Johnson & Johnson announced encouraging Phase 1b data for bleximenib (JNJ-75276617), an investigational selective menin inhibitor, showing significant antileukemic activity when combined with venetoclax and azacitidine for treating acute myeloid leukemia patients with specific genetic alterations. The results were presented at the 2025 European Hematology Association Congress.
Strong Efficacy Signals Across Patient Populations
The Phase 1b dose-finding study evaluated 125 patients with AML harboring KMT2A gene rearrangements (KMT2Ar) or NPM1 gene mutations (NPM1m), including both newly diagnosed patients ineligible for intensive chemotherapy and those with relapsed or refractory disease. At the recommended Phase 2 dose of 100 mg twice daily, bleximenib in combination with venetoclax and azacitidine achieved an overall response rate of 82% and a composite complete response rate of 59% in relapsed or refractory patients.
The newly diagnosed, intensive chemo-ineligible patient population demonstrated even stronger results, with a 90% overall response rate and 75% composite complete response rate. These outcomes represent significant improvements for patient populations with historically poor prognoses.
Favorable Safety Profile Supports Continued Development
Safety analysis across the study population showed a manageable profile comparable among dose groups, genetic subtypes, and disease settings. At the recommended Phase 2 dose, differentiation syndrome events were reported in only two of 49 patients (4%), addressing a key concern with menin inhibitors. Importantly, bleximenib continued to demonstrate no QTc prolongation signal, with no Grade 3 or higher cardiac events and only three Grade 1 events (6%).
The most common all-grade treatment-emergent adverse events included nausea (65%), thrombocytopenia (61%), neutropenia (59%), and anemia (49%). Grade 3 or higher events were primarily hematologic, with thrombocytopenia (59%), neutropenia (59%), and anemia (49%) being most frequent.
Targeting High-Risk Genetic Subgroups
Bleximenib specifically targets the menin-KMT2A interaction, a key oncogenic pathway driving leukemic cell growth in patients with KMT2Ar or NPM1m mutations. These genetic alterations are associated with particularly aggressive disease and poor outcomes, with relapsed/refractory disease survival as short as 2-3 months after second relapse.
"AML encompasses a spectrum of genetically diverse cancers affecting the bone marrow and blood, which progress rapidly, making it an extremely challenging cancer to treat," said Andrew M. Wei, MBBS, PhD, from Peter MacCallum Cancer Centre. "These data highlight the potential of this targeted therapy in combination with VEN + AZA for patients with newly diagnosed AML who are ineligible for intensive chemotherapy or with disease that has relapsed after prior therapy."
Dual Mechanism of Action
Beyond direct cytotoxicity, bleximenib demonstrates a unique dual mechanism that includes immune system engagement. The drug disrupts the menin-KMT2A interaction while also upregulating major histocompatibility complex molecules through epigenetic changes. This restoration of antigen presentation makes AML cells more visible to immune surveillance, potentially enhancing the effectiveness of combination therapies.
Advancing Through Clinical Development
The ongoing Phase 1b study (NCT05453903) is designed to enroll approximately 200 patients and determine the optimal dosing strategy for Phase 2 development. Patients receive venetoclax and azacitidine in combination with oral bleximenib twice daily, with bleximenib started on day 4 without requiring step-up dosing.
"Building on our heritage of leadership and innovation in hematologic malignancies, we are committed to delivering transformative treatment options that address the significant unmet needs of patients with acute myeloid leukemia," said Jeffrey Infante, M.D., Vice President of Early Clinical Development and Translational Research at Johnson & Johnson Innovative Medicine.
The company is currently exploring bleximenib's potential as both monotherapy and in combination with standard-of-care regimens in additional Phase 2 and 3 studies that are actively enrolling patients. This comprehensive development strategy reflects the significant unmet medical need in AML, where the five-year survival rate remains the lowest among leukemias despite recent treatment advances.
