e15110 Background: Cancers with deficient mismatch repair (dMMR) have high microsatellite instability (MSI-H) and are reported to be sensitive to Werner syndrome helicase inhibition (WRNi), via synthetic lethality. WRNi in MSI-H cells leads to loss of genomic integrity and ultimately cell death while not affecting microsatellite stable (MSS) and healthy cells. SOC for patients with MSI-H tumors includes surgery and immunotherapy (checkpoint inhibitors CPIs such as pembrolizumab pembro), however ~30 to 50% of patients do not respond to first-line immune CPIs or acquire resistance. A critical unmet medical need exists for new therapies. EIK1005, a novel, potent and selective WRN inhibitor has potential for targeted antitumor activity in MSI-H or dMMR solid tumors. EIK1005 demonstrated in vitro activity leading to cell death in MSI-H cells while sparing microsatellite stable (MSS) cancer and healthy cells. In in vivo mouse studies, EIK1005 was well-tolerated and had robust antitumor effects. Based on the mechanism of action and favorable nonclinical pharmaceutical and toxicology profile, EIK1005-001 was planned. Methods: EIK1005-001 is a Phase 1 randomized, double-blind, single ascending dose study evaluating the safety, tolerability and pharmacokinetic (PK) profile of EIK1005 in healthy participants (pts). In Period 1 (P1) and Period 2 (P2), a single dose of EIK1005 or placebo, was given to pts in a fasted and fed state, respectively. Safety follow-up ensued (clinical research unit stay of 3 days; follow-up through Day 36). 8 pts were randomized 3:1 at each dose level (DL) in P1, then a DL was chosen for P2 (EIK1005 50 mg). Results: At data cutoff (13 Oct, 2025), 23 pts (P1 n = 15; 11 active, 4 placebo and P2 n = 8; 6 active, 2 placebo) were randomized to receive EIK1005 (P1: 50 mg n = 5, 100 mg n = 6), or placebo (n = 4); in P2, 50 mg (n = 6) or placebo (n = 2). All pts completed the study. In the safety population (17 active, 6 placebo), EIK1005 was well tolerated; all AEs were unrelated and mild, except one moderate AE, with no clinically significant events. Median Tmax (P1) was 3-4 hours, and T 1/2 was 9.4 days (post 100 mg). Descriptive PK results indicated that EIK1005 exposure increased in a dose-related manner; no clinically significant food effect was observed in the parallel group assessment of EIK1005 50 mg (P1, P2); dosing can occur without regard to food. Urine PK parameters were noncalculable indicating that renal excretion was negligible. Multiomics analysis did not reveal any changes in protein expression (up to 72 hours), or in RNA gene expression profiles (up to 24 hours) in blood after single doses, consistent with WRNi having no measurable activity in MSS cancer or healthy cells. Conclusions: EIK1005 had a favorable safety profile at the 50 and 100 mg single doses evaluated in healthy pts. PK and safety data support a starting dose of 50 mg given in patients in EIK1005-002 (NCT#007262619). Clinical trial information: ACTRN12625000334404.
Ryan et al. (Thu,) studied this question.