Abstract 4076: SGI-110, a novel subcutaneous (SQ) second generation DNA hypomethylating agent achieves improved pharmacodynamics (PD), safety and pharmacokinetics (PK) in comparison to IV decitabine in a non-human primate in vivo study
Authors: Pietro Taverna, Jason Scholl, Chongtie Shi, Aram Oganesian, Sanjeev Redkar, Mohammad Azab
Journal: Cancer Research (2012)

Abstract SGI-110, is a novel second generation DNA methylation inhibitor that is currently in Phase I/II clinical study for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). SGI-110 is a dinucleotide of DAC and deoxyguanosine designed to be more stable than decitabine to deamination by cytidine deaminase, thus offering a promising alternative to current hypomethylating agents approved in MDS. We report here the results of a preclinical study in which safety, PK, and PD of different dosing regimens of SGI-110 SQ were compared to the clinical dose and regimen of DAC IV in 4 groups of male cynomolgus monkeys (n=4). The treatment groups consisted of: 1) Control group of DAC IV 1-h infusion at a dose equivalent to the clinically approved regimen of 20 mg/m2 x 5 (1.7 mg/kg daily x5); 2) 1.7 mg/kg SGI-110 SQ daily x 5 (molar equivalent to 42% of the clinical DAC dose); 3) 3.0 mg/kg SGI-110 SQ daily x 5 (molar equivalent to 75% of the clinical DAC dose); and 4) 3.0 mg/kg of SGI-110 SQ once weekly x3 (molar equivalent to 44% of the total clinical DAC dose). DAC and SGI-110 plasma levels were measured and monkeys were monitored for 28 days for hematological changes, and global DNA methylation (LINE-1). Reversible hematological changes included a reduction in leukocytes, red blood cells (RBCs), and neutrophil counts with the nadir counts generally occurring between D8 and D14 and recovery occurring D21 to D28. The DAC-treated group showed the greatest reduction and slowest recovery compared to all SGI-110 treated groups. Changes in methylation patterns of LINE-1 and miRNA-29b were evaluated in DNA extracted from monkey blood as PD markers of biological efficacy after treatment with SGI-110 or DAC. All groups achieved a decrease in LINE-1 methylation of approximately 15-20% from baseline between Day 8 and 21 with remethylation back to baseline levels by day 28. Both SGI-110 SQ dailyx5 regimens achieved slightly more hypomethylation than DAC IV on days 8 (group 3) and 11 (group 2). Overall, the magnitude and duration of the decrease in DNA methylation at lower molar equivalent doses of SQ SGI-110 were similar to or better than DAC IV. SGI-110 appeared to convert to DAC resulting in similar exposure window compared to IV DAC. The dose-adjusted plasma DAC exposures, on molar equivalence basis, were somewhat lower compared to the DAC group. The Cmax ranged 52-163 vs 215-525(DAC) ng/mL, while dose-adjusted AUCs were 21.6-51.6 vs 98.6-221(DAC) ng*hr/mL. In conclusion, these preclinical studies showed that SQ SGI-110 may represent a more convenient and tolerable option for delivering DAC where either the weeklyx3 or dailyx5 regimens at a lower dose achieved DNA hypomethylating effects that were similar to or better than seen with DAC IV and with less myelosuppressive effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4076. doi:1538-7445.AM2012-4076