Daewoong Pharmaceutical (South Korea)

Background and objectiveThe metabolic benefits of sodium-glucose co-transporter 2 inhibitors in clinical application are well established; however, there is dearth of knowledge on their impact on adipokine regulation. This study investigated the effect of enavogliflozin on adiponectin and leptin in patients with type 2 diabetes.MethodsThis secondary analysis of a phase III randomized, double-blind, placebo-controlled trial evaluated changes in serum adiponectin and leptin over 24 weeks. Analysis of covariance was used with baseline values and weight change as covariates to examine whether the effects of enavogliflozin persisted after adjusting for weight change. Correlations between adipokine changes and key metabolic parameters were also assessed.ResultsOver the 24 weeks, the enavogliflozin group showed increased adiponectin levels with a least squares (LS) mean difference of 0.98 mg/L compared with the placebo group, while leptin levels showed a significant decrease with an LS mean difference of −2.99 µg/L. Enavogliflozin significantly reduced leptin levels over 24 weeks after adjusting for weight change; however, adiponectin changes were not significant after adjusting for weight change. Adiponectin levels significantly increased across weight loss categories, but leptin showed no significant differences. Leptin changes over 24 weeks significantly were positively correlated with changes in homeostasis model assessment of insulin resistance and homeostasis model assessment of β-cell function but significantly negatively correlated with changes in serum ketone and urinary glucose-to-creatinine ratio.ConclusionsEnavogliflozin treatment decreased leptin over 24 weeks in patients with type 2 diabetes, and this effect remained significant after adjusting for weight change, suggesting an improved adipokine profile. Reductions in leptin were also associated with improvements in insulin resistance and increases in serum ketone levels. These results highlight enavogliflozin as a potential treatment beyond glycemic control, offering additional benefits in managing metabolic dysregulation associated with type 2 diabetes.Trial registrationNot applicable (post hoc analysis).Supplementary InformationThe online version contains supplementary material available at 10.1186/s12933-025-02917-z.

Abstract A significant portion of tumors with BRCA1 or BRCA2 mutations exhibit only weak responses to PARP inhibitor (PARPi) treatment, and often develop resistance to PARPi over time. Both Polθ and PARP1 play critical roles in MMEJ for DNA double-strand break repair, and Polθ inhibition holds the potential to overcome PARPi resistance driven by BRCA reversion mutations. To address these challenges, we have developed DWP223, a novel selective and potent Polθ inhibitor. This compound can be used as a single agent or in combination with PARPi to treat tumors harboring BRCA mutations.DWP223 has shown potent and selective inhibition of BRCA-deficient cell proliferation in vitro, achieving an IC50 value below 20 nM, while demonstrating minimal impact on parental cell lines. In vivo, DWP223 monotherapy is effective at doses as low as 30 mg/kg, and when used in combination with PARP inhibitors, it induces over 50% tumor regression at a lower dose. Notably, even at high doses, DWP223 is well-tolerated, with no observable weight loss or hematological toxicity in animal models.Furthermore, DWP223 extends therapeutic potential by exhibiting synthetic lethality in tumors deficient in non-homologous recombination (HR), broadening its application to patients without homologous recombination repair (HRR) mutations. The compound’s favorable pharmacokinetic profile and robust safety data across multiple species underscore its suitability for clinical development, highlighting the opportunity to reduce hematological toxicity and target PARP inhibitor-resistant cancers.Collectively, DWP223 represents a promising therapeutic candidate, either as a standalone treatment or in combination with PARPi, for targeting HR-deficient cancers and potentially overcoming PARPi resistance. DWP223 is advancing toward IND filing in 2025. Citation Format: Juno Kim, Jie Luo, Bin Cao, Ling Zhao, Xiaojing Zhang, Xiaohua Lin, Xiaojing Lin. Transforming treatment paradigms: A cutting-edge polθ Inhibitor (DWP223) targeting PARP resistance in BRCA-mutant cancers [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 2896.

Pueraria lobata root and Glycine max (L.) Merrill are rich in phytoestrogens. However, these bioactive ingredients have limited bioavailability due to their high molecular weight. In this study, we extracted two natural products and fermented with Lactiplantibacillus plantarum before mixing the fermented extracts (FPE-FGE). To understand whether FPE-FGE could alleviate menopause with dyslipidemia, we examined their effects on ovariectomy (OVX)-induced dyslipidemia in mice. Oral administration of the FPE-FGE (1:9, 3:7, and 9:1) did not affect safety-related biomarkers, such as uterus index (%), vagina index (%), aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine. Furthermore, FPE-FGE (1:9, 3:7, and 9:1) increased the levels of 17β-estradiol (E2) and expression of uterus estrogen receptor β (ERβ); there was little effect on the expression of uterus estrogen receptor α (ERα), and reduced the levels of gonadotropins, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). However, only the FPE-FGE (3:7) reduced the levels of blood lipids, including total cholesterol (TC) and LDL-cholesterol (LDL-C). Accordingly, FPE-FGE (3:7) upregulated endothelial nitric oxide synthase (eNOS), nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG). In conclusion, FPE-FGE (3:7) attenuated themenopausal dyslipidemia by upregulating eNOS-NO-cGMP signaling pathway.

By applying ‘yarn inlay’ technology using reinforcing fibers, a double raschel GCCM that improved the structural elongation control and reinforcement ability of knitted fabrics was manufactured. In order to improve the cross-sectional reduction of GCCM due to curing shrinkage of concrete, the effects of blowing agent content and concrete filling rate were analysed as a result of the bending strength test, Double raschel GCCM showed the improved brittleness compared to that of general concrete. In addition, it was confirmed that the durability of Double Cell GCCM did not decrease significantly even after 10 days of concrete curing. Finally, the bending strength in special environments such as seawater, freeze-thaw, acidic and alkaline solutions was analysed, and the durability of double raschel GCCM in application environments was confirmed.

BIOVITA 3 bacterial species (BIOVITA 3), a probiotic blend powder containingClostridium butyricum IDCC 1301,Weizmanniacoagulans IDCC 1201 and Bacillus subtilis IDCC1101, has been used as a food ingredient for gut health. However, its efficacyin improving constipation has not been reported. Therefore, we aimed toinvestigate the functional effects of oral administration of BIOVITA 3 as wellas its component strains alone (at 1.0×109 CFU/day) inSprague-Dawley (SD) rats with loperamide-induced constipation. The studyincluded fecal analysis, gastrointestinal transit ratio, histopathologicalanalysis, short chain fatty acids (SCFAs), and metagenome analysis. As results,the BIOVITA 3 group showed significant improvements in fecal number, watercontent, gastrointestinal transit ratio, and thickening of the mucosal layer. Inthe SCFAs analysis, all probiotic-treated groups showed an increase in totalSCFAs compared to the loperamide-constipated group. Changes in microbialabundance and the diversity index of three groups (normal, constipated, andBIOVITA 3) were also defined. Of these, the BIOVITA 3 showed a significantimprovement in loperamide-constipated SD-rats. This study suggests thepossibility that BIOVITA 3 can be applied as an ingredient in functional foodsto relieve constipation.

Filamentous fungi produce several beneficial secondary metabolites, including bioactive compounds, food additives, and biofuels. Trichoderma, which is a teleomorphic Hypocrea that falls under the taxonomic groups Ascomycota and Dikarya, is an extensively studied fungal genus. In an ongoing study that seeks to discover bioactive natural products, we investigated potential bioactive metabolites from the methanolic extract of cultured Trichoderma gamsii. Using liquid chromatography-mass spectrometry (LC-MS), one major compound was isolated and structurally identified as 6-pentyl-α-pyrone (6PP) based on nuclear magnetic resonance data and LC-MS analysis. To determine its antioxidant and anti-inflammatory activity, as well as the underlying mechanisms, we treated lipopolysaccharide (LPS)-stimulated Raw264.7 mouse macrophages with 6PP. We found that 6PP suppresses LPS-induced increase in the levels of nitric oxide, a mediator of oxidative stress and inflammation, and restores LPS-mediated depletion of total glutathione by stabilizing nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidative factor, and elevating heme oxygenase-1 levels. Furthermore, 6PP inhibited LPS-induced production of proinflammatory cytokines, which are, at least in part, regulated by heme oxygenase-1 (HO-1). 6PP suppressed proinflammatory responses by inhibiting the nuclear localization of nuclear factor kappa B (NF-κB), as well as by dephosphorylating the mitogen-activated protein kinases (MAPKs). These results indicate that 6PP can protect macrophages against oxidative stress and LPS-induced excessive inflammatory responses by activating the Nrf2/HO-1 pathway while inhibiting the proinflammatory, NF-κB, and MAPK pathways.

PrabotulinumtoxinA has been identified as an effective agent against crow's feet. Our study, which included Korean patients with moderate to severe crow's feet, was undertaken to compare the efficacy and safety of PrabotulinumtoxinA and placebo treatments. Of the 90 study participants, 60 received prabotulinumtoxinA (24 U), whereas 30 received a placebo. The primary outcome assessment included facial wrinkle grading by investigators. At week 4, 69.64% of patients in the prabotulinumtoxinA group exhibited minimal crow's feet severity; in contrast, a 0% improvement was observed in the placebo group (p < 0.0001). At week 12, the improvement rates were 30.36% for prabotulinumtoxinA and 6.90% for the placebo, demonstrating a significant difference (p = 0.0152). Based on the independent review panel's assessment at week 4, the improvement rate was 39.29% in the prabotulinumtoxinA group and 3.45% in the placebo group during maximum smiling. Additionally, patient satisfaction was notably higher in the prabotulinumtoxinA group (32.14%) than in the placebo group (10.34%) at week 4 (p = 0.0289). Both treatments displayed comparable safety profiles, with only mild local reactions reported as ADRs for one patient from the prabotulinumtoxinA group. Thus, prabotulinumtoxinA demonstrates significant potential as a potent and safe remedy for crow's feet.

The objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, and predict efficacious doses for the first-in-human study using various translational approaches. A mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed-effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug-specific factors. Human parameters were refined using early clinical data. Model-predicted PK and PD outcomes were compared to observations before and after parameter refinement. The PK/PD model of DWP16001 was developed using a 2-compartment model with first-order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half-maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2-fold difference between the model prediction and observation. This study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first-in-human study.

ABSTRACT Background DWP16001, a sodium-glucose cotransporter-2 inhibitor, has shown promise for improving blood glucose control and facilitating weight loss. Co-administration with phentermine could enhance these effects. So, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of DWP16001 and phentermine. Methods We conducted a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study involving 24 healthy adults. Participants received either DWP16001 (2 mg), phentermine (37.5 mg), or a combination of both once daily for 7 days. Blood samples, urine samples, and body weights were collected to evaluate the PK and PD. Results The PK of the combination was found to be similar to that of the monotherapy. The geometric mean ratio (GMR) of Cmax,ss, and AUCtau,ss were 0.98 and 1.00, respectively, for DWP16001, and 1.01 and 0.94, respectively, for phentermine. Co-administration did not significantly affect the 24-hour urinary glucose excretion compared to DWP16001 monotherapy, and the GMR was 0.90. Participants tended to experience greater weight loss in the combination therapy group, and all demonstrated good tolerance. Conclusions Our findings indicate that there were no significant interactions during co-administration. These results suggest that the combination of DWP16001 and phentermine may be safe and effective for the treatment of obesity and diabetes. Clinical trial registration NCT05321732