A healthy volunteer study with lomonitinib predicts pharmacokinetics and pharmacodynamics in a relapsed refractory AML study

Abstract Background. Lomonitinib is a highly potent and selective pan-FLT3/ IRAK4 inhibitor derived from a novel in silico modeling approach that avoided multiple alternative targets commonly inhibited with commercially approved FLT3 inhibitors. Lomonitinib targets clinically relevant FLT3 resistant mutations as well as IRAK4, a putative escape pathway for FLT3-driven AML. 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. While both drugs have long terminal half-life, only lomonitinib has minimal toxicity in pre-clinical toxicology studies enabling a loading-maintenance schedule of administration to rapidly attain therapeutic level of drug. Given lomonitinib's broad therapeutic index, we hypothesized that application of a healthy volunteer study would offer the potential to initiate an AML clinical trial with both a schedule of administration and dose close to a therapeutic level that inhibits FLT3-ITD. Methods. To test this pharmacokinetic/pharmacodynamic hypothesis along with identifying different drug clearance properties that might exist between healthy volunteers and relapsed AML patients we have completed a Phase 1, single-center, prospective, randomized, double-blind placebo-controlled study of lomonitinib administered orally to healthy adult participants (NCT06399315) and initiated a Phase 1, global study in FLT3 mutated relapsed or refractory AML (NCT06366789). Pharmacodynamic inhibition of FLT-ITD phosphorylation was examined using a modified method from the previously described FLT3 plasma inhibition assay (PIA). This analysis focuses on the 6 MAD cohorts and 3 AML cohorts. Results. Due to the extended half-life and safety of lomonintib demonstrated in the Phase 1 SAD study2, we utilized a loading strategy on Day 1 to rapidly reach steady state (Css) enabling faster therapeutic effect (versus delayed steady state exposures as observed with other FLT3 inhibitors). This was followed by a maintenance dose on Days 2-7. A total of 48 subjects were enrolled in the Phase 1 MAD study of lomonitinib, 36 subjects receiving lomonitinib and 12 receiving placebo. Lomonitinib was well tolerated with no significant treatment-related safety signals reported in any MAD cohort. Pharmacokinetic (PK) data from the MAD cohort 1 confirmed that the loading dose followed by a maintenance dose achieved steady state exposures by Day 4. PIA demonstrated inhibition at all dose levels. A total of 11 relapsed and refractory AML patients have been treated with lominitinib. The pharmacokinetic parameters and pharmacodynamic FLT3 PIA of Lomonitinib directly correlate with that observed in the healthy volunteer study. Conclusion. Lomonitinib demonstrates favorable PK and safety profiles with dose-proportional increases in systemic exposure that is consistent between healthy volunteers and relapsed and refractory AML patients. 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. 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 identified from pre-clinical models.