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

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: Mar 2025 ➔ Aug 2026

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

Exploring new horizons in menin: it's bleximenib's turn. (PubMed, Haematologica) - "Not available."

Journal

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

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 completion date: Mar 2026 ➔ Mar 2027

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

Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions. (PubMed, Int J Cancer) - "Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A-rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A-complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors."

Journal • Review • Acute Myelogenous Leukemia • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • AFF1 • KMT2A • MLLT10 • MLLT3 • NPM1 • NUP98

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

Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia. (PubMed, Haematologica) - "Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DNMT3A • KMT2A • MEIS1 • MLLT3

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

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 • Cardiovascular • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Leukopenia • Neutropenia • Oncology • Pain • Thrombocytopenia • KMT2A • 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

Johnson & Johnson to showcase strength of its broad hematology portfolio and pipeline at the 2024 American Society of Hematology Annual Meeting (PRNewswire) - "Johnson & Johnson...announced today more than 90 abstracts featuring data from the Company's differentiated blood cancer portfolio and pipeline will be presented at the 66th American Society of Hematology (ASH) Annual Meeting in San Diego from December 7-10. Clinical trial and real-world data will highlight the Company's broad and expanding portfolio of hematologic therapies, deepening its leadership in novel approaches to treat multiple myeloma as well as myeloid and B-cell malignancies."

Clinical data • Real-world evidence • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

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 | N=150 ➔ 200

Combination therapy • Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

A Study of JNJ-75276617 in Combination With Conventional Chemotherapy for Pediatric and Young Adult Participants With Relapsed/Refractory Acute Leukemias (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Janssen Research & Development, LLC | N=80 ➔ 0 | Not yet recruiting ➔ Withdrawn

Combination therapy • Enrollment change • Trial withdrawal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • KMT2A • NPM1 • NUP214 • NUP98

CR109124: A Study of Bleximenib in Combination With Acute Myeloid Leukemia (AML) Directed Therapies (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: May 2024 ➔ Mar 2025

Combination therapy • Trial primary completion date • 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 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

Preclinical efficacy of potent and selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias. (PubMed, Blood) - P1, P1/2 | "JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice...A co-crystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory (R/R) acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903)."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • MEIS1 • NPM1

PHASE 1B STUDY OF MENIN-KMT2A INHIBITOR JNJ-75276617 IN COMBINATION WITH VENETOCLAX/AZACITIDINE OR HIGH INTENSITY CHEMOTHERAPY IN NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA WITH KMT2A/NPM1 ALTERATIONS (EHA 2024) - "This abstract is embargoed until Friday, June 14, 2024 (09:00 CEST). Presentation during EHA2024: All (e)Poster presentations will be made available as of Friday, June 14, 2024 (09:00 CEST) and will be accessible for on-demand viewing until Thursday, August 15, 2024 on the Congress platform."

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

Novel approaches for diagnosis & treatment of acute lymphoblastic and myeloid leukemia (ICKSH 2024) - "For BCP-ALL, this mainly concerns the introduction of blinatumomab and inotuzumab ozogamicin, as well as the recently developed menin inhibitor revumenib, which is mainly be of relevance for KMT2A-rearranged (infant) ALL. Other menin inhibitors are also under development, such as ziftomenib and JNJ-75276617. Other targeted therapy options are mainly relevant in Philadelphia-chromosome positive leukemias, and in adult ALL the concept of che- mo-free induction therapy is already under development consisting of combinations of tyrosine kinase inhibitors (TKIs) such as imatinib, da- satinib or ponatinib, in combination with with steroids or blinatumomab, and challenging the need for SCT in this disease...Also for T-cell ALL, newer therapy options are available including CAR T-cell therapy, for example the allogenic off-the-shelf, fractricide-resistant CD7-targeted CAR-T cell therapy studies in the WU-CART-007 study. For AML, immunotherapy is less well advanced, but next to..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Ovarian Cancer • Pediatrics • Solid Tumor • CBFA2T3 • CD123 • CD7 • FLT3 • GLIS2 • IL3RA • KMT2A • NUP98

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

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

Preclinical Efficacy of the Menin-KMT2A Inhibitor JNJ-75276617 in Combination with Venetoclax and Azacitidine in AML (ASH 2023) - P1 | "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

A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Janssen Research & Development, LLC | Phase classification: P1b ➔ P1

Combination therapy • Phase classification • 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 | "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 • P1 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • Transplantation • FLT3 • HOXA9 • ITGAM • KMT2A • MEIS1 • NPM1

ASH: Novel menin inhibitors show promise for patients with advanced acute myeloid leukemias (Eurekalert) - P1 | N=110 | NCT04811560 | Sponsor: Janssen Research & Development, LLC | "According to data from a Phase I trial led by Elias Jabbour, M.D., professor of Leukemia, the menin inhibitor JNJ-75276617 showed early clinical activity in patients with relapsed or refractory acute leukemias and genetic alterations in KMT2A or NPM1, which are associated with poor clinical outcomes. Among 66 patients able to be evaluated after one month of treatment, JNJ-75276617 monotherapy reduced bone marrow disease burden in 71%, and 33 of those patients had a decrease in bone marrow blasts of more than 50%. Median time to first response was less than two months. Similar response rates were observed across patient groups with both genetic alterations."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology