A comparative preclinical study of PARP inhibitors demonstrates superb properties for IDX-1197

Background PARP inhibitors have demonstrated clinically meaningful increase in progression-free survival as a single agent in women with recurrent ovarian cancer following a response to platinum-based chemotherapy. We aimed to develop a novel PARP inhibitor that may have potent antitumor efficacy. IDX-1197 is a novel, potent, selective, and orally bioavailable poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor in clinical development. This study examined the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of IDX-1197 as compared to approved PARP inhibitors in several preclinical models. Material and Methods In vitro assays were conducted to evaluate IDX-1197 as a PARP inhibitor using PARP enzyme assay and PARP-catalytic inhibition assay. In vivo efficacy and PK/PD of IDX-1197 against tumor growth were evaluated using xenograft models. To investigate PARP inhibition in tumors, tumor PAR levels were measured by ELISA in the xenograft models. The concentrations of IDX-1197 in plasma and tumor were determined using LC-MS/MS method. Results IDX-1197 potently inhibited PARP-1 and PARP-2 enzymes with IC 50 of 1.4 and 1.0 nM, respectively, while not sensitive to PARP-5 (Tankyrase-1) which is linked to toxicities including severe gastrointestinal effects. In the cell viability assays in human cancer cell lines, IDX-1197 was obviously superior to the other PARP inhibitors. In the single agent colony forming assays in human cancer cell lines, 15 of 18 (83.3 %) cells were sensitive to IDX-1197, while 10 of 18 (55.6 %) cells responded to Olaparib. In the xenograft model, oral administration of IDX-1197 exhibited significant PAR inhibition in tumor until 24 hr post dose. IDX-1197 also dose-dependently led to potent tumor growth inhibition compared to Olaparib treatment group. Conclusions IDX-1197 administration induces potent antitumor activities in multiple preclinical models. The potent antitumor activity induced by IDX-1197 is consistent with its high exposure and durable PARP inhibition in tumor. These preclinical data demonstrate the efficacy of IDX-1197, which has the potential for a best-in-class profile. Based on these findings, IDX-1197 is under clinical Phase 1 trials in Republic of Korea. Funded by National OncoVenture. Citation Format: Myongjae Lee, Joon-Tae Park, Yoon Suk Lee, An-Na Moon, Dong-Gu Jeong, Jeong-Ah Kim, Ji-Hoon Yang, Dohee Kim, Jeongcheol Shin, In-Gyu Je, Kyungsun Kim, Hong-Sub Lee, Nam Seok Baek, Sungsook Lee, Hun-Kyo Kim, YongMan Kim, Jung Yong Kim, Soobong Park. A comparative preclinical study of PARP inhibitors demonstrates superb properties for IDX-1197 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4842.