Abstract 3905: Translational efficacy and safety modeling and simulation to support the clinical development of JNJ-64619178, a PRMT5 inhibitor
Authors: Guo Yue , Haddish-Berhane Nahor , Millar Hillary J. , Verhulst Tinne , Greway Tony , Zhou Junguo , DeZwart Loeckie , Gaffney Dana , Portale Joseph , Brehmer Dirk , Boeckx An , Heerde Erika Van , Ouellet Daniele 
Published: August 2019

Abstract
Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme with oncogenic properties. JNJ-64619178 (JNJ178) is a potent, selective, structurally unique PRMT5 inhibitor with good preclinical efficacy in inhibiting the growth of hematologic and solid tumor cell lines. Toxicology studies showed that JNJ178 decreased reticulocytes and neutrophils in rats and dogs. The objectives of translational modeling and simulation were to understand the exposure-response relationship of both safety and efficacy and provide guidance to the first-in-human clinical development of JNJ178.
Experimental data for the PK/PD (Pharmacokinetics/Pharmacodynamics) modeling included: plasma concentration after single dose of JNJ178 in non-tumor bearing mice, plasma concentration and PD markers of dimethylation of arginine (%SDMA in plasma and %SMD1/3-Me2 in tumor, respectively) after multiple doses (1 to 10 mg/kg) QD (once daily) of JNJ178 in H1048 (human small cell lung carcinoma) xenografts, and tumor volume in four xenograft mouse models (A427, human lung carcinoma; H441, human lung adenocarcinoma; H520, human squamous cell lung carcinoma; and H1048). Plasma PK were first described by a standard two-compartment model and used as a driver of PD and tumor volume (efficacy). Plasma and tumor PD were modeled using an indirect response model. A hybrid tumor growth coupled with transit compartment mediated tumor killing model was used to fit the tumor volume data. To predict the safety profile of JNJ178, lifespan based indirect response model for erythropoiesis and Friberg myelosuppression model were used to simulate hemoglobin and neutrophil kinetics in human.
The PK/PD model described the data well and validated the hypothesis that PD is driven by trough concentration. Based on the exposure-response relationship from the four xenograft models, the trough concentration needed to achieve tumor stasis for mouse was determined. In addition, the level of inhibition in tumor and plasma PD marker that was associated with tumor stasis was identified. Together with human PK parameters scaled using allometry, the dose range needed to achieve target therapeutic exposure for a typical human subject was predicted. Simulation results from erythropoiesis and Friberg myelosuppression models informed the optimal doing schedules for certain dose levels that would allow hematological toxicity to be manageable with &lt;40% reduction in hemoglobin and &gt;1.0 x 109/L neutrophil counts at all times. Overall, a translational modeling and simulation approach that considers safety and efficacy has been instrumental in the design of the first-in-human clinical development of PRMT5 inhibitor JNJ178 regarding selection of dose and schedule.
Citation Format: Yue Guo, Nahor Haddish-Berhane, Hillary J. Millar, Tinne Verhulst, Tony Greway, Junguo Zhou, Loeckie DeZwart, Dana Gaffney, Joseph Portale, Dirk Brehmer, An Boeckx, Erika Van Heerde, Daniele Ouellet. Translational efficacy and safety modeling and simulation to support the clinical development of JNJ-64619178, a PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3905.