What menin inhibitors are in clinical trials currently?

Introduction to Menin and Menin Inhibitors
Menin, the protein product of the MEN1 gene, plays critical roles in normal cell physiology and in aberrant signaling that underlies several cancers. It functions as a scaffold protein that modulates gene transcription by interacting with multiple transcription factors and chromatin regulators. In certain leukemias and solid tumors, menin cooperates with MLL (Mixed Lineage Leukemia, also known as KMT2A) proteins to drive oncogenic transcriptional programs. This essential role in gene regulation has made menin a promising target for therapeutic intervention in cancer. Several small molecules have been developed to inhibit the menin–MLL protein–protein interaction, thereby disrupting the malignant transcriptional network and potentially providing clinical benefits in refractory or high-risk cancers.

Role of Menin in Biology
Menin is involved in diverse cellular processes, including regulation of gene expression, maintenance of chromatin structure, and modulation of signaling pathways critical for cell proliferation and differentiation. Under normal conditions, it plays a dual role by participating in both tumor-suppressive functions—especially in neuroendocrine tissues—and oncogenic processes when aberrantly co-opted by fusion proteins or mutated oncogenes in hematologic malignancies such as acute myeloid leukemia (AML) and mixed lineage leukemia (MLL) rearranged leukemia. Its intricate participation in gene transcription regulation via interactions with MLL proteins makes it an indispensable cofactor for the transcriptional activation of HOX/MEIS gene programs, which are critical drivers of leukemic cell proliferation. This central role in maintaining the leukemic phenotype has prompted extensive research into the development and optimization of menin inhibitors as targeted therapies.

Development of Menin Inhibitors
The therapeutic strategy of targeting menin was advanced by the development of small-molecule inhibitors designed to interfere with the binding between menin and MLL proteins. Early inhibitor candidates showcased the potential of disrupting this interaction and inducing leukemic cell differentiation and apoptosis. Over time, medicinal chemistry efforts have yielded several classes of inhibitors—such as the thienopyrimidine derivatives—optimized for potency, selectivity, and favorable pharmacokinetic profiles. These inhibitors are designed to bind to the menin pocket at the interface with MLL, thereby preventing oncogenic protein–protein interactions without causing widespread toxicity. With promising preclinical data confirming efficacy and tolerability, several menin inhibitors have advanced into clinical testing, providing a beacon of hope for targeted therapy in indications where traditional treatments have failed.

Overview of Clinical Trials for Menin Inhibitors
Modern drug development has witnessed an increasing number of clinical trials specifically evaluating menin inhibitors, predominantly in hematological malignancies but also expanding into select solid tumors. These trials stem from robust preclinical studies demonstrating that disruption of the menin–MLL interaction can lead to marked tumor regression, deep molecular remissions, and a potentially improved safety profile relative to conventional chemotherapies.

Current Clinical Trials
Data from the Synapse database and related sources reveal that the clinical pipeline for menin inhibitors is both diverse and dynamic, with multiple agents under investigation in various clinical trial stages. From early-phase studies in refractory and relapsed acute leukemia to trials assessing combination regimens with chemotherapy, targeted agents, and even maintenance therapies post-transplant, the menin inhibitor landscape is rich with candidates. Specific trials have been registered targeting pediatric and adult populations with acute leukemias characterized by rearrangements in KMT2A (MLL) or mutations in NPM1, where menin dependency has been clearly established. In addition, some clinical trials are exploring the utility of menin inhibitors in conditions such as advanced gastrointestinal stromal tumors (GIST) and other hematologic malignancies. For instance, studies investigating Ziftomenib—a potent menin inhibitor—span various designs including combination with imatinib in GIST and maintenance therapy following allogeneic hematopoietic cell transplant, highlighting its versatility in treating different tumor types.

Phases of Clinical Trials
Menin inhibitors are currently being evaluated mostly in Phase I and Phase I/II clinical trials. In these early-phase studies, the primary focus is on determining safety, tolerability, pharmacokinetics, and initial efficacy endpoints. For example, Revumenib (formerly SNDX-5613) has advanced into Phase I trials with adult patients with relapsed/refractory AML harboring KMT2A rearrangements or NPM1 mutations. Similarly, Ziftomenib is being studied in multiple Phase I or Phase Ib trials, including its use in combination regimens for pediatric AML and maintenance therapy configurations. Other agents such as BN104 are under evaluation in Phase I/II studies for acute myeloid leukemia, with both dose-escalation and food-effect studies already initiated. These early-phase trials collectively, while aiming to establish safety profiles and dosing regimens, also provide initial signals of efficacy that will inform later stage studies if the outcomes are favorable.

Specific Menin Inhibitors in Trials

List of Menin Inhibitors
Currently, several menin inhibitors have entered clinical trials. The Synapse database and recent literature identify the following agents as actively being tested in clinical settings:

• Ziftomenib – This inhibitor is among the most studied menin-targeting agents. Multiple trials are evaluating Ziftomenib in children with relapsed/refractory acute leukemia as well as in adult populations with GIST after imatinib failure.
• Revumenib – Also known as SNDX-5613, Revumenib is being assessed in early-phase trials for its efficacy in both KMT2A-rearranged and NPM1-mutant acute myeloid leukemia. Its development is supported by encouraging preliminary response rates in heavily pretreated patients.
• Bleximenib – Currently in a Phase I/II first-in-human study, Bleximenib is being tested in subjects with acute leukemia and represents another promising candidate among small-molecule menin inhibitors.
• BN104 – Clinical trials are underway evaluating BN104 in combination with chemotherapy and/or targeted agents for acute myeloid leukemia. This inhibitor is also subjected to additional studies such as food-effect evaluations to determine optimal dosing parameters.
• HMPL-506 – This agent is being tested in a Phase I clinical study in patients with hematological malignancies and adds to the portfolio of menin inhibitors targeting similar oncogenic mechanisms.
• ZE63-0302 – While distinct from typical oncology indications, ZE63-0302 is being evaluated in healthy volunteers to assess safety, tolerability, pharmacokinetics, and pharmacodynamics. Such early-stage studies are critical in understanding the basic human pharmacology of these inhibitors before they expand into patient populations.

In addition to the above, some reports and syntheses have compiled a broader list of menin inhibitors. For instance, a list reviewed by Synapse highlights additional compounds like DS-1594, BMF-219, BN-104Mi-003, BNM-1192, D0060-319, and DS-M1 (developed by Daiichi Sankyo) that are in various developmental stages. However, the clinical trials with published details mostly list the inhibitors described above.

Trial Phases and Indications
The menin inhibitors mentioned are part of clinical investigations that span the following phases and intended indications:

• Phase I/IB Trials:
  – Ziftomenib trials involve dose-escalation studies in pediatric patients with refractory or relapsed acute myeloid leukemia and in adults with advanced gastrointestinal stromal tumors (GIST), often in combination with other agents such as imatinib, venetoclax, gemtuzumab, or quizartinib. These studies are primarily designed to determine maximum tolerated doses, pharmacokinetic parameters, and early efficacy signals.
  – Revumenib is evaluated in Phase I trials in adult patients with relapsed/refractory AML with either KMT2A rearrangements or NPM1 mutations, with the endpoints focusing on safety, molecular remission rates, and response durability.
  – HMPL-506 is also in Phase I trials for various hematologic malignancies, where the focus is to assess safety profiles in patients who are often heavily pretreated with previous therapies.

• Phase I/II Trials:
  – Bleximenib is currently in a combined Phase I/II study targeting patients with acute leukemia. This study design allows for concurrent dose-finding and preliminary efficacy evaluation, which is key in determining whether a subsequent larger trial is warranted.
  – BN104 is undergoing a Phase I/II, multicenter, open-label study evaluating safety, pharmacokinetics, and preliminary efficacy in AML patients. There are also ancillary studies such as food-effect evaluations that are designed to refine dosing strategies for BN104.

• Special Population and Combination Studies:
  – Several trials, such as those for Ziftomenib, have incorporated combination regimens with agents like venetoclax or quizartinib. Additionally, there is a trial assessing Ziftomenib maintenance therapy following allogeneic hematopoietic cell transplant, underscoring its potential role in both induction and maintenance phases of cancer treatment.
  – Trials with ZE63-0302, while not conducted in cancer patients, are critical in healthy volunteers to provide early pharmacodynamic data that may eventually support studies in diseases where menin inhibition might be beneficial.

Potential Outcomes and Implications

Expected Efficacy and Safety
The therapeutic rationale behind menin inhibitors is bolstered by the observation that these agents can induce differentiation in leukemic blasts and disrupt critical oncogenic gene expression programs. In early-phase clinical trials, menin inhibitors such as Revumenib and Ziftomenib have demonstrated encouraging signs of efficacy, including notable overall response rates and deep molecular remissions—with some patients achieving MRD (minimal residual disease) negativity.
Safety remains a primary endpoint in these early-phase trials. The data so far indicate that these agents are generally well tolerated, even in heavily pretreated patient populations, although challenges such as differentiation syndrome and hematologic toxicities have been observed in some cases. Optimizing the tolerability and efficacy balance is a central goal of the ongoing Phase I/II trials. Moreover, ancillary studies such as food-effect analyses (e.g., with BN104) are aimed at fine-tuning the administration protocols to maximize patient benefit and minimize adverse events.

From a mechanistic perspective, inhibiting the interaction between menin and MLL not only affects leukemic cell proliferation but also disrupts a network of downstream gene expressions (e.g., HOX/MEIS). Such transcriptional reprogramming is supportive of a terminal differentiation effect on blasts. This could lead to prolonged survival and improved quality of life for patients with refractory leukemias—and the early data on Revumenib and Ziftomenib already show promising trends in these areas. The safety profiles being established in these clinical trials, measured through dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) assessments, further fortify the concept that menin inhibitors may offer a targeted therapeutic option with fewer off-target effects compared to conventional chemotherapy.

Future Prospects and Research Directions
The current pipeline of clinical trials offers a glimpse into the future of targeted oncology. Should the early-phase trials of menin inhibitors such as Ziftomenib, Revumenib, Bleximenib, BN104, HMPL-506, and ZE63-0302 demonstrate consistent efficacy and acceptable safety, large-scale Phase II/III trials will likely follow. The potential for combination therapies is significant, as concurrent administration with standard chemotherapies, FLT3 inhibitors, or other targeted agents (e.g., venetoclax) may overcome resistance mechanisms and further improve clinical outcomes.

Looking ahead, research will need to focus on several key areas:
• Biomarker Development: Identifying predictive biomarkers of response to menin inhibition is critical. Understanding which patients are most likely to benefit from these inhibitors could lead to more personalized treatment strategies, especially given the diversity of genomic alterations (e.g., KMT2A rearrangements and NPM1 mutations) present in different leukemic subsets.
• Optimizing Combinations: Early-phase trials exploring the combination of menin inhibitors with other anti-leukemic agents have already shown promise. Future studies may further refine these combinations, optimizing sequencing and dosing schedules to maximize synergistic effects while minimizing overlapping toxicities.
• Expanding Indications: Although the majority of current trials focus on hematological malignancies, the potential for menin inhibitors in solid tumors is being explored. Given the role of menin in gene regulation beyond leukemia, future trials might evaluate these inhibitors in other cancers such as gastrointestinal stromal tumors (GIST) or even select endocrine and solid tumors where menin’s role has been implicated.
• Understanding Resistance Mechanisms: Emerging clinical data have begun to elucidate mechanisms behind acquired resistance to menin inhibitors, such as somatic mutations in the MEN1 gene at the inhibitor-binding interface. Future research will need to focus on overcoming these resistance mechanisms, possibly through combination therapies or the development of second-generation menin inhibitors.

An integrated approach combining clinical trial data, advanced genomic profiling, and mechanistic studies will be essential to fully realize the promise of menin inhibitors. In parallel, ongoing preclinical work will support the continued design, synthesis, and optimization of newer compounds with improved potency, specificity, and pharmacokinetic properties. These efforts will pave the way for later-phase trials and ultimately, for the incorporation of menin inhibitors into standard-of-care regimens for hematological malignancies and possibly other cancers.

Conclusion
In summary, the clinical trial landscape for menin inhibitors currently includes a robust pipeline of agents primarily targeting hematological malignancies—especially acute leukemias characterized by KMT2A rearrangements and NPM1 mutations—but also extending to certain solid tumors. The major menin inhibitors in clinical development include Ziftomenib, which is being evaluated in multiple Phase I studies both as a monotherapy and in various combination regimens for pediatric and adult populations; Revumenib (SNDX-5613), which has shown promising early efficacy in relapsed/refractory AML; Bleximenib in a Phase I/II setting for acute leukemia; BN104 under evaluation for AML, including specialized dosing and food-effect studies; HMPL-506 in Phase I trials for hematological malignancies; and ZE63-0302 undergoing first-in-human studies in healthy volunteers. These trials are predominantly in the early phases—ranging from Phase I to Phase I/II—with primary endpoints focusing on safety, tolerability, and preliminary efficacy. Complementary studies such as pharmacokinetic analyses and combination therapy trials are integral components of this evolving pipeline.

From a broader perspective, the menin inhibitors currently in trials represent a promising new frontier in targeted cancer therapy. Their ability to disrupt critical oncogenic protein–protein interactions and reprogram malignant transcriptional programs offers a potential path to improved patient outcomes with fewer adverse effects compared to conventional therapies. Moreover, the flexible trial designs—encompassing combination regimens, maintenance phases, and specialized dosing studies—reflect a comprehensive strategy to optimize the clinical utility of these agents.
Looking forward, ongoing trials will provide further insights into the expected efficacy and safety of these compounds, while future research is anticipated to focus on biomarker-driven patient selection, overcoming resistance mechanisms, and exploring synergistic combinations. Ultimately, these efforts may culminate in the approval of one or more menin inhibitors, thereby significantly impacting the treatment paradigm for acute leukemia and potentially other malignancies dependent on the menin–MLL interaction.

In conclusion, menin inhibitors in clinical trials currently encompass a diverse array of molecules—including Ziftomenib, Revumenib, Bleximenib, BN104, HMPL-506, and ZE63-0302—that are being evaluated across multiple phases and indications. Their development is founded on solid mechanistic insights into the role of menin in oncogenic transcription. As early-phase clinical data continue to emerge, the promise of these targeted agents is becoming increasingly evident, suggesting that they may play a transformative role in future cancer treatment strategies. The integration of clinical findings, advanced genomic characterization, and rational combination therapy approaches will be critical to overcoming current challenges and harnessing the full therapeutic potential of menin inhibitors in oncology.