Chemistry:Bleximenib

Bleximenib (INN: bleximenib; development code JNJ-75276617) is an orally available investigational new drug developed by Johnson & Johnson's Janssen Pharmaceuticals for the treatment of acute myeloid leukemia (AML). It belongs to a novel class of menin inhibitors that selectively disrupt the protein-protein interaction between menin and KMT2A (lysine methyltransferase 2A), representing a precision medicine strategy for patients with specific genetic alterations.

Bleximenib is designed for acute leukemias with KMT2A rearrangements or NPM1 mutations, alterations that together occur in about 40% of AML cases. The compound shows high potency with IC₅₀ values in the nanomolar range and has demonstrated encouraging activity in early-phase clinical trials, both as monotherapy and in combination with standard-of-care treatments.

Background and development

Disease context

Acute myeloid leukemia (AML) with KMT2A rearrangements and NPM1 mutations represents a significant unmet medical need in hematologic oncology. KMT2A rearrangements occur in up to 10% of acute leukemias and are associated with adverse prognosis, while NPM1 mutations occur in up to 30% of AML cases, forming the most common genetic alteration in adult acute myeloid leukemia. NPM1 mutations are found in 25–30% of adult AML patients and in 10% of pediatric AML patients.

These genetic alterations create dependency on the menin-KMT2A protein complex for maintaining leukemic cell survival and proliferation, making them attractive targets for precision therapy approaches. Traditional chemotherapy regimens have shown limited efficacy in these patient populations, particularly in the relapsed or refractory setting, highlighting the critical need for novel targeted therapies.

Drug discovery

Bleximenib was developed as part of Johnson & Johnson's targeted oncology portfolio, building upon scientific understanding of the menin-KMT2A interaction as a therapeutic target. The compound was designed to achieve high selectivity and potency against the menin protein while maintaining favorable pharmaceutical properties for oral administration.

Mechanism of action

Bleximenib functions as a highly selective, orally bioavailable inhibitor of the protein-protein interaction between menin and KMT2A. The drug demonstrates exceptional potency with IC50 values of 0.1 nM in humans, 0.045 nM in mice, and ≤0.066 nM in dogs, indicating consistent activity across species.

Molecular target

The primary target of bleximenib is the menin protein, which forms a critical complex with KMT2A in leukemic cells. Menin serves as an essential cofactor that facilitates KMT2A-mediated transcriptional activation of oncogenic programs. In normal physiology, menin acts as a tumor suppressor, but in the context of KMT2A-rearranged or NPM1-mutant leukemia, the menin-KMT2A interaction becomes essential for maintaining the leukemic phenotype.

Cellular effects

In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) acute leukemia cells, bleximenib disrupts the association of menin with KMT2A, leading to the downregulation of critical oncogenic gene expression programs including HOXA9 and MEIS1. This results in multiple downstream effects including:

• Inhibition of leukemic cell proliferation
• Induction of apoptosis (programmed cell death)
• Promotion of myeloid differentiation
• Disruption of leukemic stem cell maintenance

The selectivity of bleximenib for leukemic cells harboring these specific genetic alterations provides a therapeutic window that may minimize toxicity to normal hematopoietic cells.

Clinical development

Phase 1 monotherapy study

The primary clinical investigation of bleximenib is being conducted through a Phase 1/Phase 2 first-in-human study (NCT04811560) evaluating the drug as monotherapy in patients with relapsed or refractory acute leukemia harboring KMT2A rearrangements or NPM1 mutations.

The study employs a standard 3+3 dose escalation design in Phase 1 to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). As of a 2023 update, 58 patients had received bleximenib, with 56 patients having relapsed/refractory AML and 2 patients having relapsed/refractory ALL. KMT2A rearrangements were identified in 33 patients (57%) and NPM1 mutations in 25 patients (43%).

Recent presentations at the American Society of Hematology (ASH) annual meeting have provided updates on dose optimization and RP2D determination from this ongoing study.

Combination therapy studies

Multiple combination therapy approaches are being investigated to optimize the therapeutic potential of bleximenib:

Venetoclax and azacitidine combination

A Phase 1b study is evaluating bleximenib in combination with venetoclax and azacitidine for both relapsed/refractory AML and newly diagnosed AML patients who are ineligible for intensive chemotherapy. Data presented in 2025 demonstrated promising antileukemic activity with this triplet combination, showing encouraging response rates and manageable safety profiles.

Intensive chemotherapy combination

A separate Phase 1b study (NCT05453903) is investigating bleximenib in combination with intensive chemotherapy regimens in newly diagnosed AML patients with KMT2A rearrangements or NPM1 alterations. This approach aims to leverage the synergistic potential of menin inhibition with standard cytotoxic therapy in the frontline setting.

Clinical endpoints and biomarkers

The clinical trials are evaluating multiple endpoints including:

• Primary endpoints: Safety, tolerability, and determination of RP2D
• Secondary endpoints: Overall response rate (ORR), complete remission (CR) rate, duration of response, overall survival (OS), and progression-free survival (PFS)
• Exploratory endpoints: Minimal residual disease (MRD) assessment, pharmacokinetic parameters, and biomarker correlations

Safety profile

Early clinical data suggest that bleximenib has a manageable safety profile consistent with other agents in the menin inhibitor class. In the Phase 1 monotherapy study, grade 3 or higher adverse events occurred in 17 patients (29%), including neutropenia (10%), which is expected given the mechanism of action and patient population.

Adverse events

The most commonly reported adverse events include:

• Neutropenia (low white blood cell count)
• Thrombocytopenia (low platelet count)
• Anemia (low red blood cell count)
• Gastrointestinal effects (nausea, diarrhea)
• Fatigue

Differentiation syndrome

Differentiation syndrome, a known class effect of menin inhibitors, has been reported at low rates in bleximenib clinical trials. This condition, characterized by fever, fluid retention, and pulmonary infiltrates, is manageable with appropriate monitoring and intervention protocols including corticosteroid administration.

Cardiac safety

Comprehensive cardiac safety monitoring has shown no significant QT interval prolongation (QTc) signals associated with bleximenib treatment, distinguishing it from some other targeted therapies in development.

Preclinical research

Extensive preclinical studies have established the scientific foundation for bleximenib's clinical development. Research published in peer-reviewed journals has demonstrated the compound's efficacy across multiple leukemia models both in vitro and in vivo.

Efficacy studies

Studies published in Blood showed that bleximenib displayed robust preclinical efficacy against NPM1-mutant and KMT2A-altered AML and B-cell acute lymphoblastic leukemia (B-ALL) as monotherapy and in combination with gilteritinib, azacitidine, and/or venetoclax.

Mechanistic insights

Research published in Haematologica provided detailed mechanistic insights into how bleximenib impairs proliferation and drives differentiation of primary AML patient cells. The studies demonstrated the compound's effects on long-term proliferation capacity and immune evasion mechanisms, providing important understanding of its therapeutic potential.

Combination rationale

Preclinical studies have provided scientific rationale for various combination approaches, demonstrating synergistic effects when bleximenib is combined with:

• Venetoclax (BCL-2 inhibitor)
• Azacitidine (DNA methyltransferase inhibitor)
• Gilteritinib (FLT3 inhibitor)
• Standard cytotoxic chemotherapy agents

Chemistry and pharmacology

Chemical structure

Bleximenib has the molecular formula C
32H
50FN
7O
3 with a molecular weight of 611.82 g/mol. The compound is catalogued in multiple chemical databases including PubChem (CID: 156498110) and the IUPHAR/BPS Guide to Pharmacology (Ligand ID: 12866).

Pharmacological properties

Bleximenib is designed as an orally bioavailable small molecule with pharmaceutical properties optimized for clinical administration. The compound demonstrates:

• High selectivity for the menin-KMT2A interaction
• Nanomolar potency across preclinical species
• Suitable oral bioavailability for once-daily dosing
• Appropriate pharmacokinetic profile for clinical development

Pharmacokinetics

The compound has been designed to achieve appropriate exposure levels for therapeutic efficacy while maintaining an acceptable safety profile. Clinical studies are ongoing to characterize the complete pharmacokinetic profile in humans.

Related menin inhibitorts

Bleximenib is part of a growing class of menin inhibitors being developed for similar indications. The most advanced compound in this class is revumenib (SNDX-5613), which received FDA approval in November 2024 after demonstrating consistent efficacy across five pivotal trials, achieving MRD negativity in 50–70% of responders in both KMT2A-rearranged and NPM1-mutated leukemias.

Other menin inhibitors in clinical development include ziftomenib and DSP-5336, each with distinct pharmacological profiles and development strategies. The competitive landscape reflects the high interest in this target and the potential for multiple agents to serve different patient populations or combination strategies.

Regulatory status

As of September 2025, bleximenib remains an investigational drug without regulatory approval from any health authority. The compound is assigned the Unique Ingredient Identifier (UNII) code DCN5WEN78T by the National Center for Advancing Translational Sciences (NCATS).

See also

• NPM1
• Acute myeloid leukemia
• Revumenib
• Targeted therapy
• Precision medicine

External links

• Bleximenib at NCATS Inxight Drugs
• Clinical trial number NCT04811560 for "A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (cAMeLot-1) (cAMeLot-1)" at ClinicalTrials.gov
• Clinical trial number NCT05453903 for "A Study of Bleximenib in Combination With Acute Myeloid Leukemia (AML) Directed Therapies" at ClinicalTrials.gov