bleximenib (JNJ-6617) / J&J - LARVOL DELTA

Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure. (PubMed, Blood Adv) - "The 84 patients (63% KMT2Ar, n=53; 23% NPM1c, n=19) who received MENINi were heavily pre-treated: 86% (n=72) had prior intensive chemotherapy (IC), 77% venetoclax (VEN, n=67), and 38% (n=32) allogeneic stem cell transplantation...Of the 60% (n=50) that were treated, common regimens were hypomethylating agent (HMA)/VEN (26%, n=13), clinical trial (26%, n=13), and gilteritinib-based therapy (18%, n=9)...All CR/CRi occurred with HMA/VEN (n=2, 15%), IC+VEN (n=4, 67%), or MENINi switching (bleximenib to revumenib, n=1, 50%)...Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • FLT3 • KMT2A • MEN1 • NPM1 • WT1

The promise of menin inhibitors: from approval to triplet regimens. (PubMed, Hematology Am Soc Hematol Educ Program) - "Next-generation agents (ziftomenib, bleximenib, enzomenib, BMF-219) have displayed similar composite complete remission rates (20-35%) and overall response rates (45-65%) in heavily pretreated KMT2Ar and NPM1m acute myeloid leukemia (AML) with measurable residual disease (MRD) negativity and prolonged overall survival (5-7 months)...Acquired mutations in the menin gene described in 39% of post-revumenib relapses have not been identified following other inhibitors (ziftomenib, bleximenib), prompting new questions about resistance mechanisms. These promising results swiftly led to the launch of multiple trials of menin inhibitors combined with intensive (cytarabine and anthracycline) and nonintensive (venetoclax and hypomethylating) chemotherapy backbones...Ongoing/pending phase 3 trials will clarify whether menin blockade should be incorporated into frontline and maintenance regimens for all patients with KMT2A rearranged or NPM1 mutant disease. In the current era, menin..."

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

Phase 1b study of bleximenib in combination with venetoclax in Acute Myeloid Leukemia with KMT2A or NPM1 alterations (ASH 2025) - P1 | "Four of 13 (30.8%) pts proceeded to transplant.ConclusionsIn this Phase 1b trial, this all-oral doublet regimen had a tolerable safety profile with no DS observed andlimited discontinuations due to TEAEs. Bleximenib in combination with VEN demonstrated preliminaryclinical activity in pts with R/R AML harboring KMT2A or NPM1 alterations, including those with priorexposure to VEN and other menin inhibitors, and prior allogeneic transplant."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Novel Coronavirus Disease • Respiratory Diseases • Thrombocytopenia • KMT2A • NPM1

The outcomes of patients who are relapsed or refractory to menin inhibitors is poor with a limited overall survival (ASH 2025) - "Prior to MENINi, 86% (n=72)received intensive chemotherapy (IC) and 77% (n=65) received venetoclax (VEN)-based therapy, including65% (n=55) who had received both. Thirty-eight percent (n=32) of pts previously underwent alloSCT.Revumenib was the most used MENINi (n=61, 73%), followed by bleximenib (n=12, 14%) and ziftomenib(n=9, %)...The most common therapiesafter MENINi failure were hypomethylating agent (HMA) and VEN (n=13; 15%), investigational agents(n=13, 15%), and gilteritinib-based regimens (GILT; n=9, 11%)... MENINi are promising in AML, but outcomes after failure are poor. VEN-based regimens,especially in VEN-naïve pts, and MENINi switching can yield responses associated with improved survival.Studies addressing optimal sequencing as well as preventing and overcoming resistance are needed."

Clinical • Leukemia • FLT3 • KMT2A • MEN1 • NPM1 • NUP98 • WT1

Camelot-2: A phase 3 randomized, double-blind, placebo-controlled, study of bleximenib, venetoclax and azacitidine for the treatment of participants with newly diagnosed Acute Myeloid Leukemia harboring KMT2A rearrangements or NPM1 mutations, who are ineligible for intensive chemotherapy (ASH 2025) - P1, P3 | "Treatment will be administered on a 28-day cycle and continued until progression or unacceptabletoxicity.Primary endpoints are CR rate and overall survival (OS). Secondary endpoints include event-free survival(EFS), duration of CR, time to CR, rate of CR without measurable residual disease (CRMRD-), transfusionindependence, allogeneic stem cell transplantation rate, incidence of adverse events, clinical laboratoryparameter abnormalities, and serum concentration of bleximenib."

Clinical • P3 data • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Nephrology • Pulmonary Disease • Renal Disease • Respiratory Diseases • Solid Organ Transplantation • KMT2A • NPM1

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

Bleximenib in combination with intensive chemotherapy: A phase 1b study in newly diagnosed Acute Myeloid Leukemia with KMT2A or NPM1 alterations (ASH 2025) - P1 | "We now report updated safety andefficacy data (clinical cut-off: July 2025) from this combination treatment in IC-eligible ND AML pts (CohortC1).MethodsIn the ALE1002 Phase 1b, multicenter, dose-finding study (NCT05453903), pts in Cohort C1 received astandard '7+3' regimen of cytarabine 200 mg/m2/day and daunorubicin 60 mg/m2/day intravenous (IV) oridarubicin 12 mg/m2/day IV in combination with bleximenib. Median duration of response was not reached. Four pts receiving bleximenib 100 mg BID incombination with '7+3' proceeded to allogenic transplant.ConclusionsIn ND NPM1m or KMT2Ar AML, the safety profile of bleximenib + '7+3', including count recovery, wasconsistent with a '7+3' IC backbone, with no DS adverse events and no QTc prolongation signal observed.Combined with early efficacy, the clinical data are supportive of a planned Phase 3 study of bleximenib +'7+3' in IC-eligible ND AML pts harboring KMT2Ar or NPM1m."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • FLT3 • KMT2A • NPM1

Bleximenib or placebo in combination with standard induction and consolidation therapy followed by maintenance for the treatment of patients with newly diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia eligible for intensive chemotherapy: A double-blind Phase 3 study (HOVON 181 AML / AMLSG 37-25) (ASH 2025) - P1 | "In Arm 1, participants will receiveinduction therapy with bleximenib in combination with cytarabine plus daunorubicin or idarubicin. In Arm 3, participants will receive placebo insteadof bleximenib throughout, with the same chemotherapy schedule as Arms 1 and 2.The primary endpoint is event-free survival (EFS). Secondary endpoints include OS, rate of CR withoutmeasurable residual disease (CRMRD-), duration of CR, and incidence of adverse events.Enrollment is planned to begin in late 2025."

Clinical • Combination therapy • P3 data • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Leukemia • Respiratory Diseases • Solid Organ Transplantation • KMT2A • NPM1

Preclinical Efficacy of the Menin-KMT2A Inhibitor JNJ-75276617 in Combination with Venetoclax and Azacitidine in AML (ASH 2023) - P1, P1/2 | "Hypomethylating agents (e.g. azacitidine, decitabine) in combination with venetoclax have significantly improved clinical outcomes for AML patients and have become a preferred frontline treatment for AML patients ≥75 years of age, or who have comorbidities that preclude use of intensive induction chemotherapy. These studies suggest that the doublet combinations of either JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination could potentially provide a beneficial treatment option for KMT2A- or NPM1-altered AML, and support the recently initiated clinical trial investigating JNJ-75276617 in combination with AML-directed therapies, including venetoclax and azacitidine (NCT05453903). JNJ-75276617 is also being clinically investigated as a monotherapy for R/R acute leukemia (NCT04811560)."

Combination therapy • Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • NPM1

CR109124: A Study of Bleximenib in Combination With Acute Myeloid Leukemia (AML) Directed Therapies (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Oct 2024 ➔ Oct 2026

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • 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

Discovery of BTC-86, a Novel Second-Generation Menin-MLL Inhibitor to Overcome the Acquired Resistance in MEN1 for R/R Acute Leukemia (ASH 2024) - "BTC-86 is the most potent one in inhibition of menin-MLL1 binding against all the MEN1 acquired mutations among all five clinical molecules, including SNDX-5613, JnJ-75276617, and KO-539. IND-enabling study of BTC-86 is in progress. Further studies in clinical setting are warranted to confirm BTC-86 as a second-generation menin-MLL inhibitor for overcoming acquired resistance in MEN1."

Preclinical • Biliary Tract Cancer • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • MEN1 • NPM1

Discerning the Landscape of Menin Inhibitor Resistance (ASH 2024) - "With higher dose MI therapy, only 1 of 5 mice developed a MEN1 mutation and in the remaining mice MEN1 WT cells persisted and slowly expanded over the course of ≥6 months of therapy despite on-target gene expression changes : decreased MEIS1 and HOXA cluster genes, increased CD11b, CD13, CD14.Given that CRISPR-Cas9 base editing previously predicted some of the MEN1 mutations that arose with revumenib, we utilized improved base editing technology to help discern the landscape of MEN1 acquired mutations for four additional MIs currently in clinical trials (DS-1594, DSP-5336, JNJ-75276617, ziftomenib). An in vitro technique leveraging large starting cell numbers validates this base editor screening approach, which resulted in rapid development of resistant MEN1 mutant clones in less than 4 weeks of treatment. Identifying MEN1 mutations in patients receiving MIs is important because there may be opportunities for patients with select MEN1 mutations to derive benefit from an..."

Hematological Malignancies • Leukemia • Oncology • ANPEP • CD14 • ITGAM • KMT2A • MEIS1 • MEN1 • NPM1

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

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

Bleximenib in Combination With Standard Induction and Consolidation Therapy Followed by Maintenance for Treatment of Patients With Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P3 | N=875 | Not yet recruiting | Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland

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

RP2D DETERMINATION OF BLEXIMENIB IN COMBINATION WITH VEN+AZA: PHASE 1B STUDY IN ND & R/R AML WITH KMT2A/NPM1 ALTERATIONS (SIE 2025) - P1, P1/2 | "We present updated data evaluating the RP2D of bleximenib in combination with venetoclax (VEN) and azacitidine (AZA) in patients with R/R or newly diagnosed (ND) AML unfit for intensive chemotherapy. The combination exhibits a favorable safety profile, with no QTc prolongation observed. Enhanced pharmacodynamic effects and improved response depth at this dose support its use in further studies, including the Phase 3 cAMeLot-2 trial."

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

Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Scoping Review of Safety and Efficacy (SOHO 2025) - " Thirteen clinical trials evaluating six menin inhibitors—revumenib (SNDX-5613), ziftomenib (KO-539), bleximenib (KO-2806), enzomenib (DS-1594), BMF-219, and JNJ-75276617—were analyzed. These findings demonstrate the potent efficacy of menin inhibitors in genetically defined subsets of leukemia. However, their clinical application requires careful management of toxicity profiles, including QTc prolongation and differentiation syndrome. Additionally, menin inhibitors exhibit synergistic effects with agents like venetoclax and FLT3 inhibitors, enhancing therapeutic efficacy and potentially improving outcomes in KMT2A-rearranged and NPM1-mutated AML."

Clinical • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • NPM1

The role of menin inhibitors in acute myeloid leukemia. (PubMed, Curr Opin Oncol) - "These findings justify the integration of menin inhibitors into the AML therapeutic landscape, and support ongoing randomized trials to confirm their benefit in both frontline and relapse or refractory settings."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • MEN1 • NPM1

Recommended Phase 2 Dose (RP2D) Determination of Bleximenib in Combination With Venetoclax+Azacitidine (VEN+AZA): Phase Ib Study in Newly Diagnosed (ND) and Relapsed/ Refractory (R/R) Acute Myeloid Leukemia (AML) With KMT2A or NPM1 Alterations (SOHO 2025) - P1, P1/2 | "Data informed a bleximenib plus VEN+AZA RP2D of 100 mg BID for R/R and ND AML harboring KMT2Ar or NPM1m. The combination demonstrates acceptable safety and promising efficacy, supporting further exploration in the phase III cAMeLot-2 study."

Combination therapy • P1 data • P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

ALLG AMLM30: Bleximenib or Placebo in Combination with Standard Induction and Consolidation Therapy followed by Maintenance for the Treatment of Patients with Newly Diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia Eligible for Intensive Chemotherapy: a double-blind phase 3 study. (ANZCTR) - P3 | N=45 | Not yet recruiting | Sponsor: Australasian Leukaemia and Lymphoma Group

New P3 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • KMT2A • NPM1

Bleximenib Dose Optimization and Determination of the Recommended Phase 2 Dose (RP2D) From a Phase 1 Study in Patients With Relapsed/ Refractory Acute Leukemia (AL) With KMT2A and NPM1 Alterations (SOHO 2025) - P1/2 | "Bleximenib RP2D was determined at 100 mg BID (after a 50-mg BID step-up dose) with optimal safety, pharmacokinetic exposure, pharmacodynamic response, and promising antileukemic activity. No cardiac safety signals were observed; mitigation measures were used 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 • P2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

Phase 1b Study of Menin-KMT2A Inhibitor Bleximenib in Combination With Intensive Chemotherapy (IC) in Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) with KMT2Ar or NPM1 Alterations (SOHO 2025) - P1 | "Objectives: Safety and preliminary efficacy of bleximenib plus IC for ND AML; safety and preliminary efficacy of bleximenib plus intensive cytarabine+daunorubicin/idarubicin, followed by cytarabine consolidation for ND NPM1mor KMT2Ar AML participants eligible for IC. Dose escalation is ongoing. Preliminary results demonstrate that bleximenib in combination with 7+3 IC regimen in participants with ND AML has an acceptable safety profile. Preliminary antileukemic activity is observed in participants with ND NPM1m or KMT2Ar AML treated with bleximenib in combination with IC."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review. (PubMed, Diseases) - "Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options."

Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • KMT2A • MEIS1 • NPM1

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