therapy

Overexpression of NAMPT has been reported in numerous tumor types including breast, ovarian, prostate, colorectal, and hematological malignancies. Cancer cells, due to their high metabolic demands and rapid proliferation rates, are particularly dependent on efficient NAD⁺ regeneration to sustain energy production and to fuel NAD⁺‐dependent DNA repair mechanisms. This phenomenon has led to the identification of cancer “addiction” to elevated NAMPT activity. Inhibiting NAMPT thus emerges as a targeted strategy to deplete cellular NAD⁺, provoking metabolic stress and ultimately leading to cell death. This approach is further supported by preclinical studies that have shown that even short‐term treatment with NAMPT inhibitors can induce a marked collapse of NAD⁺ levels and provoke cell death across varied tumor models. Furthermore, as resistance mechanisms to conventional chemotherapies are often linked to enhanced metabolic recovery and robust DNA repair pathways—both tightly coupled to NAD⁺ metabolism—targeting NAMPT is hypothesized to not only directly kill cancer cells but also to sensitize tumors to other therapeutic agents.

Overview of NAMPT Inhibitors

Mechanism of Action

NAMPT inhibitors function by competing with the natural substrate nicotinamide for binding to the active site of NAMPT, thereby blocking the formation of NMN and the downstream production of NAD⁺. The loss of NAD⁺ leads to a cascade of metabolic perturbations such as ATP depletion, impaired glycolysis, and reduced activity of NAD⁺‐dependent enzymes, which cumulatively drive tumor cells toward apoptosis or necrosis. Many of the small molecule inhibitors developed are also designed as dual inhibitors—simultaneously targeting complementary pathways. For example, compounds such as KPT-9274 and ATG-019 inhibit both NAMPT and PAK4, a serine/threonine kinase implicated in cancer cell migration, survival, and cytoskeletal organization. The dual inhibition mechanism is postulated to amplify antitumor effects by both blocking the metabolic supply lines (NAD⁺ biosynthesis) and interfering with survival and proliferation signals.

Development History

The historical efforts in developing NAMPT inhibitors began with compounds like FK866 (APO866), which provided proof-of-concept that NAMPT is an actionable target in oncology. Despite robust antitumor activities demonstrated in preclinical models, early clinical trials with agents such as FK866 were marred by dose-limiting toxicities (for example, thrombocytopenia and gastrointestinal disturbances) that curtailed their clinical development. Learning from these early setbacks, the focus shifted towards optimizing the therapeutic index. This led to the development of second-generation inhibitors that attempted to address the toxicity issues and to expand the spectrum of activity. Among these are dual inhibitors like KPT-9274 and ATG-019, which have progressed into clinical trials due to their improved pharmacokinetic profiles and potential for synergistic effects through multi-target inhibition. In parallel, novel strategies such as antibody-drug conjugates (ADCs), proteolysis-targeting chimeras (PROTACs), and even immunotherapeutic approaches using monoclonal antibodies targeting extracellular NAMPT (eNAMPT) have also emerged, reflecting the evolving landscape of NAMPT inhibitor development.

Current Clinical Trials of NAMPT Inhibitors

List of Active Clinical Trials

Based on the most reliable and structured data from synapse, several NAMPT inhibitors have advanced into clinical trials, including:
- ATG-019
- KPT-9274
- GMX1777 (also referred to as CHS 828 in earlier studies)
- OT-82
- RPT1G
- ALT-100 (a monoclonal antibody targeting the extracellular form of NAMPT)

Each of these compounds is designed with a unique mechanism or formulation that distinguishes it from earlier inhibitors such as FK866, whose development suffered from severe toxicity issues.

Phase and Status of Each Trial

ATG-019

ATG-019 is a dual inhibitor targeting both PAK4 and NAMPT, currently under investigation in Phase I trials in patients with advanced solid tumors or non-Hodgkin’s lymphoma (NHL). The trial focuses on safety and tolerability and, in some study designs, examines ATG-019 both as a single agent and in combination with niacin to mitigate potential toxicities related to NAD⁺ depletion. Early data suggest that modulating NAD⁺ biosynthesis in solid tumors and lymphoid malignancies might offer a therapeutic benefit, although final outcomes have yet to be published.

KPT-9274

KPT-9274 is another dual inhibitor that targets both NAMPT and PAK4. It is undergoing Phase I open-label studies in patients with advanced solid malignancies and has also been assessed in a trial involving patients with relapsed and refractory acute myeloid leukemia (AML). As an orally bioavailable small molecule, KPT-9274 is of particular interest due to its potential for improved patient compliance and ease of administration. Interim findings indicate that KPT-9274 is tolerable with manageable side effects, although its antitumor efficacy is still under evaluation. The trial in AML also highlights the importance of investigating NAMPT inhibitors in hematologic cancers where metabolic dependencies may differ from those in solid tumors.

GMX1777 (CHS 828)

GMX1777, the water-soluble prodrug of GMX1778 (CHS 828), has been evaluated in a Phase I clinical trial focusing on patients with refractory solid tumors or lymphomas. Although early studies using GMX1777 demonstrated potent NAMPT inhibition and antitumor activity, the clinical development of this compound has been historically limited by toxicity profiles. Nonetheless, the trial provided valuable insights into dosing schedules and safety monitoring, which are being used to inform the next generation of NAMPT inhibitors.

OT-82

OT-82 is being tested in a Phase I study in patients with relapsed or refractory lymphoma. As a novel NAMPT inhibitor, OT-82 has shown promising preclinical efficacy by inducing NAD⁺ depletion and subsequently triggering cell death in hematological cancer cell lines. The clinical investigation is designed to determine the optimal dosing regimen, evaluate its safety profile, and provide early signals of antitumor activity in aggressive lymphomas that have traditionally been challenging to treat with standard therapies.

RPT1G

RPT1G is a newer agent in the NAMPT inhibitor class that is evaluated in a Phase I trial involving healthy adult participants. This randomized, placebo-controlled, double-blinded study aims to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPT1G following single and multiple dosing regimens. Although the trial is conducted in healthy volunteers rather than cancer patients, the data are expected to provide critical information on the metabolic impact and potential dose-limiting toxicities of this NAMPT inhibitor. Such early-phase studies are essential to determine whether the agent can proceed to efficacy trials in patient populations with metabolic dependencies related to NAD⁺ deficiency.

ALT-100

ALT-100 represents a different approach by employing a monoclonal antibody to neutralize extracellular NAMPT (eNAMPT) rather than inhibiting its enzymatic activity intracellularly. The development of ALT-100 includes its evaluation in a First-in-Human study in healthy volunteers, and further trials, such as a Phase II study, have been initiated in populations with conditions like moderate/severe acute respiratory distress syndrome (ARDS). Although not directly an anti-cancer therapy, the modulation of eNAMPT has broad implications given its cytokine-like roles in inflammation and metabolism. The clinical data generated from ALT-100 trials may eventually inform strategies to harness antibody-based inhibition of NAMPT in oncologic as well as inflammatory settings.

Key Findings and Interim Results

Interim results from these clinical trials have provided a multifaceted perspective on the potential of NAMPT inhibitors:
- ATG-019 Trials: Early-phase data from ATG-019 studies have enabled investigators to evaluate both its safety and tolerability. Although specific efficacy results are still emerging, the trials are designed to assess whether the addition of niacin can offset the metabolic stress associated with NAMPT inhibition, thereby reducing adverse events while preserving antitumor activity.
- KPT-9274 Trials: Studies involving KPT-9274 have reported manageable side effects and have identified a dosing window that appears to balance efficacy with acceptable toxicity, especially in the context of relapsed/refractory AML. Its dual mechanism of blocking both NAMPT and PAK4 is particularly attractive since it may anatomically combine metabolic disruption with interference in tumor cell survival signaling, offering a potential advantage over single-target agents.
- GMX1777 Studies: The Phase I clinical trial for GMX1777 in refractory solid tumors or lymphomas offered early insights into infusion protocols and monitoring strategies for managing dose-limiting toxicities. Although its future clinical development remains uncertain because of prior safety concerns, the data contributed to a better understanding of how to modulate NAMPT activity in a clinical context, guiding subsequent drug designs.
- OT-82 Trials: For OT-82, preliminary results suggest that it may effectively lower NAD⁺ levels in lymphoma cells and demonstrate antitumor activity in patients with relapsed or refractory lymphoma. These early indications are significant given the historically limited treatment options in this disease area.
- RPT1G Studies: As the study in healthy volunteers, RPT1G is expected to reveal important pharmacokinetic and pharmacodynamic characteristics that may allow researchers to project its utility in later-stage trials with cancer patients. The clear demonstration of dose-proportional effects on NAD⁺ metabolism and a favorable safety profile in these initial studies would be a positive indicator for its potential utility in oncology.
- ALT-100 Developments: In the realm of antibody-based strategies, ALT-100 has shown promising initial tolerability in healthy volunteer studies, and subsequent evaluation in patients with ARDS is ongoing. Although its application in cancer is not primary at this stage, these studies provide proof-of-concept for adopting immunotherapeutic strategies targeting eNAMPT, which might be applicable to specific oncologic scenarios where extracellular NAMPT contributes to tumor progression and immune modulation.

Collectively, these clinical evaluations underscore a diversity in the approaches taken to modulate NAMPT activity. By exploring small-molecule inhibitors, dual inhibitors (which target complementary proteins such as PAK4), and even antibody-based strategies, current research is advancing our understanding of how best to exploit the vulnerabilities associated with NAD⁺ metabolism in cancer.

Challenges and Future Perspectives

Clinical Challenges and Side Effects

Despite the promising antitumor potential of NAMPT inhibitors, several clinical challenges remain that have emerged from both early-phase trials and preclinical investigations. One of the most critical challenges revolves around dose-limiting toxicities. Early inhibitors, such as FK866 and GMX1777, while demonstrating potent enzymatic inhibition and antitumor activity in preclinical models, were soon found to be associated with significant toxicities including thrombocytopenia, gastrointestinal disturbances, and other off-target effects. These toxicities underline the challenge of suppressing such a central metabolic enzyme without adversely impacting normal tissue, where NAD⁺ is also essential for cell viability and repair.

Another concern is the balancing act required in targeting a fundamental pathway involved in both cancer cells and normal host cells. Fine-tuning the degree of NAD⁺ depletion necessary to induce tumor cell death without causing systemic metabolic collapse is a key obstacle. Trials such as those involving ATG-019 are exploring whether adjunct therapies (for instance, supplementation with niacin) can provide a “rescue” effect for healthy cells without mitigating the antitumor effects. Similarly, the differential effects observed in hematological versus solid tumors in trials with compounds like OT-82 and KPT-9274 illustrate the complexity of patient selection and dosing strategies.

Pharmacokinetic variability is another challenge. Agents such as RPT1G, which are in early-phase studies in healthy volunteers, are closely examined for their metabolism and distribution characteristics. Detailed pharmacodynamic data are required to ensure that the inhibitor reaches the tumor at a therapeutic concentration while minimizing adverse effects elsewhere in the body. In addition, for dual inhibitors like KPT-9274 and ATG-019, isolating the contribution of each target (NAMPT and PAK4) to both efficacy and toxicity remains a challenge that complicates dosing regimen optimization.

Future Research Directions

Future research must focus on improving the therapeutic index of NAMPT inhibitors further by enhancing selectivity for tumor cells. One promising avenue is the development of combinatorial strategies that make use of the metabolic dependencies unique to cancer cells. For instance, combining NAMPT inhibitors with agents that modulate alternative NAD⁺ biosynthetic pathways, or those that sensitize tumor cells to metabolic stress, may allow for more selective tumor targeting while sparing normal tissues.

Advances in biomarker discovery are also crucial. Reliable biomarkers indicating both NAMPT expression and NAD⁺ levels within tumors can help tailor dosing and patient selection. This is particularly important given the metabolic heterogeneity observed even within a single tumor type. In this respect, detailed pharmacodynamic studies as done in the RPT1G trial are emblematic of the type of research needed to refine patient stratification and real-time dosing adjustments.

Another significant direction for future research is on the design of next-generation dual inhibitors. Agents like KPT-9274 and ATG-019 represent the current frontier wherein dual inhibition of NAMPT and secondary targets (such as PAK4) may provide synergistic benefits, with increased antitumor efficacy and potentially a different toxicity profile relative to single-target inhibitors. Furthermore, the use of advanced medicinal chemistry techniques, computer-aided drug design, and structure-based optimization—as seen in the recent patents and papers—may give rise to novel NAMPT inhibitor chemotypes that overcome previous limitations.

Attention is also being directed toward developing antibody-based therapies, as exemplified by ALT-100. Although primarily tested in non-oncologic settings like ARDS currently, these agents hold promise for selectively modulating extracellular NAMPT, which has been implicated in the inflammatory milieu that can drive tumor progression. Future studies may explore the role of ALT-100 or similar antibodies in cancer, particularly in tumors where eNAMPT contributes to the tumor–stroma interaction or in settings where conventional small-molecule inhibitors have limited efficacy.

Potential for Combination Therapies

Given the central role of NAD⁺ metabolism in cell survival, it is perhaps not surprising that combination strategies are gaining traction in the clinical development of NAMPT inhibitors. A key rationale for combination therapy is that while high-level inhibition of NAMPT can induce tumor cell death, complete systemic NAD⁺ depletion can also lead to unacceptable toxicity. Therefore, combining lower doses of NAMPT inhibitors with other anticancer agents—such as PARP inhibitors, chemotherapeutics, or targeted therapies—might synergistically enhance antitumor effects while allowing each drug to be used at a lower, less toxic dose.

Preclinical studies have also suggested that combination regimens involving NAMPT inhibitors may overcome resistance mechanisms associated with alternative NAD⁺ biosynthetic pathways. For instance, there is evidence that cancers with reduced expression of NAPRT (nicotinic acid phosphoribosyltransferase) are more sensitive to NAMPT inhibition; thus, combining NAMPT inhibitors with agents that further suppress compensatory NAD⁺ synthesis pathways could lead to improved therapeutic efficacy. The dual-action compounds (e.g., KPT-9274 and ATG-019) already serve as an inbuilt combination by targeting both metabolic and signaling pathways, thereby obviating the need for multiple separate agents.

Combination therapies might also mitigate some of the dose-limiting toxicities. In some clinical trials, adjuvant supplementation with niacin or nicotinic acid has been explored as a means to rescue normal tissues from the effects of NAD⁺ depletion while maintaining antitumor efficacy. Such strategies are being rigorously evaluated in Phase I trials with agents like ATG-019 where the interplay between NAMPT inhibition and niacin supplementation might widen the therapeutic window.

Additionally, the integration of novel NAMPT inhibitors with immunotherapy is a promising frontier. Given that NAD⁺ levels also regulate immune cell function and that NAMPT has extracellular cytokine-like activities, coupling NAMPT inhibition with immune checkpoint inhibitors or adoptive cell therapies might enhance the overall antitumor response. Future clinical trials will likely incorporate well-defined biomarkers to identify patients who may benefit most from such combination regimens.

Conclusion

In summary, current clinical trials are actively testing a diverse array of NAMPT inhibitors that have evolved significantly from the early compounds like FK866. The clinical candidates include ATG-019, a dual inhibitor of PAK4 and NAMPT in Phase I trials targeting advanced solid tumors and NHL; KPT-9274, another dual inhibitor currently under investigation in both advanced solid malignancies and relapsed/refractory AML; GMX1777 (also known as CHS 828), which has been assessed in a Phase I setting in patients with refractory solid tumors or lymphomas; and OT-82, which is being evaluated in Phase I trials for relapsed/refractory lymphoma. Additionally, RPT1G is in early-phase trials in healthy adults to determine its pharmacokinetic and pharmacodynamic profile, setting the stage for future oncologic studies. An alternative approach is represented by ALT-100—a monoclonal antibody directed against extracellular NAMPT—currently being examined in Phase 1 evaluations in healthy volunteers and in Phase II trials for conditions like ARDS.

Overall, while these trials demonstrate promising avenues for exploiting the metabolic dependency of cancer on NAD⁺, several challenges persist. These include achieving a balance between effective tumor cell kill and minimizing toxic effects on normal tissues, managing dose-limiting toxicities that have historically impeded earlier compounds, and clearly delineating the contributions of dual targets like PAK4 alongside NAMPT inhibition. The future of NAMPT inhibition in oncology appears to lie in the optimization of combination therapies, improved patient selection based on reliable biomarkers, and the development of next-generation inhibitors with enhanced selectivity and more favorable toxicity profiles. With ongoing trials generating important pharmacokinetic, pharmacodynamic, and early efficacy data, the coming years are expected to refine our understanding of how best to leverage NAMPT inhibitors in the therapeutic landscape.

In conclusion, the clinical trials currently evaluating NAMPT inhibitors provide a multi-angled perspective on targeting cancer metabolism. From small-molecule inhibitors like ATG-019, KPT-9274, GMX1777, and OT-82 to novel agents such as RPT1G and antibody-based approaches like ALT-100, each candidate contributes unique insights into how inhibition of NAD⁺ biosynthesis might translate into clinical benefit. The overall strategy is to disrupt the metabolic machinery that sustained tumor growth while concurrently exploring combination regimens that can mitigate toxicity and address resistance mechanisms. The structured and ongoing evaluation of these agents, as evidenced by robust phase I studies and emerging Phase II trials, underscores both the promise and the complexity of developing NAMPT-targeted therapies in oncology. Continuous efforts toward understanding the molecular underpinnings of efficacy and side effects, alongside innovations in drug design and combination therapy strategies, are expected to pave the way for a new generation of antitumor treatments that exploit the vulnerabilities of tumor metabolism.