Abstract 7278: Non-clinical toxicity studies of S-CP201

Abstract Edelfosine, an anticancer alkylphospholipid, has been widely investigated. Inter alia, it integrates into cell membranes (including mitochondria and ER) and acts via CD95-driven apoptosis, AKT3/PI3K inhibition, phospholipase C and protein kinase C inhibition, and impacts cholesterol metabolism. It exhibits antiangiogenic and antimetastatic effects, selectively targets malignant cells, and has shown efficacy in preclinical xenograft models, (e.g metastatic breast and prostate cancers), and in phase 2 trials across tumor types. The main adverse event was dose-dependent, reversible gastrointestinal toxicity. Many non-clinical toxicity reports on edelfosine are available. Since edelfosine is racemic, its S-enantiomer (S-CP201) was chosen for development due to PK/ PD advantages over the R-counterpart. Key data of a GLP-/ICH S9 and M3-conform, IND-enabling toxicity package for S-CP201 is stated below. In addition to a 4-week dose range-finding (DRF) study, S-CP201 was given in a 13-week rat toxicity study per os (p.o.) at 3, 9, 27, and 40 mg/kg/day (d) (15 rats per sex and group). The 2 high dose groups showed reversible liver enzyme increases. One female in the 27 mg/kg group exhibited an enlarged pituitary; 9/15 males showed seminal vesicle atrophy, and 10/15 tubular vacuolation in the testes. In the 40 mg/kg group, dilated intestines, cecum, and reddened duodenal mucosa were observed. The NOAEL was set at 9 mg/kg/d. In a maximum tolerated dose (MTD)/DRF study in minipigs, escalating doses reached 96 mg/kg/d for 3 d in the DRF phase and 12 mg/kg/d for ≤6 d in the MTD phase. Doses ≥12 mg/kg/d resulted in soft feces, dark duodenal mucosa, and reduced appetite/body weight (BW) loss. MTD was 6 mg/kg/d. Safety pharmacology tests of S-CP201 (core battery) were also conducted. In Wistar rats, single oral doses ≤40 mg/kg showed no notable respiratory effects (whole-body barometric plethysmography). Similarly, single doses ≤14 mg/kg in telemetered male Beagle dogs showed no adverse effects on blood pressure, heart rate, ECG, or body temperature, confirming prior negative hERG assay results. Soft feces were found at doses ≥9 mg/kg, but no other changes in BW or food consumption were noted. In a modified Irwin test, single oral doses ≤100 mg/kg in Sprague-Dawley rats produced no signs of behavioral, neurological, or autonomic effects. A pilot Ames fluctuation test showed no mutagenic potential across a broad concentration range. In a standard Ames test, low mutagenic effects were seen only at high concentrations in 3 of 4 tested S. typhimurium strains. A new Ames test under similar conditions did not reveal mutagenic effects. An in vitro micronucleus assay showed no effects at therapeutic concentrations, and an in vivo micronucleus test in male rats receiving S-CP201 (≤200 mg/kg/d p.o.) showed no clastogenic or aneugenic effects. An in vitro hemolysis test (up to 20 µM) was negative for S-CP201. Overall, this S-CP201 non-clinical safety package supports proceeding to Phase 1 studies. Citation Format: Michael Ahrweiler, Wolfgang Meyer, Daniel Perrissoud, Axel Zander. Non-clinical toxicity studies of S-CP201 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7278.