bleximenib (JNJ-6617)

P3, N=600, Not yet recruiting, Janssen Research & Development, LLC

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.

P1, N=200, Recruiting, Janssen Research & Development, LLC | Trial completion date: Mar 2026 --> Mar 2027

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.

P1, N=200, Recruiting, Janssen Research & Development, LLC | N=150 --> 200

P1, N=0, Withdrawn, Janssen Research & Development, LLC | N=80 --> 0 | Not yet recruiting --> Withdrawn

P1, N=150, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: May 2024 --> Mar 2025

P1/2, N=350, Recruiting, Janssen Research & Development, LLC | N=150 --> 350 | Trial completion date: Feb 2026 --> Oct 2027

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).

P1/2, N=150, Recruiting, Janssen Research & Development, LLC | Phase classification: P1 --> P1/2

P1, N=150, Recruiting, Janssen Research & Development, LLC | N=110 --> 150

P1, N=150, Recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

P1, N=80, Not yet recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2026 --> Jan 2030

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2025 --> Oct 2025

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).

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.

To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2026 --> Jun 2025

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2025 --> Jun 2026

P1, N=80, Ongoing, Janssen-Cilag International NV

P1, N=80, Not yet recruiting, Janssen Research & Development, LLC | Initiation date: Dec 2022 --> Feb 2024

P1b, N=150, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Jan 2026

P1, N=80, Not yet recruiting, Janssen Research & Development, LLC

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Aug 2024 --> Jun 2025

P1b, N=150, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

P1b, N=150, Not yet recruiting, Janssen Research & Development, LLC

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2024 --> Aug 2024

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Apr 2024