Astellas Research Articles

The role of cardiac acoustic biomarkers in monitoring patients with heart failure: A systematic literature review.

Heart failure (HF) creates a considerable clinical, humanistic and economic burden on patients and caregivers as well as on healthcare systems. To attenuate the significant burden of HF, there is a need for enhanced management of patients with HF. The use of digital tools for remote non-invasive monitoring of heart parameters is gaining traction, and cardiac acoustic biomarkers (CABs) have been proposed as a complementary set of measures to assess heart function alongside traditional methods such as electrocardiogram and echocardiography. We conducted a systematic literature review to evaluate associations between CABs and HF outcomes. Embase and MEDLINE databases were searched for recent studies published between 2013 and 2023 that evaluated CABs in patients with HF. Additional grey literature (i.e., conference, congress and pre-print publications from January 2021 to May 2023) searches were included. Two reviewers independently examined all articles; a third resolved conflicts. Data were extracted from articles meeting inclusion criteria. Extracted studies underwent quality and bias assessments using the Joanna Briggs Institute (JBI) critical appraisal tools. In total, 3074 records were screened, 73 full-text articles were assessed for eligibility and 27 publications were included. Third heart sound (S3) and electromechanical activation time (EMAT) were the CABs most often reported in the literature for monitoring HF. Fifteen publications discussed changes in S3 characteristics and its role in HF detection or outcomes: six studies highlighted S3 assessment among various groups of patients with HF; four studies evaluated the strength or amplitude of S3 with clinical outcomes; five studies assessed the relationship between S3 presence and clinical outcomes; and one study assessed both S3 presence and amplitude in relation to HF clinical outcomes. Eleven publications reported on EMAT and its derivatives: five studies on the relationship between EMAT and HF and six studies on the association of EMAT and HF clinical outcomes. Studies reporting the first and fourth heart sound, left ventricular ejection time and systolic dysfunction index were limited. Published literature supported S3 and EMAT as robust CAB measures in HF that may have value in remote clinical monitoring and management of patients with HF. Additional studies designed to test the predictive power of these CABs, and others less well-characterized, are needed. This work was funded by Astellas Pharma Inc.

C5 inhibitor avacincaptad pegol treatment for geographic atrophy: A comprehensive review.

Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.

Zolbetuximab: First Approval.

Zolbetuximab (VYLOY™), a recombinant, chimeric, anti-claudin 18.2 (CLDN18.2) monoclonal antibody (mAb), is being developed by Astellas Pharma Inc. for the treatment of patients with HER2-negative (HER2-), CLDN18.2-positive (CLDN18.2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and CLDN18.2+ advanced pancreatic adenocarcinoma. In March 2024, zolbetuximab was approved in Japan for the treatment of patients with HER2-, CLDN18.2+ unresectable, advanced/recurrent gastric cancer (the gastric cancer indication includes GEJ cancer). Zolbetuximab is also undergoing regulatory review for HER2-, CLDN18.2+ advanced gastric or GEJ adenocarcinoma in the USA, the EU, China, Australia and several other countries. This article summarizes the milestones in the development of zolbetuximab leading to this first approval for the treatment of patients with CLDN18.2+ gastrointestinal malignancies.

Beta-3 Adrenergic Receptor Activation Increases Resting Energy Expenditure and Brown Adipose Tissue Activity in a Cool Environment

Purpose: Brown adipose tissue (BAT) is highly thermogenic and contributes to non-shivering thermogenesis. Acute mirabegron (MIRA) ingestion, ranging in doses from 50-200 mg, stimulates beta-3-adrenergic receptors in BAT. This increases resting energy expenditure (REE) and elevates supraclavicular skin temperature (Tsc, marker of BAT activation) in thermoneutral environments for up to 4 h. However, it is not known if the thermogenic effects of different MIRA doses are also observed during exposure to a cool environment. We tested the hypotheses that EE and markers of BAT activity during a 6 h cool environmental exposure would be greater following each dose of MIRA (100 mg, 150 mg and 200 mg) versus a placebo (PLA). Methods: 11 healthy adults (age: 22±2 y; BMI: 26±4 kg/m2; 5 women) completed four, double-blind, randomized study visits involving the acute ingestion of 100 mg, 150 mg, and 200 mg of MIRA (Myrbetriq; Astellas Pharma US) or PLA. 30 min following ingestion, subjects rested in a semi-recumbent position for 6 h in a whole-body indirect calorimeter (20°C, 50% RH). REE was calculated for each study visit. O2 consumption (VO2; ml/kg/min), CO2 production (VCO2; ml/kg/min), and respiratory exchange ratio (RER) were averaged over the last 10 min of each 30 min block. BAT activity was estimated using Tsc assessed via infrared thermography every 30 min and expressed relative to sternal skin temperature and as the area under the curve (AUC) for relative Tsc for each study visit. Mean skin temperature (Tsk; 12 sites), and rectal temperature (Tc) were measured every 30 min. Thermal comfort (1=comfortable, 4=very uncomfortable) and sensation (1=cold, 7=hot) were measured every 30 min. Values are reported as mean ± SD. Results: REE during the 6 h intervention was greater following ingestion of 100 mg (494±75 kcal; p < 0.001), 150 mg (481±67 kcal; p = 0.017), and 200 mg (492±69 kcal; p = 0.001) of MIRA vs. PLA (456±67 kcal). However, there were no differences in REE between doses ( p > 0.05 for all comparisons). There was a main effect of drug dose for VO2 ( p = 0.010), which was greater following ingestion of 100 mg (3.88±0.19 ml/kg/min; p = 0.007) and 150 mg (3.82±0.22 ml/kg/min; p = 0.046) of MIRA vs. PLA (3.59±0.11 ml/kg/min). There was a main effect of drug dose for VCO2 ( p = 0.019), which was greater following ingestion of 100 mg of MIRA vs. PLA (3.03±0.10 vs. 2.84±0.05 ml/kg/min; p = 0.004). There were no dose x time interactions or main effects of dose ( p = 0.421) for RER or BAT activity indexed via relative Tsc ( p > 0.237). However, the AUC for Tsc was greater following ingestion of 100 mg (12.54±7.51°C x min; p = 0.011), 150 mg (10.01±6.05°C x min; p = 0.021), and 200 mg (9.17±5.95°C x min; p = 0.028) of MIRA vs. PLA (4.74±3.86°C x min). There was a main effect of drug dose for Tsk ( p = 0.040) but there was no dose x time interaction ( p = 0.608) and there was no main effect of dose ( p = 0.155) for Tc. There was a main effect of dose for thermal sensation ( p = 0.040), which was greater following ingestion of 100 mg (2.9±0.3; p = 0.011) of MIRA vs. PLA (2.4±0.4). There was no dose x time interaction ( p = 0.528) or main effect of dose ( p = 0.080) for thermal comfort. Conclusions: Our data indicate that acute doses of MIRA (100 mg, 150 mg and 200 mg) elicit greater REE and BAT activity vs. PLA during a 6 h of exposure to a cool environment. However, REE and BAT activity was not different between the MIRA doses. This suggests that beta-3 adrenergic receptor activation in BAT appears to be a physiologically effective method to enhance thermogenesis in cool environments. Funded by: Offce of Naval Research N00014-21-1-2276. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

De-novo use of generic tacrolimus (Adoport) in renal transplant recipients: A single center experience from Türkiye

Objective: Renal transplantation is the best treatment for end-stage kidney disease, and tacrolimus has become an important immunosuppressive treatment for kidney transplant patients since it was introduced. After the first generic tacrolimus has been approved by the FDA, studies have begun to compare the effectiveness and safety of generic tacrolimus with the original tacrolimus. When using generic immunosuppressive therapies, it is also necessary to ensure that it provides adequate immunosuppression and does not cause severe toxicity. This study aims to compare clinical outcomes, including acute rejection, graft loss and adverse reactions, in patients receiving brand tacrolimus (Prograf, Astellas Pharma, U.S.) or generic tacrolimus (Adoport, Sandoz, UK) from the start of kidney transplant therapy. Study Design: Renal transplant recipients between 1 January 2015-1 March 2020 were screened retrospectively. All patients receiving de novo generic tacrolimus (n:51) and randomly selected 102 control renal transplant recipients receiving original tacrolimus were included in this study. Materials and Methods: We evaluated and recorded demographic, clinical and laboratory data including age, gender, primary kidney disease, donor type (live or dead), induction and death regimen, tacrolimus dose, tacrolimus through levels, serum creatinine, biopsy-confirmed acute rejection episodes, delayed transplant function, positive BK polyomavirus in the urine, BK polyomavirus-related nephropathy, cytomegalovirus infection in 1-year follow-up. Results: Most of the patients were male (64.1%) with a mean age of 38.3 years. There was no significant difference in demographic characteristics between the original and generic tacrolimus groups. No differences were found in terms of creatinine levels, total daily dose of tacrolimus and tacrolimus trough levels at discharge and the first year. Additionally, biopsy-confirmed acute rejection in the following year after transplantation, BKPyV positivity in urine, BKPyVAN, CMV viremia and adverse reactions related to tacrolimus were similar between the two groups. Conclusion: With this study, we aimed to contribute to the literature with our experience on the use of generic tacrolimus from our country. As a result of our study, we noted that generic tacrolimus can be safely preferred for de-novo use with close drug-level monitoring because it is an immunosuppressant agent with a narrow therapeutic index. There is a continuing need for randomized prospective-designed and multi-centric studies with a wide range of patients.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

BackgroundNo treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.MethodsWe conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin–pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival.ResultsA total of 886 patients underwent randomization: 442 to the enfortumab vedotin–pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin–pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin–pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin–pembrolizumab group and in 69.5% of those in the chemotherapy group.ConclusionsTreatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.)

Postoperative Intimal Hyperplasia: Review from My Research.

Postoperative intimal hyperplasia is the major cause of the vein graft occlusion. It is very important to establish an animal model for the start of research. After my vascular surgery residency in Japan, I started my research work on postoperative intimal hyperplasia at the University of Wisconsin-Madison. My research showed that endothelial injury and monocyte infiltration is the key for postoperative intimal hyperplasia, which is very similar to Ross' pathogenesis of atherosclerosis as an inflammatory disease. Focusing on postoperative intimal hyperplasia as an inflammatory disease, especially on tumor necrosis factor-α, FR-167653 (tumor necrosis factor-α suppressive agent, inhibitor of p 38 mitogen-activated protein kinase; Fujisawa Pharmaceutical Co., Ltd., Japan) is found to suppress postoperative intimal hyperplasia in a rat model by reducing serum monocyte chemoattractant protein-1 levels. However, FR-167653 is not commercially available today. Because endothelial injury is the first step of postoperative intimal hyperplasia, I investigated whether the free radical scavenger, edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan), which alleviates the endothelial injury in vitro , can also suppress postoperative intimal hyperplasia. Moreover, the free radical scavenger edaravone (Radicut®, Mitsubishi Tanabe Pharma Co.) is also found to suppress postoperative intimal hyperplasia, by alleviating endothelial injury. In clinical settings, it is very important to detect postoperative intimal hyperplasia before its establishment. Hepatocyte growth factor is not only a hepatic growth factor but also a vascular endothelial growth factor. Recently, serum hepatocyte growth factor level was found to be a candidate biomarker for postoperative intimal hyperplasia in our rat model.

Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study)

Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied. In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9ng/ml; Standard Care arm), or an initial 7-day fixed 5mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19. The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI-5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ. This is the first study to show that an initial fixed dose of 5mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation. Investigator-initiated trial, financial support by Astellas Pharma GmbH.

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.

Fms-like Tyrosine Kinase 3 Ligand Kinetic Profile Is the Strongest Factor Predicting Refractoriness after Induction and Event-Free Survival in Adults with AML: A Filo Prospective Multicentric Study

Background: Recently, a monocentric study has shown in adults with a non-previously treated acute myeloid leukemia (AML) that the stagnation of low levels of Fms-like tyrosine kinase 3 ligand concentration (FLc) in plasma, up to day 22 after an intensive induction, was associated with refractoriness and lower survivals (Peterlin et al, 2021). The present study wanted to confirm these results prospectively on a larger cohort of patients and in a multicentre way. Methods: This was a prospective non-interventional multicentre investigator sponsored trial (FLAMVAL study, clinicaltrials.gov: NCT04641910. One of the main objective was to study the impact on various outcomes of FL levels, evaluated during an intensive induction, in adults (&amp;gt;=18 year (y) old) with a non-previously treated non-M3 AML. Patients could receive a standard intensive induction chemotherapy combining anthracycline + cytarabine as part of a trial or not. Outcomes to be studied were responses, 1y overall survival (OS) and event-free survival (EFS), and 1-y leukemia-free survival (LFS) and relapse in responders. Response was evaluated according to ELN2017 criteria at day+30 after induction. Using a new cytokine multiplex assay from Milliplex (MILLIPLEX®), FL levels (expressed in pg/mL) were evaluated at Day (D) 1, D8, D15 and D22 from Day 1 of induction. Results: Between June 2021 and August 2022, 226 patients from 16 FILO centres were included but 204 with full evaluation of FL levels (816 samples) were considered for analyses. Their characteristics are reported in Table 1. At the time of analysis (July 2023), 1-y OS, EFS and LFS were 87+-5%, 78.3+-6% and 59.8+-8%, respectively. Median [Q1-Q3] FLc were 1.22 [0-4.19] at D1, 13.83 [2.26-72.46] at D8, 128.55 [13.06-293.43] at D15 and 24.14 [4.60-155.14] at D22. The number of refractory patients was significantly higher for those patients with a FLc &amp;lt; median at Day 8 (30.4% vs 13.7%, p=0.01), D15 (35.6% vs 8%, p&amp;lt;0.001) and D22 (31.1% vs 12.9%, p=0.007). 1-y OS and LFS were similar between patients with a FLc &amp;lt; or &amp;gt;= median at the four times considered. This was true also for 1y-EFS at D1 and D22. However, 1-y EFS was significantly worse for those with a FLc &amp;lt; median at D8 (48.5 % (41-55) vs 31 % (25-37), p=0.004) and at D15 (47.6 (40-55) vs 31% (25-37), p=0.002). As reported before (Peterlin et al, 2021), all patients but 4 (with a decrease of levels all along) can be categorized according to three FLc kinetic profiles: i) sustained increase from days 1 to 22 (FLI group n=39, 19% of the cohort), ii) increase from days 1 to 15, then decrease at day 22 (FLD group, n=86, 42% of the cohort) and iii) stagnation of low levels all along (&amp;lt;100 pg/mL from days 1 to 22, FLL group, n=75, 37% of the cohort). OS and LFS were similar between these three groups while 1-y EFS was significantly lower for the FLL group (45% [33; 57]) compared to FLI and FLD groups (64% [49; 79] and 71% [ 61; 80], p&amp;lt;0.001) ( Figure 1). This difference was due to a higher proportion of refractory patients in the FLL group (n=45/75 42.7% vs FLI =5/39, 12.8% vs FLD n=8/86, 9.3%, p&amp;lt;0.001, 2 patients not evaluated for response). Similar incidence of relapse was observed for responders comparing the three groups. Interestingly, only 8.8% (n=11/125) of the FLI/FLD patients had a FLc level &amp;lt;100 pg/ml at both times D8 and D15, suggesting that a FLL status can be predicted as soon as D15. For multivariate analyses, we compared FLc kinetic profiles (FLL vs FLI/FLD) on one hand and FLc medians (D1 D8 D15 and D22) on the other hand with other factors associated with a p value &amp;lt;0.20 by univariate analyses. In both models, only FLc kinetic profile and medians together with ELN2017 classification were found to be independent factors predicting response and EFS. However, FLL status was the strongest factor associated with refractoriness (OR: 6.2, 95%CI: 2.94-13.73, p&amp;lt;0.001, ELN favorable vs Intermediate p=0.003, favorable vs adverse p=0.002) and lower EFS (OR: 2.58, 95%CI: 1.40-4.79, p=0.002, ELN p=0.01 and 0.004). Conclusion: This large prospective multicentre trial confirms that a stagnation of low levels of FLc during a first-line induction in adults with non-M3 AML is the strongest factor (above ELN classification) associated with refractoriness and lower EFS in these patients. The study suggests also that this simple test could be useful to envisage salvage therapy including allotransplant just after D15 of induction. Funding This study was funded by Astellas Pharma Inc.

329. Vancomycin area under the concentration-time curve monitoring from Bayesian modeling in outpatient parenteral antimicrobial therapy

Abstract Background Current vancomycin monitoring guidelines recommend area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) monitoring for patients with serious MRSA infections. Most AUC monitoring studies have included hospitalized patients only; however, many patients complete vancomycin therapy in the outpatient setting. While traditional two-level AUC calculations are logistically challenging for outpatients, Bayesian modeling software can allow for single level AUC estimations. There are sparse data on the feasibility, safety, and efficacy of vancomycin AUC monitoring in OPAT. Methods We conducted a single-center, quasi-experimental, interrupted time series study of adult patients enrolled in the OPAT program at our institution for vancomycin management. Our institution implemented a pharmacist-driven vancomycin monitoring program using AUC targets from September 8th, 2019 to February 25th, 2020, and again from September 25th, 2022 to March 16th, 2023. Patients enrolled in the monitoring program underwent vancomycin monitoring using an AUC goal of 400-600 mg*hr/L, estimated using Bayesian modeling. A cohort comprising all patients enrolled in the OPAT program from July 4th, 2021 through August 27th, 2022 for trough only vancomycin monitoring was used for comparison. Patients were excluded from analysis if they were undergoing renal replacement therapy at baseline, enrolled in OPAT for ≤ 72 hours, or did not have vancomycin levels drawn for ≥ 14 days. The primary outcome was nephrotoxicity defined as a serum creatinine increase by ≥ 0.5 mg/dL or ≥ 50% during outpatient vancomycin therapy. Results There were 63 patients in the AUC arm, and 60 patients in the trough-only arm. The incidence of nephrotoxicity was lower in the AUC cohort (6.3% vs 23.3%, p=0.01). There was no difference in other vancomycin-related adverse event rates (1.6% vs 10.0%, p=0.06). Vancomycin discontinuation due to adverse event was lower in the AUC arm (6.3% vs 20.0%, p=0.03). Conclusion Patients undergoing AUC monitoring were significantly less likely to develop nephrotoxicity during outpatient vancomycin treatment. Bayesian modeling represents a viable and safe option for vancomycin AUC monitoring in OPAT. Disclosures David W. Kubiak, PharmD, BCPS, BCIDP, FIDSA, Astellas Pharma, Inc.: Advisor/Consultant|AVIR Pharma Inc: Advisor/Consultant|Cidara Therapeutics: Advisor/Consultant|Shionogi Inc: Grant/Research Support

2438. Positive Cerebrospinal Fluid Cultures from Intraventricular Reservoirs for CLN2 Patients: One Institution's Experience

Abstract Background Enzyme replacement therapy (ERT) with cerliponase alfa (Brineura) has been shown to slow progression of milestone deterioration in Neuronal Ceroid Lipofuscinosis Type 2 (CLN2), an inherited neurodegenerative lysosomal storage disorder. Brineura must be administered intraventricularly every 2 weeks, necessitating the placement of ventricular reservoirs and requiring frequent access. Traditionally, positive cerebrospinal fluid (CSF) cultures are managed with device replacement and antibiotic treatment. We sought to establish which circumstances might allow for careful observation without device removal. In this study, we report our single-institution experience with clinical outcomes of positive CSF cultures in 16 CLN2 patients over 6 years. Methods We retrospectively reviewed a cohort of 16 patients with CLN2 disease who had ventricular reservoirs placed for ERT administration. At each ERT infusion, CSF was collected by sterile technique and cultured by both thioglycolate broth and agar plate. Epidemiologic and microbiologic data, symptomatology, total antibiotic days, removal and replacement of ventricular reservoir, hospital length of stay, and mortality were analyzed for each patient. Results In our cohort, 11 of 16 patients (69%) had at least one positive CSF culture (Fig 1). Of the 11 with positive cultures, only 3 had their device removed and replaced for a positive culture with concurrent antibiotic treatment at our center, and 2 patients subsequently have been treated with prophylactic antibiotics at infusions (Fig 2). Out of 1401 total CSF cultures, 64 (4.56%) were positive. The most common organism grown was Cutibacterium acnes, which typically grew in only broth culture (82%), suggesting low bacterial burden (Fig 3). The other 7 patients with positive cultures remained asymptomatic with no intervention required. Conclusion At our institution, we have found that in asymptomatic patients with frequently accessed ventricular reservoirs, positive CSF culture with low virulence skin flora was common, and rarely required intervention. This strategy reduced the risks of invasive surgery, prolonged antibiotic courses, and missed infusions. In the future, routine screening cultures in asymptomatic patients can be avoided. Disclosures Raymond Wang, MD, Biomarin Pharmaceutical: Advisor/Consultant|Biomarin Pharmaceutical: Grant/Research Support|Biomarin Pharmaceutical: equity interest Antonio C. Arrieta, MD, FIDSA, FPIDS, Astellas Pharma Global Development, Inc.: Advisor/Consultant|Astellas Pharma Global Development, Inc.: Grant/Research Support|Astellas Pharma Global Development, Inc.: Honoraria|Cumberland Pharmaceutical: Grant/Research Support|IDbyDNA: Advisor/Consultant|IDbyDNA: Grant/Research Support|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Nabriva: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Pfizer, Inc: Advisor/Consultant|Pfizer, Inc: Grant/Research Support|Roche/Genentech: Grant/Research Support|The Medicine Company: Grant/Research Support

Beat AML S8 Group 2: Gilteritinib (GILT) in Combination with Decitabine (DEC) and Venetoclax (VEN) in Untreated FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Age ≥60 with High and Low Variant Allele Frequency (VAF)

Background: GILT is a potent oral selective FLT3 kinase inhibitor ( FLT3i) approved for the treatment of patients with relapsed/refractory FLT3 mutated ( FLT3m) AML. However, the optimal combination in older, newly diagnosed (ND) FLT3m AML patients is unknown. GILT in combination with azacitidine (AZA) had higher initial response rates, but did not improve overall survival (OS), compared to placebo in the LACEWING trial (Wang et al. Blood 2021). GILT followed by decitabine (DEC) was also tested and found to be safe, but the efficacy did not meet pre-determined criteria (NCT03013998, S8 Group 1). In the interim, VEN + AZA/DEC emerged as the new standard of care for older/unfit patients with AML (DiNardo et al. NEJM 2020). Thus, the Beat AML S8 study was amended to assess the safety and efficacy of GILT in combination with DEC and VEN in newly diagnosed FLT3m AML patients aged ≥60 years (NCT03013998, S8 Group 2). Methods: The S8 Group 2 sub-study was part of the multicenter (15 sites) Beat AML Master Trial. Key eligibility criteria included ND FLT3m AML patients aged ≥60 years who are not able to receive intensive induction chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. A conventional 3+3 design was used to determine the recommended phase 2 dose (RP2D) of GILT+DEC+VEN. Patients were treated with GILT at three dose levels (DL). During induction, treatment consisted of GILT 120mg/day on days 1-7 then 80mg/day on days 8-28 for dose level 1 (DL1), or on days 8-21 (DL-1), or on days 8-14 (DL-2). All patients received DEC at 20mg/m 2 on days 8-12, and VEN at 400mg/day (or at 100mg/day if concomitant antifungal) on days 8-28. Patients who achieved a complete remission (CR) or CR with hematologic improvement (CRh) received GILT 80mg/day on days 1-15 (DL1) or days 1-7 (DL-1, DL-2), DEC on days 1-5 (All DLs), and VEN on days 1-15 (DL1, DL-1) or days 1-10 (DL-2) for an additional 12 consolidation cycles. The primary end point was to determine the tolerability and toxicity of GILT in combination with DEC and VEN. Secondary end point was the composite CR (CRc: CR/CRh) rate. Response was assessed using modified 2017 European LeukemiaNet (ELN) AML criteria. Results: Between 10/22/2020 and 6/13/2022, 19 patients were consented, of whom 18 started treatment and were included in the analysis. The median age was 73 and baseline patient characteristics are shown in Table 1. The first 2 patients treated at DL1 both experienced hematologic dose-limiting toxicities (DLTs) with persistently low absolute neutrophil count (ANC). Therefore, the GILT dose was de-escalated to DL-1, where 8 patients were enrolled and treated. Among the 6 evaluable patients on DL-1, DLTs occurred in 2 patients; one had hematologic DLT and the other had failure to thrive. This led to dose de-escalation to DL-2. In DL-2, 2/8 patients experienced hematologic DLTs. The protocol was then amended to include DL-3 and DL-4, but the trial was closed by the sponsor due to priority transition and enrollment was halted so further dose reductions were not evaluated. Adverse events (AEs) were mostly hematologic, and 11 patients had treatment-related adverse events (TAEs), 10 of them grade 3 or higher. Median (range) time on treatment was 6 (1-25) cycles. Most common reason for treatment discontinuation were adverse event (3, 21.4%), recurrence (2, 14.3%), stem cell transplant (2, 14.3%), and death (2, 14.3%) Nine patients achieved CR, 2 patients achieved CRh and 1 patient achieved complete remission with incomplete hematologic recovery (CRi). The CRc rate (CR/CRh) was 61.1% (11/18, 95% CI: 38.6%-83.6%). After a median follow up of 19.7 months, the median overall survival and duration of response were not reached. One-year overall survival (OS) was 71.8% (95% CI: 44.9-87.2). Conclusion: Triplet therapy of GILT+DEC+VEN inND FLT3m AML patients ≥60 years old induced a high response rate (CRc rate 61.1%), and the median OS was not reached at time of this report (median follow-up 19.7 months). The typical dose of GILT 120mg/day with DEC+VEN was associated with significant hematology toxicities, which required multiple dose level reductions. At the reduced dose (GILT 80mg/day on days 1-7), the combination therapy was generally safe and well tolerated. A Phase 2 clinical trial sponsored by Astellas of GILT+AZA+VEN as frontline treatment for ND older patients with FLT3m AML is now enrolling (NCT05520567). Funding: this study was funded by Astellas Pharma Inc.

Optimizing the Integration of Genetic Testing in AML Care in Community Practice: Insights from a Quality Improvement Initiative

Background The treatment landscape for acute myeloid leukemia (AML) is rapidly evolving, and with many of the more recently FDA approved treatments being targeted therapies, timely and actionable molecular and cytogenetic testing is critical to the management of AML patients. However, many challenges and barriers to optimal testing workflows impede clinicians' ability to integrate genetic testing in treatment decision-making. To improve quality care related to genetic testing in AML, we conducted a quality improvement (QI) study focused on evidence-based integration of genetic testing into routine practice for AML patients in community oncology clinics. Methods This QI initiative is comprised of baseline (N = 72) and follow-up provider surveys, and pre- and post-surveys of providers participating in small-group, team-based audit-feedback (AF) sessions across 5 community clinics. Survey questions were designed to assess knowledge, confidence, and experiences with genetic testing in AML. Care teams from each clinic, along with an expert AML oncologist and a hematopathologist, participated in AF sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Results Provider Surveys: Providers top reported challenges encountered with integrating genetic testing into routine practice include determining whether to begin treatment prior to receipt of genetic testing result (56%)and applying genetic testing results to treatment decision-making (29%). For patients with AML, 70% of providers stated they were likely to start treatment prior to receiving testing results. When asked to report routine molecular testing practice patterns, 72% of providers reported testing for FLT3 mutations, 62% for IDH1/2 mutations, 65% for TP53 mutations, and 63% for NPM1 mutations; with further suboptimal reported practices in the use of NGS panels (58%; average turnaround time 15 days) and PCR (52%; average turnaround time 8 days). Overall, providers reported a 56% satisfaction rate with the processes implemented in the clinic related to sample preparation, timely review, and turnaround time of molecular diagnostics testing reports. AF Sessions: Providers participating in the AF sessions also reported determining whether to begin treatment prior to receipt of molecular testing results, long turnaround times and deciding on the appropriate molecular tests as top barriers to integrating testing in routine AML care. Clinicians reported improvements in high/very high confidence in their ability to select appropriate genetic tests to order for patients with AML (35% to 50%) and select targeted therapies based on genetic test results for AML patients (34% to 59%). Care teams set goals to improve turnaround times and testing workflows with pathology partners, as well as to maximize opportunities for patients to receive AML therapies for their specific mutation profile. Action plans to achieve these goals include improve team skills in choosing guideline-based genetic testing methods and targeted therapies and collaborate among clinical teams to improve ordering workflow and diagnostic sample preparation for genetic testing. Follow-Up Surveys: In 90-day follow up surveys, 100% of clinic champions reported upshifts in patients with targetable driver mutations receiving guideline-recommended treatment based on genetic testing results, and 4/5 clinics reported improved selection of guideline-recommended genetic testing prior to treatment initiation for AML patients. Conclusions Through this QI initiative, clinical teams identified barriers to integrating genetic testing into routine AML care, creating and implementing action plans to optimize genetic testing workflows and guideline-recommended targeted therapy selection. While meaningful confidence and action plan gains were demonstrated, these data underscore clinical practice gaps to address in future initiatives to support the integration of evidence-based genetic testing into AML care, including integrated education sessions with clinicians and pathologists. Study Sponsor Statement The study reported in this abstract was funded by independent educational grants from AbbVie, Inc. and Astellas Pharma Global Development, Inc., who had no role in the study design, execution, analysis, or reporting.

A Phase 1b Multi-Center Study of the FLT3 Inhibitor Gilteritinib in Combination with the IDH1 Inhibitor Ivosidenib or the IDH2 Inhibitor Enasidenib for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring FLT3/IDH1 or FLT3/IDH2 Mutations

Background: Mutations in isocitrate dehydrogenase isoenzymes 1 and 2 (IDH1 and IDH2) occur in 15- 25% of patients with acute myeloid leukemia. Enasidenib and ivosidenib, inhibitors of mutant IDH2 and IDH1 respectively, decrease intracellular levels of 2-HG, restore myeloid maturation, and lead to complete or partial remissions in approximately 40% of patients with IDH-mutant AML. While this response rate is remarkable in a relapsed and refractory AML population, nearly 60% of patients fail to respond. Approximately 30% of patients with IDH1/2 mutations have co-occurring mutations in the FMS like tyrosine kinase 3 (FLT3). Correlative science suggests that the acquisition of FLT3 mutations (either an internal tandem duplication (ITD) or tyrosine kinase domain (TKD)) is a common mechanism of resistance to IDH inhibitor monotherapy. Gilteritinib is a FLT3 inhibitor that targets the ITD and TKD mutations. This clinical trial (NCT05756777) will evaluate the safety and efficacy of concurrent IDH and FLT3 inhibition, while determining the maximum tolerated dose (MTD) for each of the combinations. Methods: NCT05756777 is a multi-center, open-label, experimental, interventional study evaluating the safety, tolerability, and preliminary efficacy of the combination of gilteritinib + ivosidenib (Cohort 1 - IDH1/FLT3 co-mutation) and gilteritinib + enasidenib (Cohort 2 - IDH2/FLT3 co-mutation) in patients with relapsed/refractory (R/R) acute myeloid leukemia with co-occurring FLT3 (ITD or TKD) and IDH1 or IDH2 mutations. Treatment with gilteritinib + ivosidenib will be administered for patients with IDH1/FLT3 co-mutations and gilteritinib + enasidenib will be administered for patients with IDH2/FLT3 co-mutations. Patients in both cohorts will dose daily throughout the 28-day cycle and without pause between cycles. The study will enroll 36 patients with relapsed/refractory AML with co-occurring FLT3 (ITD or TKD) and IDH1 or IDH2 mutations. The dose escalation schema will use the Bayesian Optimal Interval (BOIN) design. This study is open for accrual at Memorial Sloan Kettering Cancer Center. The study population will include patients with AML with dual FLT3 and IDH1/IDH2 mutations R/R to initial intensive induction therapy, or for patients treated with low intensity therapy, the patient must be refractory to treatment with a single agent hypomethylating agent (HMA) or low dose cytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination with venetoclax (at least one cycle) or another standard of care therapy (e.g. gemtuzumab ozogamicin, glasdegib/LDAC). Patients with a history of autologous or allogeneic stem cell transplant for AML are permitted to participate in the study. This study is partially supported by Astellas Pharma Global Development, Inc. Clinical trial information: https://classic.clinicaltrials.gov/ct2/show/NCT05756777

Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer

BackgroundEMBARK, a controlled trial reported elsewhere, showed enzalutamide plus leuprolide (combination) and enzalutamide monotherapy prolonged metastasis-free survival versus placebo plus leuprolide (alone) in patients with high-risk biochemically recurrent prostate cancer. Health-related quality of life was also analyzed but not reported.MethodsIn EMBARK, patients with biochemical recurrence (prostate-specific antigen doubling time of ≤9 months) were randomly assigned (1:1:1) to combination (n=355), leuprolide-alone (n=358), or enzalutamide monotherapy (n=355). In this article we provide the patient-reported outcomes (PROs) from EMBARK at baseline and every 12 weeks until metastasis or death. The key end point was time to first and confirmed clinically meaningful deterioration (TTFD/TTCD) in pain and health-related quality of life using four PRO measures and predefined thresholds.ResultsAt baseline, all groups had high health-related quality of life. For worst pain, the median TTFD was 19.35 months with leuprolide alone, 13.93 months with combination (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.30) and 16.59 months with monotherapy (hazard ratio, 1.09; 95% CI, 0.90 to 1.31). The median TTCD was 66.27 months with leuprolide alone, 80.00 months with combination (hazard ratio, 0.82; 95% CI, 0.65 to 1.04), and 60.91 months with monotherapy (hazard ratio, 1.02; 95% CI, 0.82 to 1.28). For Functional Assessment of Cancer Therapy–Prostate total score, the median TTFD was 11.10 months with leuprolide alone, 8.31 months with combination (hazard ratio, 1.14; 95% CI, 0.95 to 1.36), and 8.38 months with monotherapy (hazard ratio, 1.17; 95% CI, 0.98 to 1.39). The median TTCD was 36.53 months with leuprolide alone, 38.77 months with combination (hazard ratio, 1.04; 95% CI, 0.85 to 1.28), and 30.55 months with monotherapy (hazard ratio, 1.16; 95% CI, 0.95 to 1.41).ConclusionsThe PROs from EMBARK show that both enzalutamide combination and monotherapy versus leuprolide alone, with oncologic benefits noted above, preserved high health-related quality of life in patients with high-risk biochemical recurrence of prostate cancer. (Funded by Pfizer and Astellas Pharma; ClinicalTrials.gov number, NCT02319837.)

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer

BackgroundPatients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.MethodsIn this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety.ResultsA total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P=0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.ConclusionsIn patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.)

Safety and efficacy of peficitinib in Asian patients with rheumatoid arthritis who had an inadequate response or intolerance to methotrexate: results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study

The efficacy and safety of the oral Janus kinase inhibitor peficitinib were investigated in Asian patients with rheumatoid arthritis (RA). In this double-blind, phase 3 study, patients from mainland China, Korea, and Taiwan with RA and an inadequate response/intolerance to methotrexate were randomized (1:1:1) to once-daily placebo (N=128), peficitinib 100mg(N=129), or 150mg(N=128) in combination with non-biologic DMARDs. At Week 24, patients receiving placebo switched to peficitinib 100mg or 150mg. American College of Rheumatology (ACR) 20 response at Week 24/early termination (ET) was the primary endpoint. Adverse events (AEs) were assessed. The study was registered at ClinicalTrials (NCT03660059). 385 patients were included in the analysis. ACR20 responses were statistically significantly higher in both peficitinib 100mg (56.6%) and 150mg (56.3%) groups versus placebo (24.2%); Odds Ratio (95% confidence interval, CI) 4.14 (2.42, 7.08) and 4.07 (2.38, 6.96), respectively (both P<0.001) at Week 24/ET. The incidence rate of herpes zoster related disease (herpes zoster and varicella) was higher in patients who received peficitinib versus placebo, but no dose dependency was observed (incidence rate/100 patient-years (95% CI): peficitinib 6.7 (4.32, 10.37); placebo 3.7 (0.93, 14.88). In Asian patients with RA and an inadequate response/intolerance to methotrexate, peficitinib 100mg and 150mg demonstrated superiority to placebo in the reduction of RA symptoms and was well tolerated. No additional benefit was observed with use of the higher peficitinib dose in this study population of predominantly Chinese patients. Astellas Pharma.

FRI420 Prevalence Of Ovarian Hormone Suppression Is High Among Regularly Cycling Reproductive-aged Women With Overweight Or Obesity

Abstract Disclosure: A. Caldwell: None. A.J. Polotsky: None. A.P. Bradford: None. H. Smyth: None. K. Kuhn: None. J. Siegart: None. N.F. Santoro: Advisory Board Member; Self; Astellas Pharma, Menogenix Inc., Que Oncology, Project Ember/Amazon. Grant Recipient; Self; Menogenix Inc. Other; Self; Ansh Labs Scientific Consultant. V.A. Catenacci: None. Endo Abstract Background: The prevalence of ovarian hormone suppression in regularly cycling, pre-menopausal women with overweight or obesity (termed relative hypogonadotropic hypogonadism of obesity) is not fully appreciated, as there are no overt symptoms aside from subfertility in women trying to conceive. In addition to impacting fertility, ovarian hormones play an important role in energy homeostasis and fat distribution. Other states characterized by ovarian hormone suppression (polycystic ovarian syndrome, PCOS and menopause) are associated with increased cardiometabolic disease risk. It is therefore critical to have a better understanding of the prevalence of ovarian hormone suppression in women with overweight or obesity. Methods: We compared cycle length and ovarian hormones in pre-menopausal women (age 18-40) who had regular menstrual cycles, no history of PCOS or diabetes, and were not using hormonal birth control (currently or in the past 3 months) and were either with overweight or obesity (OW/O, BMI 27-40 kg/m2, n=23) or healthy weight (HW, BMI 18-25kg/m2, n=15). Both groups provided daily, first-morning voided urine samples over a complete menstrual cycle. Progesterone and estrogen metabolites were assayed (pregnanediol-3-glucuronide [Pdg], estrone-1 conjugates [E1c]; Centaur CP; Siemens) and adjusted for creatinine. Hormones were assessed using whole cycle area under the curve (AUC) measurement. Ovarian hormone suppression was defined a priori as Pdg AUC &amp;lt; 25th percentile of the HW control group. T-tests and Spearman correlations were used to compare groups and examine associations between hormones and BMI. Mean±SD are presented. Results: Cycle length was not different between groups, but BMI (OW/O: 34.3±5.3, HW: 21.6±1.3 kg/m2) and age (OW/O: 34.6±5.3, HW: 29.2±4.2 years) were (p &amp;lt; 0.01), thus all analyses controlled for age. Pdg was significantly lower (p&amp;lt;0.01) in OW/O (AUC = 21.29±13.98 ug/mg Cr) relative to HW (AUC = 39.13±22.20 ug/mg Cr) and the majority (82.6%) of the OW/O women exhibited ovarian hormone suppression. E1c was also significantly lower (p&amp;lt;.0001) in the OW/O (AUC = 384.8±211.4 ng/mg Cr) group relative to HW (AUC = 1740.00±627.20 ng/mg Cr). Across the full sample, there were negative correlations between BMI and Pdg AUC (rpartial = -0.34, p = .03) and BMI and E1c AUC (rpartial = -0.61, p &amp;lt; .0001). Conclusion: Ovarian hormone suppression was observed in a majority of our sample of pre-menopausal women with overweight or obesity. Despite the difficulty of identifying this phenotype clinically, it may have important implications for weight management and cardiometabolic disease risk, in addition to fertility, and warrants further investigation to improve women’s health during the reproductive lifespan and beyond. Presentation: Friday, June 16, 2023

Fezolinetant: First Approval.

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signalling in the central nervous system is a non-hormonal strategy to modulate the activity of neurones that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause. This article summarizes the milestones in the development of fezolinetant leading to this first approval in this indication.