PII-126 - QUANTITATIVE SYSTEMS TOXICOLOGY (QST) MODELING USING DILISYM INFORMED SAFE DOSE SELECTION OF EMVODODSTAT IN ACUTE MYELOID LEUKEMIA (AML) PATIENTS.

K. Yang¹, R. Kong², P. Maliakal², R. Spiegel², J. Baird², K. O'Keefe², P. Watkins³, B. Howell¹; ¹DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, NC, USA, ²PTC Therapeutics, Inc., South Plainfield, NJ, USA, ³University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Emvododstat (EMV) clinical trials for the treatment of solid tumors was terminated after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. Subsequent investigations supported that EMV might be effective in treating AML at lower doses. DILIsym was employed to predict liver safety of the proposed dosing of EMV in AML clinical trials.

Methods: In vitro mechanistic toxicity data of EMV and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population.

Results: DILIsym simulations predicted the ALT elevations observed in prior EMV clinical trials, but ALT elevations were not predicted to occur with the dosing proposed for the AML clinical trials (Table 1). Among 33 patients who participated in the AML clinical trial (PTC299-HEM-001-LEU), only 5 patients experienced AST/ALT elevations, all of which were mild (Grade 1), all resolving within a short period of time and no patient showed symptoms of hepatotoxicity.

Conclusion: DILIsym retrospectively predicted the liver safety liabilities of EMV in solid tumor trials and prospectively predicted the liver safety of reduced doses in AML clinical trials. The modeling enabled regulatory approval to proceed with the AML clinical trial where the predicted liver safety was confirmed.

Table 1. Observed and simulated frequencies of ALT elevations for emvododstat.