Report on Ziftomenib (KO-539): A Novel Menin Inhibitor for Acute Myeloid Leukemia

I. Introduction and Executive Summary

Ziftomenib, also known by its developmental code name KO-539, is an orally bioavailable, investigational small molecule drug poised to introduce a new paradigm in the treatment of specific, genetically defined subsets of Acute Myeloid Leukemia (AML).[1] As a member of the novel therapeutic class of menin inhibitors, Ziftomenib employs a highly targeted mechanism of action, designed to disrupt a critical protein-protein interaction that drives cancer cell proliferation and survival in certain leukemias.[3]

The clinical development of Ziftomenib is precisely focused on AML patient populations with a profound unmet medical need: those whose disease is characterized by mutations in the nucleophosmin 1 (NPM1) gene or rearrangements of the lysine methyltransferase 2A (KMT2A, formerly known as MLL) gene.[3] These genetic alterations are found in a significant portion of AML cases, and for patients who relapse or are refractory to initial therapies, the prognosis is exceptionally poor, with limited effective treatment options currently available.[6]

The comprehensive clinical program for Ziftomenib is anchored by two key studies. The KOMET-001 trial, a Phase 1/2 study, evaluated Ziftomenib as a monotherapy in patients with relapsed/refractory (R/R) AML. This trial successfully identified a recommended Phase 2 dose and, most critically, demonstrated significant and durable clinical activity in the NPM1-mutant cohort, providing the pivotal data supporting a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA).[9] The KOMET-007 trial is exploring Ziftomenib in the frontline setting, where its combination with standard-of-care chemotherapy has yielded exceptionally high rates of deep, molecular remissions in newly diagnosed patients with both

NPM1 mutations and KMT2A rearrangements.[11]