Abstract NRT-YHD_001, a modified antisense miRNA targeting let-7i-5p for liver cancer therapy, acts as a key regulator of macrophage activity within the tumor microenvironment. Through in vitro pharmacology studies, we identified anticancer effects not only on cell growth, proliferation, viability, migration, and invasion but also through the enhancement of macrophage phagocytosis. To evaluate the in vivo efficacy of NRT-YHD_001, we used a Ras-transgenic mouse liver cancer model which develops spontaneous liver cancer mass after 15 ∼ 20 weeks of birth. Based on dose-dependent and injection interval studies, the optimal regimen was determined to be 1 mg/kg administered weekly. We confirmed that weekly intravenous injections of 1mg/kg NRT-YHD_001 showed significantly greater therapeutic efficacy than the sorafenib-treated group. Additionally, xenograft assay using human liver cancer cells in athymic-nude mice showed that weekly injection of NRT-YHD_001 led to improved survival and tumor growth inhibition compared to the untreated group. We performed Absorption, Metabolism, Distribution, and Excretion studies for NRT-YHD_001, stability studies in serum and liver homogenate, and metabolite identification and profiling analysis were completed in mice and cynomolgus monkeys. In maximum tolerated dose (MTD) studies conducted in mice and cynomolgus monkeys, no toxicity of NRT-YHD_001 was observed at doses up to 500 mg/kg administered intravenously. Furthermore, comprehensive evaluations across 4-week repeated dose toxicity and toxicokinetic in mice and monkey, safety pharmacology, and genetic toxicity studies revealed no adverse findings with NRT-YHD_001. For NRT-YHD_001, Drug Substance (DS) and Drug Product (DP) were produced by a global CDMO with experience in U.S. FDA approval of oligonucleotide drugs, and the analysis method was established.These results enabled us to complete the IND-enabling study package for NRT-YHD_001, a liver cancer therapy candidate with FTO analysis completed and intellectual property (IP) fully secured. Regulatory approval submissions to the Korea MFDS and the U.S. FDA are planned for 2025. Citation Format: Suk Woo Nam, Jin Woong Ha, Sang Yean Kim, Min Jeong Na, Soyoung Jeon, Bee Yoo, In Seop Yoon, Hyunmin Lee, Chang Won Park. IND enabling study of NRT-YHD_001, a macrophage immune checkpoint inhibitor in liver cancer [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 3209.

Abstract NRT-YHD_001, a modified antisense miRNA targeting let-7i-5p for liver cancer therapy, acts as a key regulator of macrophage activity within the tumor microenvironment. Through in vitro pharmacology studies, we identified anticancer effects not only on cell growth, proliferation, viability, migration, and invasion but also through the enhancement of macrophage phagocytosis. To evaluate the in vivo efficacy of NRT-YHD_001, we used a Ras-transgenic mouse liver cancer model which develops spontaneous liver cancer mass after 15 ∼ 20 weeks of birth. Based on dose-dependent and injection interval studies, the optimal regimen was determined to be 1 mg/kg administered weekly. We confirmed that weekly intravenous injections of 1mg/kg NRT-YHD_001 showed significantly greater therapeutic efficacy than the sorafenib-treated group. Additionally, xenograft assay using human liver cancer cells in athymic-nude mice showed that weekly injection of NRT-YHD_001 led to improved survival and tumor growth inhibition compared to the untreated group. We performed Absorption, Metabolism, Distribution, and Excretion studies for NRT-YHD_001, stability studies in serum and liver homogenate, and metabolite identification and profiling analysis were completed in mice and cynomolgus monkeys. In maximum tolerated dose (MTD) studies conducted in mice and cynomolgus monkeys, no toxicity of NRT-YHD_001 was observed at doses up to 500 mg/kg administered intravenously. Furthermore, comprehensive evaluations across 4-week repeated dose toxicity and toxicokinetic in mice and monkey, safety pharmacology, and genetic toxicity studies revealed no adverse findings with NRT-YHD_001. For NRT-YHD_001, Drug Substance (DS) and Drug Product (DP) were produced by a global CDMO with experience in U.S. FDA approval of oligonucleotide drugs, and the analysis method was established.These results enabled us to complete the IND-enabling study package for NRT-YHD_001, a liver cancer therapy candidate with FTO analysis completed and intellectual property (IP) fully secured. Regulatory approval submissions to the Korea MFDS and the U.S. FDA are planned for 2025. Citation Format: Suk Woo Nam, Jin Woong Ha, Sang Yean Kim, Min Jeong Na, Soyoung Jeon, Bee Yoo, In Seop Yoon, Hyunmin Lee, Chang Won Park. IND enabling study of NRT-YHD_001, a macrophage immune checkpoint inhibitor in liver cancer [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 3209.

The objective of the current study was to evaluate the rate and extent of absorption of a test formulation (sitagliptin hydrochloride) and a reference formulation (sitagliptin phosphate). An open-label, randomized, single-dose, single-center, 2-sequence, 2-period, and cross-over phase 1 study was implemented to assess the pharmacokinetic bioequivalence of the test and reference formulations containing a single dose of sitagliptin 100 mg in 32 healthy volunteers under fasting conditions. The differences between the test and reference formulations in terms of the area under the curve from dosing to the time of the last measured concentration (AUC_last) and the maximum concentration (C_max) were found to be not significant. The 90% confidence intervals of sitagliptin Ln-transformed AUC_last and C_max were within the pharmacokinetic bioequivalence acceptance range of 80%-125%. The test formulation with sitagliptin hydrochloride was bioequivalent to the reference formulation with sitagliptin phosphate in healthy male volunteers under fasting conditions.

<b>Background:</b> To repurpose carbutamide (CBT), a discontinued sulfonylurea-class anti-diabetic drug, as an anti-inflammatory bowel disease (IBD) drug, CBT azo-linked with salicylic acid (CAA) was designed and synthesized as a colon-specific prodrug to co-release CBT and mesalazine (5-ASA) selectively in the large intestine. <b>Methods:</b> CAA exhibited reduced lipophilicity and decreased transintestinal transport compared to CBT, as shown in an ex vivo experiment using isolated rat jejunal segments. It also underwent cleavage into CBT and 5-ASA when incubated with cecal contents of rats. Additionally, oral administration of CAA and Sulfasalazine (SSZ), a colon-specific prodrug of 5-ASA currently used for IBD treatment, resulted in similar levels of 5-ASA accumulation in the rat cecal region. <b>Results:</b> In a dinitrobenzene sulfonic acid-triggered colitis model in rats, CAA produced a more pronounced improvement in colon injury and inflammation than SSZ. Furthermore, rectal co-administration of CBT and 5-ASA conferred enhanced protective outcomes compared to monotherapy with either agent alone, suggesting a combined anticolitic action. The two drugs also jointly suppressed valacyclovir uptake via peptide transporter 1 (PepT1) in the distal colon, supporting PepT1 as a target contributing to their combined anticolitic effect. Unlike CBT, which significantly reduced blood glucose following oral administration, equimolar administration of CAA did not alter glycemic levels, consistent with reduced systemic exposure to CBT. <b>Conclusions:</b> In conclusion, CAA functions as a colon-specific mutual prodrug that surpasses SSZ in anticolitic performance while minimizing hypoglycemia risk, thus facilitating the repurposing of CBT as a treatment for IBD.

Fibrotic disease involves excessive fibrous connective tissue accumulation in organs, leading to dysfunction and irreversible damage. Metabolic alterations can sometimes contribute to fibrosis development. This study aimed to develop dual agonists for farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor alpha (PPARα), targeting anti-fibrosis and metabolic regulation. Benzoxazole derivatives were found to potently activate both FXR and PPARα in hepatocytes. Among them, MHY5396 showed the most potent effects with low EC₅₀ values. MHY5396 reduced lipid synthesis and enhanced beta-oxidation in hepatocytes, decreasing lipid accumulation. It also suppressed TGFβ-induced fibrosis in hepatic stellate cells. In a methionine/choline-deficient diet mouse model, MHY5396 reduced lipid accumulation, liver damage, and fibrosis. In a thioacetamide-induced liver fibrosis model, MHY5396 had an anti-fibrotic effect comparable to obeticholic acid, a potent FXR agonist. MHY5396 also significantly reduced inflammation and fibrosis in renal cells and a folic acid-induced renal fibrosis mouse model. Pharmacokinetic studies showed that orally administered MHY5396 was well absorbed (<i>F</i> = 98.6%) and primarily metabolized by hepatic CYP1A2 with negligible urinary excretion. Overall, MHY5396, with dual FXR and PPARα agonist activity, exhibited significant anti-fibrotic and metabolic regulatory properties in liver and kidney fibrosis models, presenting a novel therapeutic potential for fibrotic diseases.