Phase 1 Interim Population Pharmacokinetic/Pharmacodynamic Model and Phase 2 Dose Exploration for IMM-1-104, a Novel Concept Oral Deep Cyclic MEK Inhibitor.
Authors: de Jong Jan , Yamamura Amy , Axel Amy , King Peter , Funt Jason , Foley Elisabeth Madec , Kovar Christina , Bergstrand Martin , Mezzalana Enrica , Chenel Marylore , Hayreh Vinny , Hall Brett 
Published: February 2025

Objectives: Activating RAS mutations are present in a third of all cancers. Approved MEK inhibitors chronically inhibit the downstream signaling of RAS, causing significant toxicity. IMM-1-104 was designed to have high oral bioavailability and a short half-life with a near-zero drug trough, to achieve Deep Cyclic Inhibition (DCI). Preclinical data indicated that DCI can significantly improve the safety margin by allowing daily pathway recovery in healthy tissues while limiting adaptive resistance in tumor cells (1). The current analysis was aimed at identifying Phase 2 dosing regimens that achieve the desired DCI pattern in the targeted patient populations. Methods: First-in-human Study IMM1104-101 recently completed Phase 1 dose expansion (2,3). PK/PD sampling was performed after overnight fasting, pre-dose and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 and 24 h post-dose, on Days 1 and 15 of the study (1-24 h for PD). An ex-vivo surrogate PD endpoint was the inhibition of MEK and downstream ERK phosphorylation in the A549 (KRAS-G12S) cell line, expressed as the ratio of phosphorylated/total kinase, relative to pre-dose baseline. Non-compartmental analysis and population PK/PD analysis were performed using Phoenix 8.3 and NONMEM 7.5, respectively. Results: Interim PK data are available from 21 out of 45 participants treated with IMM-1-104 as single agent at daily doses of 40 (n=1), 80 (n=1), 160 (n=3), 240 and 320-mg (n=8 each). While most PK profiles showed a rapid absorption with tmax within 1 h of dosing, a two-compartment model with first-order absorption and lag time plus first-order elimination best described the interim PK dataset. Weight-based allometric scaling was applied to clearance, distribution volume and inter-compartmental clearance. The mean elimination half-life at steady-state ranged from 1.4-2.5 h across doses, without indications of non-linearity. Less than 5% of unchanged IMM-1-104 is renally cleared. PD assay results correlated to IMM-1-104 plasma concentrations, with maximal inhibition (target engagement) achieved mostly at 1 h, returning to baseline phospho-ERK (pERK) levels between 8 and 24 h. A direct Imax model, with a Hill coefficient fixed to 1, could be successfully applied to describe PK/PD and to calculate time above and below selected inhibitory concentrations. The derived pERK IC50 of 102 ng/mL (48 nM unbound) corresponded well with in vitro pERK inhibition data. Conclusion: At the two candidate doses explored per FDA Optimus guidance, 240 and 320 mg, plasma concentrations are predicted to be above the pERK IC90 for on average approximately 1.5 and 2.5 h, respectively, and the vast majority of patients are predicted to have less than 20% of maximum inhibition at the daily drug trough (87% at 240 mg once daily and 84% at 320 mg). PK/PD modeling combined with Phase 1 safety and activity data suggests that 240 and 320 mg are viable doses that promote DCI of the MAPK pathway.Citations: [1] P Nair et al, Predicting activity of IMM-1-104 as single agent and in combination for patients with RAS or RAF mutant tumors, AACR-NCI-EORTC 2023.[2] A Phase 1/2a Study of IMM-1-104 in Participants with Previously Treated, RAS-Mutant, Advanced or Metastatic Solid Tumors - NCT05585320.[3] V Chung et al, Preliminary phase 1 safety and activity of IMM-1-104, an orally dosed universal RAS inhibitor that drives deep cyclic inhibition of the MAPK pathway at MEK, in patients with advanced unresectable or metastatic solid tumors - ESMO 2024, submitted.