Preclinical Efficacy of the Menin-KMT2A Inhibitor JNJ-75276617 in Combination with Venetoclax and Azacitidine in AML

Background: JNJ-75276617 is a highly selective and orally bioavailable small molecule targeting the menin- histone-lysine N-methyltransferase 2A (KMT2A) protein-protein interaction. Pharmacologic disruption of this interaction was previously shown to induce differentiation and block progression of KMT2A-r or NPM1c acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (ALL) in preclinical models (Kwon, ASH 2022). Small-molecule inhibitors including JNJ-75276617 are being explored clinically as a treatment for KMT2A- and NPM1-altered leukemias, which represent an area of high unmet medical need. 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. Although promising responses are seen in the frontline setting, unfortunately many patients relapse highlighting the need for better therapies and more effective combinations. JNJ-75276617 was previously shown to inhibit HOX/Meis1 stemness genes and induce differentiation genes in KMT2A- or NPM1-altered leukemic cells. Here, we evaluated whether JNJ-75276617, which induces differentiation followed by cell death, could enhance the mechanisms of action triggered by venetoclax plus azacitidine, which primarily drives apoptosis by displacing anti-apoptotic proteins.

Results: JNJ-75276617 exhibited synergistic effects with venetoclax alone or in combination with azacitidine in AML cells bearing KMT2A-r in vitro. Proliferation assays in KMT2A-r MOLM-13 AML cells showed that doublet combination of JNJ-75276617 plus venetoclax induced a synergistic antiproliferative effect in vitro that was significantly increased when compared to JNJ-75276617 or venetoclax monotherapy. The triplet combination of JNJ-75276617 plus azacitidine and venetoclax further induced a synergistic antiproliferative effect that was significantly increased when compared to JNJ-75276617 monotherapy or the doublet combination of venetoclax plus azacitidine.

In the disseminated KMT2A-r MOLM-13 model in mice, monotherapy treatment with JNJ-75276617 at 10 mg/kg and azacitidine at 2 mg/kg induced a significant ILS of 35% each compared to the vehicle control group (p<0.0001 each), while 6% ILS was observed for mice treated with 100 mg/kg venetoclax (p=0.0076). The combination of azacitidine plus venetoclax, resulted in a significant ILS of 53% compared to the vehicle control (p<0.0001). Doublet combination treatment with either JNJ-75276617 plus azacitidine or plus venetoclax resulted in a significant ILS of 106% or 256%, respectively, as compared to the vehicle control (p<0.0001 each). The JNJ-75276617 triplet combination with azacitidine plus venetoclax induced a significant ILS of 277%, as compared to the vehicle control group (p<0.0001). These results further showed that either the doublet combinations of JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination provided a superior increase in survival as compared with the clinical standard regimen of azacitidine plus venetoclax (p<0.0001 each). In a disseminated NPM1c model (OCI-AML3), JNJ-75276617 doublet or triplet combination with azacitidine and venetoclax also yielded superior survival versus the standard azacitidine plus venetoclax regimen, however triplet efficacy seemed most strongly driven by JNJ-75276617.

Conclusions: 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).