A Randomized Placebo-Controlled Phase 1 Trial in Healthy Volunteers Investigating the Safety, Pharmacokinetics and Pharmacodynamics of a Novel FLT3/IRAK4 Inhibitor, Lomonitinib (ZE46-0134)

Background. Lomonitinib is a highly potent and selective pan-FLT3/ IRAK4 inhibitor that targets clinically relevant FLT3 mutations as well as IRAK4, a putative escape pathway for FLT3-driven AML. The relative selectivity of Lomonitinib compared to other FLT3 inhibitors was derived from a novel in silico modeling approach that avoided multiple alternative targets commonly inhibited with commercially approved agents. In vitro studies with FLT3-ITD cell lines demonstrated potent inhibition and differential decrease of FLT3 protein expression compared to gilteritinib. Multiple in vivo studies with both xenograft and syngeneic immune competent murine models demonstrated that lomonitinib has superior efficacy to gilteritinib in ITD and gatekeeper mutation-dependent disease and demonstrated synergistic efficacy when administered in combination with Bcl-2 or menin inhibitors¹. Unlike gilteritinib, lomonitinib had minimal toxicity observed in pre-clinical rodent and dog toxicology studies at exposures well beyond the anticipated therapeutic exposure. A first-in-human clinical trial of lomonitinib in healthy volunteers was initiated in August 2023. Application of healthy volunteer studies with agents having a broad therapeutic index such as lomonitinib offer the opportunity to enter a subsequent AML patient clinical trial at a clinically effective dose. Additionally, these studies provide better prediction of tolerability in AML patients. We bring forward this new model of myeloid leukemia drug development for targeted therapies.

Methods. We conducted a Phase 1, single-center, prospective, randomized, double-blind placebo-controlled study of lomonitinib administered orally to healthy adult participants (NCT06399315). The primary objective was pharmacokinetics (PK), the secondary objective was safety, and an exploratory objective was pharmacodynamics (FLT3 target engagement). This analysis focuses on the 3 MAD cohorts and a SAD cohort investigating drug-drug interaction (DDI) with itraconazole, a strong CYP3A4 inhibitor.

Results. Due to the extended half-life and safety of lomonintib demonstrated in the Phase 1 SAD study², we utilized a loading strategy (50 mg or 100 mg Day 1) to rapidly reach steady state (Css) to enable immediate therapeutic effect (versus delayed steady state exposures as observed with other FLT3 inhibitors). This was followed by a maintenance dose of 10 mg or 20 mg QD on Days 2-7. A total of 24 subjects were enrolled in the Phase 1 MAD study of lomonitinib. Six subjects dosed with 50 mg on Day 1 and 10 mg on Days 2-7, 6 subjects dosed with 50 mg Day 1 and 10 mg Days 2-7 in the presence of a proton pump inhibitor (PPI), and 6 subjects dosed with 100 mg on Day 1 and 20 mg on Days 2-7. Six subjects across 3 cohorts were dosed with placebo on Days 1-7. To provide a preliminary estimate of the effect of CYP3A4 inhibitors on the exposure level of lomonitinib, 6 subjects were dosed with 50 mg of lomonitinib on Day 1 combined with itraconazole (given BID on day -4 and QD on day -3 through day 1) as part of the SAD study. Lomonitinib was well tolerated with no treatment-related safety signals reported in any MAD or SAD cohort. Pharmacokinetic (PK) data from the MAD cohort 1 confirmed that the loading dose of 50 mg on Day 1 with 10 mg QD maintenance achieved steady state exposures by Day 4. The exposure of lomonitinib was minimally affected by the PPI and no significant influence on PK was observed with itraconazole. Consistent with studies in human cells in vitro, oral administration of lomonitinib in healthy human subjects demonstrated target engagement of FLT3-ITD in an ex vivo plasma inhibition assay at doses of ≥ 10 mg, which is anticipated to be in the therapeutic dose range based on preclinical data.

Conclusion. Lomonitinib demonstrates favorable PK and safety profiles with dose-proportional increases in systemic exposure, FLT3 target engagement, and no treatment-related adverse events. Furthermore, little PK interaction was observed with protein pump or CYP3A4 inhibitors. The safety profile of lomonitinib enables rapid FLT3 engagement by using a loading dose (5-fold higher than the maintenance dose) which is not possible with other long half-life FLT3 inhibitors with less favorable therapeutic indices. A phase 1B study in R/R AML with mutated FLT3 is underway in Australia as well as in the US in collaboration with The Leukemia & Lymphoma Society Beat AMLâ.

1. Sharpe, C., ASH 2023
2. Byrd, JC, EHA 2024