bleximenib (JNJ-6617) / J&J, Blackstone Health - LARVOL DELTA

Identifying novel ’druggable’ targets via Npm1A-turboid fusion and mass spectrometry to overcome genetic or adaptive resistance to menin inhibitors in mtNPM1 AML (ASH 2025) - "Treatment with revumenib may also cause emergenceof hot spot mutations in menin (e.g., S160T, M327V, M327I, G331D, G331R, and T349M) exhibitingreduced affinity to MI-binding...OCI-AML3 MEN1-M327I cells were resistant toSNDX-50469, ziftomenib, and DS1594b, but sensitive to the second-generation MI, bleximenib, aspreviously reported.To identify novel 'druggable' targets in mtNpm1 AML cells either sensitive or resistant to MI, we knockedin TurboID by CRISPR/Cas9 into the C-terminus of the mtNpm1 gene in OCI-AML3 cells...When combined with a BET inhibitor (pelabresib) ora novel dual BET/HAT inhibitor (NEO2734/EP31670), both RocA and talazoparib induced synergisticlethality in the sensitive OCI-AML3 and OCI-AML2-Npm1A KI, as well as the MI-resistant (OCI-AML3-Menin-M327I or the OCI-AML3 MITR) cells...Exvivo treatment with EP31670 and RocA or talazoparib induced synergistic loss of viability in MI (SNDX-50469)-resistant, patient-derived (N = 3) mtNpm1 AML cells. In the..."

IO biomarker • Acute Myelogenous Leukemia • AURKA • CDK9 • CDKN1A • EIF4A1 • EIF4A2 • FLT3 • HOXA9 • IL7R • IRAK4 • KMT2A • MEIS1 • MEN1 • MYC • NPM1 • PLK1 • S100A8 • SF3B1 • SMARCA2 • TP53

Menin Inhibitors in Acute Myeloid Leukemia: Clinical Integration, Resistance, and the Path Beyond Monotherapy. (PubMed, Cancers (Basel)) - "We explore data from the landmark AUGMENT-101 and KOMET-001 trials, which have led to regulatory approval of revumenib and ziftomenib for select patients...We highlight resistance mechanisms that have emerged from the use of contemporary menin inhibitors and efforts aimed at addressing this resistance, with a focus on emerging clinical data on enzomenib and bleximenib. Finally, we discuss prospects on the putative role of menin inhibitors in the measurable residual disease (MRD)-positive and maintenance settings in AML. Menin inhibitors have successfully transitioned from biological proof-of-concept to approved targeted therapy, and future advances will depend on rational front line combination strategies, MRD-guided treatment, post-transplant maintenance strategies, and therapeutic sequencing informed by mechanisms of resistance."

Journal • Monotherapy • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • HOXA9 • KMT2A • NPM1

A PHASE 1B STUDY OF THE MENIN-KMT2A INHIBITOR JNJ-75276617 IN COMBINATION WITH VENETOCLAX AND AZACITIDINE IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA WITH ALTERATIONS IN KMT2A OR NPM1 (EHA 2024) - P1, P1/2 | "In this first analysis of a Phase 1b study exploring the triplet combination of JNJ-75276617+VEN+AZA in RRKMT2A-altered and NPM1m AML, the safety profile has been acceptable, with no DLTs observed and theRP2D(s) yet to be determined. To date, no AEs of DS, QTcF prolongation or TLS have been reported. Preliminary antileukemic efficacy with this triplet combination in RR AML was demonstrated, including in ptspreviously exposed to VEN."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Leukopenia • Neutropenia • Oncology • Thrombocytopenia • HEY1 • KMT2A • NPM1

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P2/3 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | Phase classification: P1/2 ➔ P2/3 | Trial completion date: Dec 2028 ➔ Dec 2032 | Trial primary completion date: Dec 2028 ➔ Dec 2032

Biomarker • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NPM1

A First-in-Human Phase 1 Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Adult Patients with Relapsed/Refractory Acute Leukemia Harboring KMT2A or NPM1 Alterations (ASH 2023) - P1/2 | "Dose escalation in 75276617ALE1001 is ongoing with the RP2D(s) yet to be determined. Pts in dose expansion will receive JNJ-75276617 at the identified RP2D(s). Preliminary results of this FIH Phase 1 study demonstrate that JNJ-75276617 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring KMT2A or NPM1 alterations."

Clinical • First-in-human • P1 data • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • FLT3 • HOXA9 • ITGAM • KMT2A • MEIS1 • NPM1

Bleximenib Dose Optimization and Determination of RP2D from a Phase 1 Study in Relapsed/Refractory Acute Leukemia Patients with KMT2A and NPM1 Alterations (ASH 2024) - P1/2 | "No cardiac safety signal was observed, and mitigation measures have been implemented for DS. Phase 2 clinical trial activation is ongoing to further evaluate bleximenib monotherapy at the RP2D in R/R AML with KMT2Ar or NPM1m."

Clinical • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • KMT2A • MEIS1 • NPM1

RP2D DETERMINATION OF BLEXIMENIB IN COMBINATION WITH VEN+AZA: PHASE 1B STUDY IN ND & R/R AML WITH KMT2A/NPM1 ALTERATIONS (EHA 2025) - P1, P1/2 | "Evaluation of safety, efficacy, and tolerability data informed bleximenib 100 mg BID as RP2D in combination with VEN+AZA for both R/R and ND pts with KMT2Ar or NPM1m AML. Bleximenib in combination with VEN+AZA has an acceptable safety profile, with no QTc prolongation signal observed to date. A bleximenib 100 mg BID dose in combination with VEN+AZA resulted in optimal PD effects and improved depth of response, consistent with established monotherapy RP2D."

Combination therapy • P1 data • Tumor mutational burden • Acute Myelogenous Leukemia • Anemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • ITGAM • KMT2A • NPM1 • TMB

Phase 1b Study of Menin-KMT2A Inhibitor Bleximenib in Combination with Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with KMT2Ar or NPM1 Alterations (ASH 2024) - P1 | "Aims : To determine the safety and preliminary efficacy of bleximenib in combination with intensive cytarabine + daunorubicin/idarubicin, followed by cytarabine consolidation for ND NPM1m or KMT2Ar AML participants (pts) eligible for IC. There is no consistent delay in neutrophil or platelet count recovery after induction. In addition, preliminary antileukemic activity is observed in pts with ND NPM1m or KMT2Ar AML treated with bleximenib in combination with IC."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Leukopenia • Neutropenia • Oncology • Thrombocytopenia • KMT2A • NPM1

GI Toxicity Profile of Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Systematic Review and Meta-Analysis of 526 Patients (ACG 2026) - "Introduction: Menin inhibitors (revumenib, ziftomenib, bleximenib, enzomenib) block the menin-KMT2A interaction to reverse leukemogenesis in KMT2A-rearranged (KMT2Ar) and NPM1-mutated (NPM1m) acute leukemia. : DS of any grade was pooled across 9 arms (N=526, events=58): incidence 10.3% (95% CI 5.0-16.9%; prediction interval [PI] 0-33.9%; I²=73.1%). DS grade â¥3: 3.3% (95% CI 0.4-8.1%; PI 0-20.8%). QTc prolongation: 1.2% (95% CI 0-4.1%)."

Retrospective data • Review • Hematological Malignancies • Leukemia • KMT2A • NPM1

A Study of 14C-Bleximenib (Radiolabeled) in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Jun 2026 ➔ Sep 2026

Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

cAMeLot-2: A Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Janssen Research & Development, LLC

New P3 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

cAMeLot-2: A Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Janssen Research & Development, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Apr 2024 ➔ Aug 2024

Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

CR108998: A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1/2 | N=150 | Recruiting | Sponsor: Janssen Research & Development, LLC | Phase classification: P1 ➔ P1/2

Phase classification • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

CR108998: A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Janssen Research & Development, LLC | N=110 ➔ 150

Enrollment change • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

CR108998: A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (cAMeLot-1) (clinicaltrials.gov) - P1/2 | N=420 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: May 2028 ➔ Sep 2030 | Trial primary completion date: Feb 2026 ➔ Jun 2026

First-in-human • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1 • NUP214 • NUP98

CR108998: A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (cAMeLot-1) (clinicaltrials.gov) - P1/2 | N=420 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Jun 2026 ➔ Feb 2027

First-in-human • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1 • NUP214 • NUP98

CR108998: A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (clinicaltrials.gov) - P1/2 | N=400 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Oct 2027 ➔ May 2028

Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

CR108998: A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (clinicaltrials.gov) - P1/2 | N=350 | Recruiting | Sponsor: Janssen Research & Development, LLC | N=150 ➔ 350 | Trial completion date: Feb 2026 ➔ Oct 2027

Enrollment change • Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jun 2025 ➔ Oct 2025

Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jun 2026 ➔ Jun 2025

Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

A Study of JNJ-75276617 in Participants With Acute Leukemia (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Aug 2024 ➔ Jun 2025

Trial completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

Clinical research progress of menin inhibitors for acute myeloid leukemia: latest updates from the 2025 ASH Annual Meeting. (PubMed, Exp Hematol Oncol) - "Novel menin inhibitors, including revumenib, bleximenib, ziftomenib, and enzomenib, are currently under clinical evaluation, and selected updated clinical results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting. This brief review summarizes the key findings and discusses the emerging clinical questions regarding combination strategies, treatment sequencing, and molecularly defined use of menin inhibitors."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

TRANSCRIPTIONAL REWIRING TO A MONOCYTIC STATE REVEALS THERAPEUTIC VULNERABILITIES IN MENIN INHIBITOR RESISTANCE AML (EHA 2026) - "Methods We generated three MOLM-13 acute myeloid leukemia ( KMT2A -rearranged AML) cell line models with acquired resistance to clinical-stage MENi (Revumenib, Bleximenib, and Ziftomenib) via stepwise dose escalation...This subgroup of patients exhibited a high frequency of RAS mutations, MAPK pathway activation and dependency, and resistance to venetoclax...The overlap identifies rational combination strategies, potentially the use of MEK inhibitors, to overcome resistance. Future studies will focus on validating transcriptomic RAS activity and cell-state signatures as actionable biomarkers and evaluate these combinations in vitro and in vivo."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CSF1R • KMT2A • MEIS1 • MEN1