A randomized placebo-controlled Phase 1 trial in healthy volunteers investigating safety, pharmacokinetics and pharmacodynamics of a novel menin inhibitor, balomenib (ZE63-0302): Interim analysis. Free

Background. MLL/KMT2A rearranged (KMT2Ar) and Mutant NPM1 AML which expresses a cytosolic restricted NPM1 protein (NPM1c) are driven by elevated expression of HOX genes that are dependent on the menin-KMT2A interaction, and this aberrant gene expression can be reversed by disrupting the binding of menin to KMT2A. However, current approved therapies to this therapeutic target suffer from significant cardiac toxicities (QTc prolongation). We have developed balomenib using both AI and a novel in silico modeling approach to generate a clinical stage molecule with a broad therapeutic index in animal toxicology (ratio). To de-risk the molecules pharmaceutical properties and determine on-target effects, we performed an exploratory first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) clinical trial of balomenib described herein that includes detailed pharmacokinetics and pharmacodynamics.

Methods. In April 2024 we initiated a phase 1, single-center, prospective, randomized, double-blind placebo-controlled study of 7 SAD cohorts and 3 MAD cohorts of balomenib administered orally to healthy adult participants. There were 8 participants per cohort (6 receiving balomenib and 2 receiving placebo), except SAD Cohort 5b with 4 high BMI subjects (3 receiving balomenib and 1 receiving placebo). The primary objective was pharmacokinetics (PK), secondary objective was safety, and exploratory objective was pharmacodynamics (target engagement). This interim analysis focuses on the 7 SAD cohorts (20, 100, 300 mg, 600 mg, 300 mg with food, 300 mg with food in high BMI participants, and 600 with itraconazole) and the 3 MAD cohorts (600 mg QD, 300 mg BID, and 300/600 mg BID for 7 days).

Results. A total of 52 subjects were enrolled in the Phase 1 SAD study of balomenib. Of the 52 subjects, 39 were treated with balomenib (6 subjects dosed with 20 mg, 100, 300 mg, 600 mg, 300 mg with food, and 600 mg with itraconazole; and 3 high BMI subjects dosed 300 mg with food) and 13 subjects dosed with placebo. The PK (C_max and AUC) demonstrated values that increased in a greater than dose-proportional manner as the dose increased from 20 to 300 mg and increased in approximately dose-proportional manner between 300 and 600 mg. Pre-feeding with a high fat meal had little effect on exposure while itraconazole treatment resulted in ~ 2-fold increase in Cmax and AUC. The half-life ranged from 9-10 hours (is this correct?). In the Phase 1 MAD study of balomenib, a total of 24 subjects were enrolled. Of the 24 subjects, 18 were treated with balomenib (600 mg QD, 300 mg BID, and 300/600 mg BID) and 6 subjects dosed with placebo for 7 days. There was some accumulation of exposure between Day 1 and Day 7 for Cohorts 1 and 2 (600 mg QD and 300 mg BID), and slightly greater exposure on Day 7 with BID vs QD dosing. In Cohort 3 (300 BID on Days 1-2 and 600 mg BID on Days 3-7), the exposures on Day 7 increased in roughly a dose-proportional manner as compared to MAD Cohort 2, with a mean C_max of 1136 nM and mean AUC_0-24 of 11.4 µM*h. The exposure achieved in the MAD study Cohort 3 is consistent with an efficacious exposure based on preclinical in vivo studies. In both the SAD and MAD cohorts, balomenib was generally well tolerated with no severe or serious treatment-related adverse events (TEAEs). There were no TEAEs that led to study withdrawal. The most frequent TEAE was nausea (Grade 1 or Grade 2, controllable with ondansetron). Pharmacodynamic activity was assessed in an ex vivo plasma inhibitory assay (PIA) for inhibition of Meis1 mRNA expression in the AML cell line MOLM-13 that harbors the KMT2Ar (MLLr). Preliminary results for change of Meis1 expression demonstrated inhibitor of Meis1 expression that directly correlated with exposure, with peak inhibition at Cmax.

Conclusion. At the interim analysis, balomenib demonstrated a favorable safety profile when administered orally to all tested SAD and MAD cohorts. Dose-proportional systemic exposure was observed, and target engagement was established. The safety of balomenib in both pre-clinical and clinical studies thus far suggest it will be an exceptional therapeutic to combine with other agents in KMT2A/MEN1 dependent malignancies.