Takeda Pharmaceutical Company Research Articles

Advancing the drug discovery ecosystem for innovative medicines

Axcelead Drug Discovery Partners (Axcelead DDP) Inc is the first integrated drug discovery solution provider in Japan. Leveraging drug discovery platforms and knowledge inherited from Takeda Pharmaceutical Company, Ltd. alongside the latest science and technology, our experienced scientists with rich track records promote drug discovery research and contribute to co-creation of innovative drugs together with customers. In this article, we provide an overview landscape of the pharmaceutical industry and emerging trends in drug discovery research, and introduce Axcelead DDP's services, its unique strengths, and the value (solutions) delivered to customers. Furthermore, we describe the current state of Japan's bio-community and the roles and challenges for the development and enhancement of a true drug discovery ecosystem in Japan.

Comparison of the efficacy and safety profiles of generic and branded leuprorelin acetate microspheres in patients with prostate cancer.

Leuprorelin acetate microspheres, a common gonadotropin-releasing hormone agonist, have certain clinical benefits for prostate cancer (PCa). The present study aimed to compare the efficacy and safety of generic and branded leuprorelin acetate microspheres in patients with PCa. The present retrospective, observational study included 116 patients with PCa who received generic (Boennuokang®; Beijing Biote Pharmaceutical Co., Ltd.) or branded (Enantone®; Takeda Pharmaceutical Company, Ltd.) leuprorelin acetate microspheres via injection (commonly 3.75 mg once every 4 weeks), defined as the test (n=64) and reference (n=52) groups, respectively. The present study showed that testosterone levels at month (M) 3 (P<0.001), M6 (P=0.012) and M12 (P<0.001) were decreased in the test group compared with the reference group. However, prostate-specific antigen (PSA) levels at baseline, M1, M3, M6 and M12 were not significantly different between the test and reference groups (all P>0.05). The median (interquartile range) testosterone and PSA levels at M12 were 15.50 ng/dl (10.00-31.25 ng/dl) and 0.01 ng/ml (0.01-0.10 ng/ml), respectively, in the test group and 28.00 ng/dl (22.00-37.00 ng/dl) and 0.02 ng/ml (0.01-0.16 ng/ml), respectively, in the reference group. No significant differences were observed in the M1-baseline, M3-baseline, M6-baseline and M12-baseline changes of testosterone or PSA levels between the two groups (all P>0.050). Additionally, the incidence of all adverse events was not significantly different between the two groups (all P>0.050). Overall, Boennuokang® leuprorelin acetate microspheres exhibited a similar efficacy for suppression of testosterone and PSA levels with a comparable safety profile compared with Enantone® leuprorelin acetate microspheres in patients with PCa.

E068 Achievement of low disease activity over 52 weeks in patients with active axial spondyloarthritis on bimekizumab treatment: results from the phase 3 studies BE MOBILE 1 and BE MOBILE 2

Abstract Background/Aims The recommended treatment target for axial spondyloarthritis (axSpA) is remission/low disease activity (LDA) according to Ankylosing Spondylitis Disease Activity Score (ASDAS) levels (ASDAS&amp;lt;2.1); however, remission is difficult to achieve for many patients. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) remains commonly used in clinical practice to assess disease activity, although limited data exist to validate cut-offs. Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. BKZ has demonstrated consistent and sustained efficacy up to Week (Wk)52 in the BE MOBILE 1 and 2 phase 3 studies, including achievement of LDA according to ASDAS by &amp;gt; 50% of patients with non-radiographic (nr-)axSpA and radiographic (r-)axSpA. Here, we report achievement of LDA, as assessed by either ASDAS&amp;lt;2.1, BASDAI&amp;lt;4, or both, to Wk52 with BKZ across the spectrum of axSpA in two phase 3 studies. Methods BE MOBILE 1 (NCT03928704) and BE MOBILE 2 (NCT03928743) comprised a 16-wk placebo (PBO)-controlled and 36-wk maintenance period. BE MOBILE 1 (nr-axSpA) patients met Assessment of SpondyloArthritis international Society (ASAS) classification criteria and had objective inflammation (MRI and/or elevated C-reactive protein). BE MOBILE 2 (r-axSpA) patients met modified New York and ASAS classification criteria. All patients had active disease (BASDAI≥4 and spinal pain≥4 [BASDAI item 2]) at baseline. Patients were randomised to subcutaneous BKZ 160 mg every 4 weeks (Q4W) or PBO. Patients randomised to PBO switched to BKZ from Wk16 (‘PBO/BKZ-switchers’). The proportion of patients that achieved LDA to Wk52, as defined by either ASDAS&amp;lt;2.1, BASDAI&amp;lt;4, or both, are presented (non-responder imputation). Results Overall, 254 patients with nr-axSpA (BKZ: 128/PBO: 126) and 332 with r-axSpA (BKZ: 221/PBO: 111) were randomised. Most had high (ASDAS≥2.1-≤3.5) or very high (ASDAS&amp;gt;3.5) disease activity at baseline (nr-axSpA: BKZ: 99.2%/PBO: 97.6%; r-axSpA: BKZ: 98.6%/PBO: 100%). At Wk16, a greater proportion of BKZ vs PBO-treated patients achieved ASDAS&amp;lt;2.1 (nr-axSpA: BKZ: 46.1%/PBO: 19.8%; r-axSpA: BKZ: 42.1%/PBO: 17.1%), BASDAI&amp;lt;4 (nr-axSpA: BKZ: 52.3%/PBO: 31.7%; r-axSpA: BKZ: 55.7%/PBO: 41.4%) and both (nr-axSpA: BKZ: 43.8%/PBO: 19.0%; r-axSpA: BKZ: 41.6%/PBO: 17.1%). Results were sustained/improved across continuous BKZ-treated patients and PBO/BKZ-switchers to Wk52, with achievement of ASDAS&amp;lt;2.1 (nr-axSpA: BKZ: 53.9%/switchers: 47.6%; r-axSpA: BKZ: 50.2%/switchers: 61.3%), BASDAI&amp;lt;4 (nr-axSpA: BKZ: 60.2%/switchers: 54.0%; r-axSpA: BKZ: 65.6%/switchers: 68.5%) and both (nr-axSpA: BKZ: 49.2%/switchers: 45.2%; r-axSpA: BKZ: 49.8%/switchers: 58.6%). Achievement of BASDAI&amp;lt;4 was consistently higher than ASDAS&amp;lt;2.1, regardless of treatment arm. Conclusion Across the full axSpA disease spectrum, BKZ resulted in rapid achievement of LDA vs PBO to Wk16, as assessed by ASDAS&amp;lt;2.1, BASDAI&amp;lt;4, or both; improvements continued to Wk52. Most patients achieving ASDAS&amp;lt;2.1 also achieved BASDAI&amp;lt;4. These data suggest ASDAS&amp;lt;2.1 is a more stringent criterion for LDA, relevant for consideration of BKZ in the context of a potential treat-to-target approach for axSpA in daily practice. Disclosure X. Baraliakos: Consultancies; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB Pharma ; grant/research support from: Novartis and UCB Pharma. Member of speakers’ bureau; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. Other; Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. S. Ramiro: Grants/research support; AbbVie, Galapagos, MSD, Novartis, Pfizer and UCB Pharma; Consultant for AbbVie, Eli Lilly, Novartis, Pfizer, Sanofi and UCB Pharma. M. Magrey: Consultancies; AbbVie, BMS, Eli Lilly, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie, BMS and UCB Pharma. M. Rudwaleit: Consultancies; AbbVie, Eli Lilly, Novartis and UCB Pharma. Member of speakers’ bureau; AbbVie, Boehringer Ingelheim, Chugai, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma. N. Haroon: Consultancies; AbbVie, Eli Lilly, Janssen, Novartis and UCB Pharma. C. Fleurinck: Other; Employees of UCB Pharma. U. Massow: Other; Employees of UCB Pharma. N. de Peyrecave: Other; Employees of UCB Pharma. T. Vaux: Other; Employees of UCB Pharma. H. Marzo-Ortega: Consultancies; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Honoraria; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Grants/research support; Janssen, Novartis and UCB Pharma. V. Navarro-Compán: Consultancies; AbbVie, Eli Lilly, Galapagos, MoonLake, MSD, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, Eli Lilly, Fresenius Kabi, Janssen, MSD, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie and Novartis.

P167 Bimekizumab achieved sustained improvements in efficacy outcomes in patients with axial spondyloarthritis, regardless of prior tumour necrosis factor inhibitor treatment: week 52 pooled results from the phase 3 studies BE MOBILE 1 and BE MOBILE 2

Abstract Background/Aims Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL17A. In the phase 3 BE MOBILE 1 and 2 studies, BKZ treatment resulted in rapid and sustained improvements in efficacy outcomes through 52 weeks (wks) in patients with active nonradiographic axial spondyloarthritis (nr-axSpA) and radiographic (r)axSpA (i.e., ankylosing spondylitis [AS]). Here, we assess the efficacy of BKZ in tumour necrosis factor inhibitor (TNFi)-naïve or -inadequate responder (IR) patients with active nr-axSpA and raxSpA through Wk52. Methods In BE MOBILE 1 (nr-axSpA; NCT03928704) patients met Assessment of SpondyloArthritis international Society (ASAS) classification criteria and in BE MOBILE 2 (r-axSpA; NCT03928743) patients fulfilled modified New York and ASAS criteria. Patients were randomised to receive subcutaneous BKZ 160mg every 4wks (Q4W) or placebo (PBO) then BKZ 160mg Q4W from Wk16. This post-hoc analysis reports pooled mean efficacy data, including disease activity, MRI inflammation, physical function, and quality of life (QoL), through Wk52, stratified by TNFi status (naïve/IR). TNFi-IR patients were defined as those who experienced intolerance, or IR, to prior treatment given at an approved dose for ≥12wks. Results This pooled analysis included 505 TNFi-naïve and 81 TNFi-IR patients. 302/505 (59.8%) TNFi-naïve and 47/81 (58.0%) TNFi-IR patients were randomised to BKZ. Higher proportions of BKZ-randomised patients vs PBO achieved Wk16 ASAS40 (TNFinaïve: 46.0% vs 23.2%, TNFi-IR: 44.7% vs 14.7%; multiple imputation) and AS Disease Activity Score (ASDAS) &amp;lt;2.1 or low disease activity (47.9% vs 20.3%, 30.2% vs 15.6%; observed case). In continuous BKZ-treated patients, responses increased to Wk52 (ASAS40: 59.9%, 55.3%; ASDAS&amp;lt;2.1: 62.0%, 54.1%). Greater reductions from baseline in ASDAS-CRP and MRI inflammation by Wk16 were achieved with BKZ vs PBO in both TNFi-naïve/-IR patients; in continuous BKZ-treated patients this was sustained or further improved through 52wks. Comparable improvements in physical function, nocturnal spinal pain and ASQoL were observed through 52wks with BKZ in TNFinaïve/-IR patients (Table). Conclusion Across the full axSpA disease spectrum, BKZ treatment resulted in clinically relevant improvements in key efficacy outcomes vs PBO, including suppression of inflammation and improvements in physical function and QoL, regardless of prior TNFi exposure. Improvements were sustained to Wk52. Disclosure M. Magrey: Consultancies; AbbVie, BMS, Eli Lilly, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie, BMS and UCB Pharma. M. Van de Sande: Consultancies; AbbVie, Novartis and UCB Pharma. Member of speakers’ bureau; Janssen, Novartis and UCB Pharma. Grants/research support; Eli Lilly, Novartis and UCB Pharma. M. Breban: Consultancies; Novartis and UCB Pharma. Grants/research support; MSD. F. Van den Bosch: Consultancies; AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Merck, Novartis, Pfizer and UCB Pharma. C. Fleurinck: Other; Employee of UCB Pharma. U. Massow: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Vaux: Other; Employee of UCB Pharma. X. Baraliakos: Consultancies; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. Grants/research support; Novartis and UCB Pharma. Other; Paid instructor for AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. H. Marzo-Ortega: Consultancies; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Honoraria; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Grants/research support; Janssen, Novartis and UCB Pharma.

Preliminary data from the CONNEX-X extension trial examining the long-term safety of iclepertin in patients with schizophrenia who completed Phase III CONNEX trials

IntroductionCognitive impairment associated with schizophrenia (CIAS) is an important unmet need as there are no effective treatments available. Iclepertin (BI 425809), a glycine transporter-1 inhibitor, has been shown to improve CIAS in Phase II trials, and Phase III trials are underway.ObjectivesThe ongoing CONNEX-X extension study aims to collect additional safety data relating to iclepertin treatment in patients with CIAS.MethodsCONNEX-X (NCT05211947/1346-0014) is a multinational, multicentre, open-label, single-arm extension study in patients with CIAS who completed 26 weeks of treatment (iclepertin 10 mg or placebo) in one of 3 Phase III CONNEX parent trials (NCT04846868/1346-0011, NCT04846881/1346-0012, NCT04860830/1346-0013). An estimated 1400 clinically stable outpatients will be treated (iclepertin 10 mg daily) for 1 year, irrespective of previous treatment (iclepertin/placebo). Patients are excluded if any of the following circumstances occur during the parent study and up to Visit 1 of CONNEX-X: suicidal behaviour or ideation (type 5 on the Columbia-Suicide Severity Rating Scale), diagnosis with moderate/severe substance use disorder, diagnosis other than schizophrenia (according to Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition), development of any condition preventing participation, a haemoglobin level decrease (&gt;25% or &lt;100g/L from baseline in parent trial) or haemoglobinopathies. The primary endpoint is the occurrence of treatment-emergent adverse events. The secondary endpoints include change from baseline (CfB) in Clinical Global Impressions-Severity (CGI-S) and CfB in haemoglobin. Further efficacy endpoints include CfB in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score, CfB in Schizophrenia Cognition Rating Scale total score and CfB in Virtual Reality Functional Capacity Assessment Tool (VRFCAT) total times.ResultsCurrently, 460 patients have been enrolled and randomised from the parent trials with 0% screening failures (-80% roll-over rate, 30 August 2023). Current study status, including recruitment, screening failures and data collection experiences, are presented.ConclusionsPatient enrolment rates from the CONNEX trials to the CONNEX-X open-label extension study are stable. CONNEX-X will allow the exploration of long-term safety, as well as descriptive analyses of cognitive and functional endpoints of iclepertin in the treatment of CIAS.FundingBoehringer IngelheimDisclosure of InterestC. Reuteman-Fowler Employee of: Boehringer Ingelheim Pharmaceuticals, Inc., Z. Blahova Employee of: Boehringer Ingelheim RCV GmbH &amp; Co. KG, S. Marder Consultant of: Boehringer Ingelheim Pharma GmbH, Merck, Biogen and Sunovion, S. Ikezawa Consultant of: Boehringer Ingelheim Pharma GmbH, Lundbeck, Takeda Pharma, Sumitomo Dainippon Pharma, Employee of: International University of Health and Welfare, Mita Hospital, Tokyo, Japan, P. Falkai Consultant of: Boehringer Ingelheim Pharma GmbH, Boehringer Ingelheim Pharma advisory board

Does the association between short-chain fatty acids and depressive symptoms vary with age? A large population-based study

IntroductionFat plays an important role in brain function; 60% of the brain’s dry weight is fat. Among fats, omega-3 fatty acids, which are long-chain fatty acids, have been reported to reduce depressive symptoms. On the other hand, there are few studies on short-chain fatty acids (SCFAs), and those that do exist are mostly animal studies, with only a few human studies (about 100 cases). This is the first study to examine the association between fecal short-chain fatty acids and depressive symptoms on a large scale in the general population.ObjectivesWe examined the association of fecal SCFAs with depressive symptoms. In addition, we analyzed the associations stratified by age and examined differences in the associations.MethodsThis study was conducted using data from the Dynamics of Lifestyle and Neighborhood Community on Health Study (DOSANCO Health Study). The target population was all residents of the city of Suttu, Hokkaido, Japan, excluding residents of special nursing homes (n=2638). 579 individuals (22% of the target population) aged 18 years and older who were able to measure fecal SCFA participated in this study with written informed consent. Approval was obtained from the Ethics Committee of Hokkaido University School of Medicine (15-002 and 15-045). Fecal SCFA was measured by high-performance liquid chromatography. We examined the association of fecal concentrations of SCFA subtypes (i.e., acetate, butyrate, and propionate) and total SCFA concentrations (mg/g wet weight as a continuous variable) with total Patient Health Questionnaire-9 (PHQ-9) scores using multiple regression analysis. We adjusted for age, sex, habitual exercise, total energy intake, and total dietary fiber intake. We performed additional multiple regression analyses with stratification by age group (18-59 years and 60 years or older). Two-tailed tests were used for all analyses with a significance level of P &lt; 0.05.ResultsThe mean age (standard deviation) of the study participants (n=534) was 58.3 (16.0) years. Among them, 48% were 18-59 years old and 54% were female. Fecal propionate concentration was significantly associated with total PHQ-9 score (beta=0.62, p&lt;0.01). Other SCFAs and total SCFA were not significantly associated with total PHQ-9 score. In addition, using stratification analyses by age group, the associations between fecal propionate concentration and total PHQ-9 score showed a different trend by age group (beta=0.18, p=0.62 for 18-59 years; beta=0.80, p&lt;0.01 for 60 years or older).ConclusionsThe study showed an association between higher concentrations of fecal propionic acid and higher levels of depressive symptoms. The association was particularly pronounced in older people, those aged 60 years and older. The results suggest that improving dietary habits to reduce fecal propionic acid may be effective in preventing depression in the elderly.Disclosure of InterestR. Okubo Shareolder of: None, Grant / Research support from: A Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (No. 22K17844), Consultant of: None, Employee of: None, Paid Instructor of: None, Speakers bureau of: Speakers bureau from Takeda Pharmaceutical Company Limited, R. Yamamura: None Declared, S. Ishikawa: None Declared, T. Kimura: None Declared, S. Ukawa: None Declared, K. Nakamura: None Declared, A. Tamakoshi: None Declared

Nature and Trend of Pharmaceutical Payments to Japanese Board-Certified Neurologists Between 2016 and 2019: A Pre-emergence Analysis Amidst the Development of Next-Generation Alzheimer's Disease Drugs.

There is insufficient data on the financial relationships between Japanese neurologists and pharmaceutical companies prior to the advent of new-generation Alzheimer's disease drugs. The purpose of this study is to evaluate the magnitude, prevalence, and trend of the financial relationship between Japanese neurologists and pharmaceutical companies between 2016 and 2019. A cross-sectional study was undertaken to evaluate the financial relationships between all board-certified neurology specialists and pharmaceutical companies in Japan from 2016 and 2019. Descriptive statistics were applied to measure the magnitude and prevalence of payments among specialists, as well as their trends during the study periods. In a four-year analysis, 77 pharmaceutical companies disbursed a total of USD 36,869,204 across 50,050 payments to 2,696 neurologists in Japan, revealing a mean payment of USD 10,809 per specialist. Notably, the Gini index of 0.997 indicated a high inequality in payment distribution, with a minority of specialists receiving a substantial proportion of payments. Trends displayed irregularities, but an overall increase in total payments from 2016 to 2019, with a significant contribution from the top 10 pharmaceutical companies accounting for 74.2% of total payments, with Takeda Pharmaceutical and Eisai Company notably increasing payments in 2019. There were notable geographical variations in neurologist and payment distribution across 47 prefectures. Our analysis of neurologist payments from pharmaceutical companies in Japan showed a substantial financial relationship with overall increases, yearly varied increments, and payment inequality. Caution is warranted as financial ties may intensify with the continued development of next-generation Alzheimer's disease drugs.

Abstract B148: Novel low-atomic cluster Ag5 induced oxidative stress and antiproliferation in Esophageal Squamous Cell Carcinoma Cells

Abstract Background: Accumulation of reactive oxygen species (ROS) intensively activates cellular stress responses leading to cell death, thus ROS levels are strictly controlled by various antioxidants in normal cells. Esophageal cancer (ESCA), the sixth most common cause of cancer deaths, highly accumulates ROS under uncontrolled redox balances to activate oxidative-stress response pathways. Arjuna Therapeutics has developed a novel low-atomic cluster Ag5 as a ROS inducer, which strongly inhibits antioxidant pathways of glutathione and thioredoxin. In this study, we pharmacologically evaluate Ag5 on its therapeutic potential in preclinical ESCA models. Materials and Methods: Gene enrichment analyses were performed with 6,327 RNA-seq data of 14 cancer types in TCGA database. Cell panel studies of ATP-based cell viability was performed in vehicle control, Ag5 (3 uM), N-acetylcysteine (NAC, 5mM), and combination treatments in 31 esophageal squamous cell carcinoma (ESCC) cell lines and 5 non-ESCC cell lines. NAC) treatment was used as a rescue control of an antioxidant. We also conducted time-lapse imaging analysis with DCFDA (ROS indicator) and SYTOX (cell death marker). The morphology of mitochondria and ER were determined by electron microscope (EM). Results: Gene enrichment analyses revealed ROS-related genes were upregulated in ESCA compared to other cancer types. In the cell panel studies, Ag5 also exhibited potent antiproliferation in large numbers of ESCC cell lines, and NAC profoundly attenuated its antiproliferative activity. Time-lapse microscopy in ESCC cell line KYSE190 demonstrated that Ag5 increased DCFDA in 20 min and SYTOX in 60 min after the treatment, respectively, while combination treatment with NAC less detected these markers. Ag5-treated KYSE190 also exhibited necrosis-like morphology of swollen- and round-shape cells. In EM, damaged mitochondria and expanded endoplasmic reticulum were frequently observed in Ag5-treated KYSE190 cells. These data indicated that Ag5 induced ROS-mediated antiproliferation in ESCC cell lines. Conclusions: Ag5 exhibited ROS-mediated antiproliferative activities in large numbers of ESCC cell lines. Our preclinical results suggest the therapeutic potential of Ag5 as a novel cancer drug candidate for ESCC. Conflict of interest disclosure: AO is a part-time employee of Astellas Pharma Inc. from 2023 as a cross-appointment system. AO was an employee of Takeda Pharmaceutical Company, Ltd. AO reported paid consulting or advisory roles for Ono Pharmaceutical Company Ltd., Craif Inc., and GEXVal Inc. out of this study. AO receives research fundings from Astellas Pharma Inc., Astellas Pharma Global Development Inc., and Daiichi Sankyo Company, Ltd. out of this study. RB and MT are board members of Arjuna Therapeutics. Citation Format: Ryo Kamata, Toyohiro Yamauchi, Yuta Sakae, Ross Breckenridge, Martin Treder, Akihiro Ohashi. Novel low-atomic cluster Ag5 induced oxidative stress and antiproliferation in Esophageal Squamous Cell Carcinoma Cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B148.

Impact of Dexamethasone (Dex) Dose Strength on Outcomes in Newly Diagnosed Multiple Myeloma (NDMM): A Secondary Analysis of SWOG Studies S0777 and S1211

Background: Dex is a key component of induction regimens for NDMM despite common toxicities including insomnia and anxiety. The E4A03 randomized trial (Rajkumar, Lancet Oncol 2010) demonstrated that dex dosed at 40 mg weekly outperformed higher-intensity dex and established this regimen as the standard of care for NDMM. In standard practice as well as clinical trials, however, dex doses are often reduced to 20 mg weekly or lower (if not stopped entirely) among older patients or among patients experiencing toxicities. As a first step toward establishing the equipoise of planned dex dose reductions in NDMM, we investigated outcomes with patients from two previous SWOG trials to understand the impact of dex dose reductions on post-induction outcomes. Methods: This was a secondary analysis of data from two completed NDMM studies, S0777 (comparing VRd vs Rd) and S1211 (comparing Elo-VRd vs VRd). For this secondary analysis, we analyzed the subset of patients who completed all eight 3-week cycles of induction (or six 4-week cycles in the S0777 Rd arm). As shown in Figure 1A, we defined DEX fullDose as patients for whom the starting dex dose (either 40 mg once per week or 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles) did not change during induction. In contrast, DEX lowered was defined as patients for whom the end-of-induction dex dose and/or frequency were lower than their starting values. As an exploratory analysis, we also compared PFS and OS between the DEX fullDose (no changes to dex strength during induction) and DEX veryLow (dex dosing reduced ≥50% during induction) subgroups. All analyses were landmarked from the end of induction, defined as 24 weeks from registration, to account for the time-dependent nature of dex treatment received. Survival curves were based on the Kaplan-Meier method and comparisons were made using the log-rank test. Results: Of 541 evaluable patients ( n = 441 from S0777, n = 100 from S1211), dex was reduced during induction in 76% ( n = 410). Compared to DEX fullDose patients, DEX lowered patients were more likely to be anemic (37% vs 26%, p = 0.02) but had similar distributions of age ≥70 (24% of DEX lowered vs 26% of DEX fullDose), Performance Status &amp;gt; 1 (15% vs 12%), ISS stage 3 disease (33% vs 27%), ≥ 60% bone marrow plasma cell burden (37% vs 31%), M-spike &amp;gt; 3 g/dL (48% vs 48%) platelets &amp;lt; 150,000 cells/mm 3 (18% vs 14%), baseline LDH ≥ 190 U/L (36% vs 41%), and baseline CRP ≥ 8 mg/L (27% vs 30%). PFS (Figure 1B) was comparable between DEX lowered (median 36 months, 95% CI 29 to 39 months) and DEX fullDose (median 33 months, 95% CI 24 to 48 months) with p = 0.90. Similarly, OS (Figure 1C) was comparable between DEX lowered [median 77 months, 95% CI 68 months to not reached (NR)] and DEX fullDose (median 92 months, 95% CI 65 months to NR) with p = 0.93. In the DEX veryLow subgroup with ≥50% reduction in dex dosing during induction, median PFS was 39 months (95% CI 34 to 50 months) and median OS was NR (95% CI NR to NR). As shown in Figure 1D and Figure 1E, PFS and OS were comparable between these patients and DEX fullDose patients. Discussion: To our knowledge, this is the first analysis of dex dosing strength in NDMM since E4A03. In two separate randomized trials, over half of patients required dex reductions below a starting dose of ~40 mg weekly. Dex dose reductions during induction had no impact on post-induction PFS and OS, even in the subset of patients who required significant dose reductions. Limitations of our post hoc analysis include heterogeneity between dex dosing schedules and lack of cytogenetic data for all patients. We could not discern specifically why dex was lowered, and it is possible that dex might have been lowered disproportionately commonly in patients who had achieved early responses and thus independently did better. Regardless, these results strongly suggest that maintaining dex 40 mg weekly for the entirety of NDMM induction may be unnecessary in the modern era. Cooperative efforts to study a planned dex de-escalation protocol (i.e., once no longer needed for symptom management or as a pre-medication) alongside patient-reported outcome assessments of symptom burden are being planned. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180820; and in part by Millennium Pharmaceuticals, Inc. (now part of Takeda Pharmaceutical Company), and by Celgene.

255. Borrelia-specific antibody profiling in joint fluid distinguishes antibiotic-refractory Lyme arthritis from antibiotic-responsive arthritis

Abstract Background Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States. It drives a multisystem disorder, of which Lyme arthritis is the most common feature of late disseminated disease, seen in approximately 60% of untreated individuals. While most Lyme arthritis resolves with oral or IV antibiotics, termed “antibiotic-responsive” arthritis, a small percentage of individuals develop progressive synovitis despite both oral and IV antibiotic therapy, called “antibiotic refractory” Lyme arthritis (LA), requiring treatment with immunosuppressive, disease modifying antirheumatic drugs (DMARDs). The primary drivers behind antibiotic refractory disease are likely multifactorial and remain incompletely understood. More specifically, it remains unclear whether antibodies, specific for Borrelia or autoantibodies, may act as biomarkers or play a mechanistic role in driving pathogenesis in the joint. Methods We performed a matched, cross-compartmental comparison of antibody profiles from blood and joint fluid of individuals with antibiotic responsive (n = 11) or antibiotic refractory arthritis (n= 31). We used a multiplexed luminex assay to perform biophysical profiling of Borrelia burgdorferi -specific antibodies to B67 lysate, CRASP1, CRASP2, DbpA, DbpB, Arp37, Flagellin, OspA, OspB, OspC, OspE, p27, p35, p39, VlsE, and autoantigen Apolipoprotein B100. Results While serum antibody profiles poorly discriminated responsive from refractory LA patients, a discrete profile of B.burgdorferi-specific antibodies in the joint fluid was able to discriminate antibiotic responsive from refractory LA patients. Cross compartmental comparison of antibody glycosylation, IgA1, and antibody-dependent complement deposition (ADCD) revealed differences across compartments, with more poorly coordinated Lyme-specific humoral responses and increased antibody-dependent complement deposition in antibiotic-refractory arthritis. Conclusion These data demonstrate B.burgdorferi-specific serological markers that may support the early stratification and clinical management of LA, but also point to immune complex driven complement activation as a key mechanism underlying persistent Lyme arthritis. Disclosures Christine Wiggins, B.S., Takeda Pharmaceutical Company: Stocks/Bonds Elizabeth Deriso, PhD, Takeda: Employee Klemen Strle, PhD, Takeda: I am an employee of Takeda. My work at Takeda does not overlap with my academic efforts in Lyme disease. John A. Branda, M.D, Analog Devices Inc.: Grant/Research Support|DiaSorin: Grant/Research Support|Gold Standard Diagnostics: Grant/Research Support|Pfizer Inc: Grant/Research Support|Zeus Scientific: Grant/Research Support Douglas A. Lauffenburger, PhD, Sanofi: Board Member|Sanofi: Honoraria|Sanofi: Honoraria Galit Alter, PhD, Leyden Labs: Ownership Interest|Moderna Therapeutics: Employee|Seromyx Systems: Ownership Interest

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial

The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.

1628-P: Role of CD38 in the Regulation of Muscle Stem Cell Functions in Aged Mice

Skeletal muscle repair and regeneration is a complex process and is known to be delayed with aging, diabetes and obesity. This is in part due to infiltration of inflammatory macrophages which can delay the recovery process. Both macrophages and satellite cells require nicotinamide adenine dinucleotide (NAD+) for their biological functions. Aging-induced decline in NAD+ have been shown to worsen insulin resistance and muscle dysfunction. CD38 is an ectoenzyme that degrades NAD+ and is increased in inflammatory macrophages in aging, obesity and other insulin-resistant states. However, how inhibition of CD38 affects satellite cell functions in aged or obese mice, remains unknown. Here, we utilized aged CD38 knockout mice to assess the role of this protein and NAD+ in the recovery process in injured muscle. CD38 KO mice were found to be resistant to diet-induced obesity and had improved insulin sensitivity. Our data show that genetic deletion of CD38 in aged mice increased NAD+ levels and thus enhanced muscle stem/satellite cells differentiation and promote myogenesis. Deletion of CD38 also resulted in an enhanced number of regenerating myofibers. Furthermore, we found that deletion of CD38 significantly reduces fibrosis of muscle and also improved limb grip strength. Pharmacological inhibition of CD38 in C2C12 myoblasts and ex-vivo primary myoblasts significantly increased NAD+ levels and also enhanced the differentiation of satellite cells into myoblasts and myofibers. We, therefore, examined the rescue effects of 78c (CD38i) on human recombinant CD38 (hCD38) inhibition of muscle stem cells. Administration of hCD38 inhibited expression of MyoD and MyoG in primary myoblasts, while this effect was rescued through 78c treatment. Taken together, these data demonstrate that restoration of NAD+ levels either through genetic deletion/pharmacological inhibition of CD38 can improve muscle stem cell functions and muscle regeneration and might promote muscle regeneration in obesity, type 2 diabetes, and aging. Disclosure A.Nawaz: None. K.Yaku: None. I.Jeelani: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. T.Nakagawa: None.

896-P: Effectiveness of Newly Prescribed SGLT2 Inhibitors as Second-Line Therapy following DPP-4 Inhibitors or Metformin as First-Line Therapy in Type 2 Diabetes Patients

Prescriptions of SGLT2 inhibitors (SGLT2i) for patients with type 2 diabetes (T2DM) are increasing. In this study real-world data were used to evaluate the long-term benefits of SGLT2i as a second-line drug for glycemic control in people with T2DM being treated with DPP-4 inhibitor (DPP4i) or metformin (MET) monotherapy. People with T2DM patients on DPP4i or MET monotherapy were followed for at least 12 months after receiving a new SGLT2i prescription. Patients were divided into DPP4i and MET groups, and patient background factors were controlled for using propensity score matching (PM). Changes in HbA1c and other indexes during the 12 months after the new prescription were compared using t-tests, and the factors affecting changes in HbA1c were examined using multiple regression analysis. After PM, there were 192 patients in the DPP4i (n=96) and MET (n=96) groups, with no significant differences in patient backgrounds. HbA1c levels 12 months after a new SGLT2i prescription were significantly lower in both groups compared to base line (8.1% to 7.0%, p&amp;lt;0.001; 8.1% to 7.1%, p&amp;lt;0.001), but there were no significant differences between the two groups in the change in HbA1c level (p=0.271), body weight (p=0.371), systolic blood pressure (p=0.828), eGFR (p=0.642), and Fib-4 index (p=0.674). The change in HbA1c was greater for those with initially higher HbA1c levels (-0.629 [-0.722-0.536], p&amp;lt;0.001) and those with shorter diabetes histories (0.024 [0.001-0.048], p=0.044), but it was not significantly different between the two groups (p=0.236). After controlling for patient background, there was no significant difference in the long-term effects of a new SGLT2i prescription between those previously receiving either DPP4i or MET monotherapy, but higher previous HbA1c levels and a shorter diabetes history may be prediction of better HbA1c 12 months after a new SGLT2i prescription, regardless of prior medication. Disclosure H.Takahashi: Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Medtronic, Novo Nordisk. Y.Suganuma: None. T.Ohno: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck &amp; Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.

1381-P: Effect of Dietary Potassium Intake and Its Interaction with Sodium Intake on Risk of Developing Cardiovascular Disease (CVD) in Persons with Type 2 Diabetes (T2D)—Japan Diabetes Complication and Its Prevention Prospective Study (JDCP Study)

Many guidelines recommend increased potassium intake. However, the relationship between dietary potassium intake and incidence of CVD in persons with T2D has not been explored, nor is it known if this relationship varies with sodium intake in such persons. Therefore, we investigated these relationships as part of the JDCP study, a nationwide study launched in 2007. A total of 1477 persons with T2D aged 40-75 years completed a brief self-administered Diet History Questionnaire at baseline, and resultant data were analyzed. Primary outcome was the 7-year risk of a CVD event. Hazard ratios (HRs) for CVD according to tertiles of dietary potassium and sodium intake were estimated by Cox regression adjusted for confounders in addition to a stratified analysis of tertiles of sodium intake. Mean daily potassium and sodium intakes in tertiles 1 to 3 were 1.9, 2.6, and 3.5 g and 3.3, 4.2, and 5.3 g, respectively. HbA1c, BMI, triglycerides, and blood pressure were well controlled. No significant associations between potassium and sodium intakes and incidence of CVD were shown for the second and third tertiles relative to the first tertile (potassium: 0.64 [95% CI, 0.34-1.23] and 0.59 [0.28-1.25]; sodium: 1.02 [0.51-2.04] and 1.15 [0.58-2.30]). In the stratified analysis of tertiles of sodium intake, in the high sodium intake groups (T2 and T3) HRs for CVD in the high potassium intake group were significantly lower compared to the low potassium intake group (T2: 0.40 [0.12-1.35] and 0.06 [0.01-0.69]; T3: 0.23 [0.07-0.82] and 0.26 [0.07-0.88]). Associations of potassium intake with CVD in those with low sodium intake (T1) were not significant. Findings suggested that high potassium intake under high sodium intake is associated with a deceased incidence of CVD in persons with T2D although potassium intake under low sodium intake was not associated with incident CVD. Disclosure C.Horikawa: None. H.Shimano: None. J.Satoh: None. Y.Hayashino: Advisory Panel; Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Sumitomo Dainippon Pharma Co., Ltd., Santen, Daiichi Sankyo, Kowa Company, Ltd. N.Tajima: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck &amp; Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca. Y.Yamasaki: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Jdcp study group: n/a. M.Takahara: None. N.Katakami: Speaker's Bureau; Abbott Japan Co., Ltd., Daiichi Sankyo, MSD, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Ono Pharmaceutical Co., Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Bayer Inc., Lilly, Teijin Pharma Limited, Kyowa Kirin Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi. Y.Takeda: None. M.Takeuchi: None. K.Fujihara: None. H.Suzuki: None. K.Tsuda: None. N.Yoshioka: None.

405-P: ROCK2 Activation and Its Role in Folic Acid–Induced Murine Model of Nephropathy

Over 2 million people currently receive treatment with dialysis or a kidney transplant throughout the world. Thus, developing a new strategy to treat chronic kidney diseases is significant from the perspective of a health economic and the prevention of cardiovascular death. The small GTPase Rho and its effector Rho-kinase (ROCK) are involved in the pathogenesis of diabetic nephropathy. In chronic kidney diseases including diabetic nephropathy, tubulointerstitial fibrosis is known to be highly associated with renal outcome. We have previously reported that ROCK inhibition prevented the progression of diabetic nephropathy in murine models. With regards to ROCK, there are two isoforms, which are ROCK1 and ROCK2. ROCK1 has been shown to be involved in the endocytosis of albumin in tubular epithelial cells via megalin/cubilin-dependent mechanism. However, the role of renal tubular ROCK2 remains to be elucidated. The aim of this study is to reveal the role of renal tubular ROCK2 in the pathogenesis of chronic kidney disease. To this end, we used a tubulointerstitial injury model known as folic acid-induced nephropathy (FAN). Importantly, ROCK2 was elevated at protein levels in FAN group compared with vehicle-treated group. We next generated tubular specific ROCK2 knockout mouse (TR2KO) by crossing Ksp-Cre mice with mice containing two loxP sites flanking in Exon 3 of ROCK2. In the Ksp-Cre transgenic mice, Cre recombinase has been demonstrated to be expressed in tubules, collecting ducts, and thick ascending limbs. Compared with vehicle-treated group, collagen deposition in the kidneys of FAN group was highly elevated as revealed by Masson’s trichrome staining. The increased collagen deposition was significantly improved in TR2KO. Our findings indicate that ROCK2 regulates the progression of tubulointerstitial fibrosis. ROCK2 may be a potential therapeutic target for the prevention of chronic kidney disease. Disclosure K.Sekiguchi: None. K.Matoba: None. S.Ohashi: None. E.Mitsuyoshi: None. Y.Nagai: None. Y.Takeda: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck &amp; Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.

631-P: Development of Noninvasive Diabetes Management Method Using Glycated Albumin in Tears

Aims/Background: Several clinical trials have demonstrated that strict glycemic control is important to minimize the risk of diabetic complications. Although frequent measurement of blood glucose levels by the invasive finger prick method is useful to achieve strict glycemic control, this method is invasive and burdensome to the patients. Glycated albumin (GA) is a biomarker which reflects the glycemic control status over the previous 2 weeks. We demonstrated GA levels in tears correlated those in blood. We hypothesized that regular GA tests in tears caused behavior change and improved glycemic control. Methods: Participants with type 2 diabetes were recruited and randomly divided to two groups. One group (intervention group) was performed tear GA tests every 2 weeks and reported the results, while the other group (control group) was not. After 8 weeks of intervention, the two groups were compared. GA levels in tears were measured by Liquid Chromatography / Mass Spectrometry. Results: We enrolled 56 participants to the study. Compared with the control group, the intervention group showed improvement in fasting blood glucose, HbA1c, GA, non-HDL cholesterol. Conclusions: Levels of GA, as a diabetes-related biomarker, in tears can be measured noninvasively. Regular measurement of the GA levels in tears could allow smoother management of diabetes mellitus and reduce the risk of complications noninvasively. Disclosure M.Aihara: None. N.Kubota: None. T.Yamauchi: Other Relationship; Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Novo Nordisk, Astellas Pharma Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim, Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Merck &amp; Co., Inc., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Tosoh Corporation, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., NTT Docomo Inc., Aero Switch, Asahi Mutual Life Insurance Company, NIPRO Medical Corporation, Abbott Japan Co., Ltd., Bayer Inc., Kyorin Pharmaceutical Company, Limited.

1672-P: Isoxanthohumol Improves Obesity and Glucose Metabolism via Regulation of Gut Barrier and Intestinal Lipid Absorption with a Bloom of Akkermansia muciniphila

Dysbiosis is an important factor that leads to metabolic disorders via disruption of the gut barrier function. A decrease in Akkermansia muciniphila (AM) is a phenotype of obesity-induced disruption of the gut barrier. Although interventions to increase AM have been reported to improve glucose metabolism, the underlying mechanism has not been fully understood. The administration of IX suppressed weight gain and steatohepatitis and improved glucose metabolism in diet-induced obese mice. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption via decreased expression of the lipid absorption transporter, CD36, in the jejunum. Moreover, IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the observed effects of IX were cancelled by antibiotics and reproduced by fecal microbiota transplantation to GF mice. 16S rRNA sequencing revealed that the microbial community structure changed with a significant increase in AM in the IX-administration group. An anaerobic chamber study showed that IX promoted the growth of AM, while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct impact of AM on lipid and glucose metabolism in monocolonized mice, we transplanted either AM or Bacteroides thetaiotaomicron to GF mice. AM monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism with decreased multiple classes of fatty acids in plasma metabolomics analysis. In summary, IX contributes to metabolic improvement by decreasing CD36 and lipid absorption in the small intestine which is associated with a bloom of AM, suggesting an important interaction between food ingredients and AM abundance in controlling metabolism. Disclosure Y.Watanabe: None. S.Fujisaka: None. S.Watanabe: None. A.Nishimura: None. T.Kado: None. M.Aslam: None. M.Bilal: None. Y.Morinaga: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. Funding Japan Society for the Promotion of Science (21K20896, 22K16424); Lotte Foundation; Yakult Bio-Science Foundation

1623-P: Identification of Gut Microbes That Prevents Metabolic Syndrome in Healthy Japanese Adults

Gut microbiota is an important driver of metabolic status. Recent studies have demonstrated that dysbiosis precedes the development of metabolic disorders. However, the bacterial species associated with metabolic syndrome and their physiological role in obesity and glucose metabolism have not been fully elucidated. In this study, we performed 16S rRNA sequencing analysis on fecal samples from 49 metabolically healthy volunteers, a detailed lifestyle questionnaire survey including diet, and an analysis on metabolic parameters. We also examined the metabolic effects of some microbes by transplantation into HFD-fed mice. The average age, BMI and HbA1c were 43.5±9.0, 23.9±3.9 and 5.5±0.3, respectively. A clear correlation was observed between lifestyle and metabolic parameters. Analysis of fecal microbial structure divided the participants into three enterotypes according to their predominant phylogenic pattern; 1) Prevotella copri group, 2) Bacteroides group, and 3) others. Enterotype 1 had higher random blood glucose (BG), and lower HDL-C, while enterotype 2 had lower random BG, BMI, and waist circumference. Eleven bacterial species were identified as being positively or negatively correlated with metabolic parameters. Relative abundances of the Family Fusobacteriaceae and Prevotella stercorea were positively correlated with BMI, fasting BG, and visceral fat mass. In contrast, the Family Rikenellaceae and Bacteroides uniformis (Bu) negatively correlated with metabolic parameters. Transplantation of Alistipes indistinctus (Ali), a major bacterium of the Family Rikenellaceae, or Bu into HFD-fed C57BL/6J mice suppressed body weight gain, improved glucose tolerance and histological findings without altering food intake. In summary, our results suggest that microbial community structure can be altered by lifestyle even in good health. Moreover, maintaining microbial species such as Ali and Bu may contribute to the prevention of metabolic disorders in Japanese adults. Disclosure H. Honoki: None. S. Fujisaka: None. Y. Watanabe: None. M. Oku: None. Y. Kondo: None. A. Nishimura: None. T. Kado: None. M. Bilal: None. A. Enkaku: None. A. Takikawa: None. D. Chujo: None. Y. Morinaga: None. K. Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. Funding Japan Society for the Promotion of Science (20K10318); Japan Association for Diabetes Education and Care

1551-P: Association between Short-Term Postprandial C-Peptide Index Recovery during Hospitalization and Future Glycemic Control in Patients with Type 2 Diabetes

Endogenous insulin secretion could be recovered by improving hyperglycemia in patients with type 2 diabetes (T2D). However, no reports have showed the associations between short-term insulin secretion recovery and future glycemic control. In this study, we investigated whether short-term C-peptide index (CPI) recovery during hospitalization could predict future glycemic control. In this study, 117 patients with T2D were included. The recovery of fasting and postprandial CPI were defined as (fasting CPI at discharge - fasting CPI at admission [index-A]) and (postprandial CPI at discharge - postprandial CPI at admission [index-B]). We compared the clinical background between the low-recovery and high-recovery groups of each index and assessed the association between the indices and metabolic parameters after discharge. Using index-A, age was significantly younger (P = 0.017) and body mass index (BMI) was significantly higher (P = 0.004) in the high-recovery group than that in low-recovery group. Using index-B, the age was significantly younger (P = 0.019) and BMI was significantly higher (P = 0.004) in the high-recovery group. Additionally, visceral fat area (P = 0.043), serum TG (P &amp;lt; 0.001), and γ-GTP levels (P = 0.009) were significantly higher in the high-recovery group. Regarding the association between CPI recovery and future glycemic control, GA levels were significantly lower in the high-recovery group than that in low-recovery group at 6 months (16.7 vs 21.1%, P = 0.045) and 12 months (16.8 vs 21.7%, P = 0.033) after discharge in the analysis using index-B. Furthermore, postprandial CPI (cut-off; 3.79 [AUC 0.698, P = 0.007]) at discharge and index-B (cut-off; 1.66 [AUC 0.657, P = 0.018]) were identified as indicators to predict HbA1c ≤ 7.0% at 6 months after discharge. In conclusion, short-term postprandial CPI recovery during hospitalization may predict future glycemic control. Disclosure A.Enkaku: None. D.Chujo: None. M.Kamigishi: None. S.Inagawa: None. W.Sakai: None. S.Matsukoshi: None. A.Takikawa: None. S.Fujisaka: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care.

298-OR: Safety and Efficacy of Immunomodulatory Therapy Using Antithymocyte Globulin and Pegfilgrastim in Japanese Patients with Type 1 Diabetes—A Pilot Randomized Clinical Trial

While immunomodulatory therapy using low-dose anti-thymocyte globulin (ATG) has been shown to be efficacious in preserving pancreatic beta-cell function in patients with type 1 diabetes (T1D) in the United States, no clinical trials of immunomodulatory therapy for T1D have been reported in Asia. In this study, we first evaluated the safety and efficacy of ATG/pegfilgrastim (PEG) therapy in Japanese patients with T1D. This was a pilot, open-label, randomized clinical trial. Twelve patients, with the age ≥ 20 years, T1D duration &amp;lt; 12 months, and serum CPR ≥ 0.3 ng/ml, were randomized into the ATG/PEG group (A/P; n = 6) and control group (Ctrl; n = 6). The A/P was administered 2.0 mg/kg ATG and six times of 3.5 mg PEG. The primary endpoint was the frequency of adverse events (AEs), which were evaluated per the CTCAE v5.0, and secondary endpoints included the percentages of decline (%Dec) in CPR-area under the curve (AUC) after mixed-meal loading, the SUIT index, and changes in glycemic control during an observation period of 104 weeks. Regarding safety, no grade 4 and 5 AEs were reported in either group. Grade 3 lymphocytopenia, which is considered to be the clinical effect of ATG, was noted in all 6 patients in the A/P. One severe AE, cellulitis, was reported in the Ctrl. The frequencies of infection were not significantly different between the two groups. Regarding efficacy, %Dec in CPR-AUC in 52 weeks was less than the median value in 5 out of 6 patients in the A/P, whereas 1 out of 5 patients in Ctrl (P = 0.03). Additionally, %Dec in the SUIT index in 104 weeks tended to be lower in the A/P than in the Ctrl (P = 0.06). Changes in HbA1c and glycated albumin levels and the amount of insulin administered were not significantly different between the two groups. In conclusion, ATG/PEG therapy was safely administered to Japanese patients with T1D. Larger scale trials and mechanistic analyses are required to confirm the efficacy of this treatment. Disclosure D.Chujo: None. N.Ohmagari: None. H.Ohyanagi: None. M.Shimoda: None. K.Ueki: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Sanofi K.K., MSD Life Science Foundation, Takeda Pharmaceutical Co., Ltd., Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Astellas Pharma Inc., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Taiho Pharmaceutical Co. Ltd., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. H.Kajio: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. A.Enkaku: None. M.Kamigishi: None. A.Takikawa: None. M.Matsushita: None. M.Kobayashi: None. K.Yamamoto: None. T.Sato: None. Y.Yamamoto: None. Funding National Center for Global Health and Medicine (28A1204); Japan IDDM Network