Bayer AG Research Articles

Hypokalaemia in patients with type 2 diabetes and chronic kidney disease: the effect of finerenone - a FIDELITY analysis.

Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo. Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium<4.0 or<3.5mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups. In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium<4.0 and<3.5mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium<4.0vs. 4.0-4.5mmol/L (hazard ratio [HR] 1.16; 95% confidence interval [CI] 1.02-1.32, P=0.022 and HR 1.20; 95% CI 1.00-1.44, P=0.055, respectively). Finerenone reduced the incidence of hypokalaemia with serum potassium<4.0mmol/L (HR 0.63; 95% CI 0.60-0.66) and<3.5mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium. A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

Best of both worlds: An expansion of the state of the art pKa model with data from three industrial partners.

In a unique collaboration between Simulations Plus and several industrial partners, we were able to develop a new version 11.0 of the previously published in silico pKa model, S+pKa, with considerably improved prediction accuracy. The model's training set was vastly expanded by large amounts of experimental data obtained from F. Hoffmann-La Roche AG, Genentech Inc., and the Crop Science division of Bayer AG. The previous v7.0 of S+pKa was trained on data from public sources and the Pharmaceutical division of Bayer AG. The model has shown dramatic improvements in predictive accuracy when externally validated on three new contributor compound sets. Less expected was v11.0's improvement in prediction on new compounds developed at Bayer Pharma after v7.0 was released (2013-2023), even without contributing additional data to v11.0. We illustrate chemical space coverage by chemistries encountered in the five domains, public and industrial, outline model construction, and discuss factors contributing to model's success.

EFFICACY AND SAFETY OF THE PROPOSED BIOSIMILAR AFLIBERCEPT, SDZ-AFL, IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: 52-Week Results From the Phase 3 Mylight Study.

The Phase 3 Mylight study was designed to confirm clinical equivalence of proposed biosimilar aflibercept (SOK583A1; Sandoz [proposed biosimilar aflibercept, SDZ-AFL]) to its reference biologic (Eylea; Regeneron Pharmaceuticals, Inc; Bayer AG [reference aflibercept, Ref-AFL]). Mylight was a prospective, double-masked, 2-arm, parallel Phase 3 study. Participants with neovascular age-related macular degeneration were randomized 1:1 to receive eight injections of SDZ-AFL (n = 244) or Ref-AFL (n = 240) over 48 weeks. The primary endpoint was mean change in best-corrected visual acuity score from baseline to Week 8. Secondary endpoints included anatomical outcomes, best-corrected visual acuity at Weeks 24 and 52, safety, and pharmacokinetics. Similarity in mean change in best-corrected visual acuity score was established between SDZ-AFL (n = 235) and Ref-AFL (n = 226) at Week 8 (difference: -0.3 [90% CI, -1.5 to 1.0]) and Week 52. No clinically meaningful differences occurred between groups in anatomical outcomes. Safety profiles were similar, with comparable incidences of treatment-related adverse events (SDZ-AFL: 2.5%; Ref-AFL: 2.9%). The incidence of anti-drug antibodies was similar between groups. Systemic free aflibercept concentrations 24 hours postdose were low and comparable between SDZ-AFL and Ref-AFL. Proposed biosimilar aflibercept matched reference aflibercept in efficacy, safety, and pharmacokinetics in participants with neovascular age-related macular degeneration. Therefore, this Phase 3 study confirmed biosimilarity of SDZ-AFL to Ref-AFL.

Application of &lt;i&gt;in vitro&lt;/i&gt; studies to predict the pharmacokinetics of rivaroxaban tablets

Introduction. The most important stage of pharmaceutical development of a generic drug is a clinical trial involving humans – a bioequivalence study. Considering the importance of finding rivaroxaban drugs in the list of vital and essential drugs, as part of ensuring technological sovereignty, the use of scientific robust and effective methods for determining the quality of the dosage form is required.Aim. Conduct a study of rivaroxaban tablets on a physiologically relevant tester to predict pharmacokinetic profiles.Materials and methods. The objects of the study are "Xarelto®, film-coated tablets, 10 mg" (series BXJS871, with an expiration date of October 31, 2024, Bayer AG, Germany), "Xarelto®, film-coated tablets, 20 mg" (series BXKDF32, with an expiration date of May 17, 2026, Bayer AG, Germany) and "Rivaroxaban, film-coated tablets, 10 mg" and "Rivaroxaban, film-coated tablets, 20 mg", domestically produced, with valid expiration dates. During the study, reagents were used to prepare dissolution media and perform quantitative determination. The physiologically relevant test was performed on the SC PRT-6 device (LLC "Scientific Compliance", Russia). The quantitative content of released rivaroxaban within the comparative dissolution kinetics test in a medium of 0.1 in a medium of 0.1 % sodium lauryl sulfate solution in a phosphate buffer solution pH 6.5 was carried out on a SF-2000 spectrophotometer (LLC "OKB Spektr", Russia). The quantitative content of released rivaroxaban within the comparative dissolution kinetics test in biorelevant dissolution media and physiological relevance test was assessed on a high-performance liquid chromatograph "Chromatec-Crystal HPLC 2014" (CJSC "Chromatec", Russia). Pharmacokinetic profiles were modeled in the PK-Sim® (Systems Biology Software Suite 11.2, Bayer Technology Services GmbH, Germany) program based on the data obtained within the physiologically relevant test. The clinical study of rivaroxaban tablets was a prospective, open-label, randomized, crossover, two-stage comparative study in two groups of volunteers with a single dose of drugs on the fast condition. The study randomized 30 healthy male volunteers aged 18–45 years.Results and discussion. A complex of in vitro tests was conducted, profiles were obtained that allow us to evaluate the dynamics and degree of release of the studied drugs in various parts of the human gastrointestinal tract. A comparison of the sequential and hybrid schemes for conducting the physiological relevance test was carried out. Within the framework of the set of tests, qualitative and quantitative correlation with the clinical trials data was observed only for the hybrid physiological relevance test scheme. Based on the results of physiological relevance test using different schemes, pharmacokinetic profiles for a pair of drugs were predicted and the prediction error was assessed.Conclusion. A set of scientific in vitro tests was conducted for the drugs "Xarelto®, film-coated tablets, 10 mg and 20 mg", "Rivaroxaban, film-coated tablets, 10 mg and 20 mg". Based on the physiological relevance test results, pharmacokinetic profiles for a pair of drugs were predicted with low error and high reliability. As part of the comparison of data obtained during clinical trial and modeling, the smallest prediction error was noted when performing physiological relevance test using a hybrid scheme.

Approaches to conducting a physiologically relevant test (PRT) in the study of medicines containing substance IIc of the BCS subclass using sorafenib as an example

Introduction. Sorafenib is an antineoplastic drug belonging to class IIc according to the biopharmaceutical classification system (BCS) due to the presence of both acidic and basic properties. In addition to low solubility, sorafenib is characterized by high variability during clinical trials, in particular bioequivalence studies (BE). To selecting batches that can be recommended for BE studies, the dissolution kinetics test is currently widely used, however, the results of this test are not always sufficient and additional tests, for example, a physiologically relevant test, are advisable. To minimize the risks of obtaining nonequivalent results during the BE study, a physiologically relevant test (PRT) was carried out with further data processing and interpretation of the results of physiologically based pharmacokinetic modeling (PBPK).Aim. The aim of the study is to conduct a physiologically relevant test (PRT) for the purpose of selecting a candidate batch for subsequent BE study of sorafenib drugs using the physiologically based pharmacokinetic model (PBPK).Materials and methods. The objects of the study are Nexavar®, film-coated tablets, 200 mg (Bayer AG, Germany) (one batch) and Sorafenib, film-coated tablets, 200 mg (two batches) (Russia). The physiologically relevant test was performed on the SC PRT-6 device (LLC "Scientific Compliance", Russia). Quantitative analysis was performed by HPLC-UV on the Chromatec-Crystal HPLC 2014 device (CJSC "Chromatec", Russia). The plasma concentration profiles were simulated using PK-Sim® software (Systems Biology Software Suite 11.2, Bayer Technology Services GmbH, Germany).Results and discussion. As part of the study, a method for the quantitative determination of sorafenib was developed and validated, a method for sample preparation was developed, and a method for conducting the PRT for sorafenib, as a representative of the IIc subclass of BCS, was developed. Based on the study results, release profiles were obtained that were used to select a candidate series for the BE study. The series were selected based on the PBPK analysis on a virtual population consisting of 36 healthy volunteers with activated enteropathic circulation, characteristic of sorafenib.Conclusion. The PRT was carried out for the drug sorafenib. Quantitative determination was carried out by HPLC-UV according to the developed and validated method. The test resulted in obtaining data that were subjected to PBPK analysis. It was shown that the studied batches have high risks of non-equivalence during the bioequivalence study.

The Alliance Between the German Cancer Research Center and Bayer: A Retrospective of an Innovative Collaboration Model.

In 2009, the German Cancer Research Center (DKFZ) and the biopharmaceutical company Bayer AG initiated an academic-industry co-discovery collaboration. The partners combined their expertise in tumor biology and drug discovery to identify and validate novel targets for cancer treatment. In the early phase of the Alliance, the focus was on target identification and validation projects. Over time, both partners realized that they could also successfully collaborate on later stages of drug discovery. As a result over the past few years, and following several contract extensions, the two partners have collaborated on several late-stage drug discovery projects. This has resulted in the achievement of several drug discovery milestones and the initiation of early clinical trials, the most recent in 2022. This success has been possible thanks to both partners' understanding of each other's needs and challenges. They jointly developed solutions to issues such as the intrinsic potential conflict of early publishing versus patent protection. Both partners also appreciated the risks involved in some of the experiments, such as starting a joint laboratory for immune-therapy with scientists from both parties working bench-to-bench. Recently, despite these successes the partners decided to terminate the Alliance, as Bayer AG wants to focus its activities on the development of its late pipeline.

Development and validation of a mortality risk prediction model for chronic obstructive pulmonary disease: a cross-sectional study using probabilistic graphical modelling

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality. Predicting mortality risk in patients with COPD can be important for disease management strategies. Although all-cause mortality predictors have been developed previously, limited research exists on factors directly affecting COPD-specific mortality. In a retrospective study, we used probabilistic graphs to analyse clinical cross-sectional data (COPDGene cohort), including demographics, spirometry, quantitative chest imaging, and symptom features, as well as gene expression data. COPDGene recruited current and former smokers, aged 45-80 years with >10 pack-years smoking history, from across the USA (Phase 1, 11/2007-4/2011) and invited them for a follow-up visit (Phase 2, 7/2013-7/2017). ECLIPSE cohort recruited current and former smokers (COPD patients and controls from USA and Europe), aged 45-80 with smoking history >10 pack-years (12/2005-11/2007). We applied graphical models on multi-modal data COPDGene Phase 1 participants to identify factors directly affecting all-cause and COPD-specific mortality (primary outcomes); and on Phase 2 follow-up cohort to identify additional molecular and social factors affecting mortality. We used penalized Cox regression with features selected by the causal graph to build VAPORED, a mortality risk prediction model. VAPORED was compared to existing scores (BODE: BMI, airflow obstruction, dyspnoea, exercise capacity; ADO: age, dyspnoea, airflow obstruction) on the ability to rank individuals by mortality risk, using four evaluation metrics (concordance, concordance probability estimate (CPE), cumulative/dynamic (C/D) area under the receiver operating characteristic curve (AUC), and integrated C/D AUC). The results were validated in ECLIPSE. Graphical models, applied on the COPDGene Phase 1 samples (n=8610), identified 11 and 7 variables directly linked to all-cause and COPD-specific mortality, respectively. Although many appear in both models, non-lung comorbidities appear only in the all-cause model, while forced vital capacity (FVC %predicted) appears in COPD-specific mortality model only. Additionally, the graph model of Phase 2 data (n=3182) identified internet access, CD4 T cells and platelets to be linked to lower mortality risk. Furthermore, using the 7 variables linked to COPD-specific mortality (forced expiratory volume in 1s/forced vital capacity (FEV1/FVC) ration, FVC %predicted, age, history of pneumonia, oxygen saturation, 6-min walk distance, dyspnoea) we developed VAPORED mortality risk score, which we validated on the ECLIPSE cohort (3-yr all-cause mortality data, n=2312). VAPORED performed significantly better than ADO, BODE, and updated BODE indices in predicting all-cause mortality in ECLIPSE in terms of concordance (VAPORED [0.719] vs ADO [0.693; FDR p-value 0.014], BODE [0.695; FDR p-value 0.020], and updated BODE [0.694; FDR p-value 0.021]); CPE (VAPORED [0.714] vs ADO [0.673; FDR p-value <0.0001], BODE [0.662; FDR p-value <0.0001], and updated BODE [0.646; FDR p-value <0.0001]); 3-year C/D AUC (VAPORED [0.728] vs ADO [0.702; FDR p-value 0.017], BODE [0.704; FDR p-value 0.021], and updated BODE [0.703; FDR p-value 0.024]); integrated C/D AUC (VAPORED [0.723] vs ADO [0.698; FDR p-value 0.047], BODE [0.695; FDR p-value 0.024], and updated BODE [0.690; FDR p-value 0.021]). Finally, we developed a web tool to help clinicians calculate VAPORED mortality risk and compare it to ADO and BODE predictions. Our work is an important step towards improving our identification of high-risk patients and generating hypotheses of potential biological mechanisms and social factors driving mortality in patients with COPD at the population level. The main limitation of our study is the fact that the analysed datasets consist of older people with extensive smoking history and limited racial diversity. Thus, the results are relevant to high-risk individuals or those diagnosed with COPD and the VAPORED score is validated for them. This research was supported by NIH [NHLBI, NLM]. The COPDGene study is supported by the COPD Foundation, through grants from AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion.

Pharmacodynamic Comparison of Two Aspirin Formulations in the Caribbean: The ARC Study.

This prospective, single-arm, crossover pharmacodynamic study assessed the effect of Bayer® low-dose enteric-coated aspirin 81mg tablets (LD EC-ASA) (Bayer AG, Leverkusen, North Rhine-Westphalia, Germany) compared to Vazalore® low-dose phospholipid-aspirin liquid-filled 81mg capsules (LD PL-ASA) (PLx Pharma Inc., Sparta, NJ, USA) on platelet reactivity with respect to aspirin reaction units (ARU). Forty-seven healthy volunteers were recruited. Platelet function was evaluated with the VerifyNow™ ARU assay (Werfen, Bedford, MA, USA) and assessed post-initiation of Bayer® LD EC-ASA daily for 14days, with a washout period of 28days, followed by Vazalore® LD PL-ASA daily for 14days, again followed by ARU testing. Participants on LD EC-ASA had a mean ARU score of 426, with 19.1% of participants having an ARU > 550; patients on LD PL-ASA derived a mean ARU score of 435, with 14.9% achieving an ARU > 550. There were no significant differences in aspirin resistance (ARU > 550) according to the formulation (Bayer® LD EC-ASA vs. Vazalore® LD PL-ASA) used. Aspirin resistance was independent of ethnicity regardless of the formulation used. In addition, there were no significant associations between body surface area (BSA) and Bayer® LD EC-ASA ARU value (p value 0.788) or Vazalore® LD PL-ASA ARU value (p value 0.477). No patients experienced any serious adverse events or treatment-emergent adverse events. There were no significant differences in aspirin resistance between Bayer® LD EC-ASA and Vazalore® LD PL-ASA. This dedicated pharmacodynamic study could potentially be informative and applicable for Trinidadian patients on dual antiplatelet therapy (DAPT). Further studies are required to confirm these exploratory findings. ClinicalTrials.gov identifier, NCT06228820, prospectively registered 1/18/2024.

Intellectual landscapes and emerging trends of non-steroidal mineralocorticoid receptor antagonists: a bibliometric and visual analysis.

With increasing studies, non-steroidal mineralocorticoid receptor (MR) antagonists have been increasingly recognized as a major novel dimension in cardiorenal disease therapy. This bibliometric analysis aimed to uncover current research status and identify future research directions in the study of non-steroidal MR antagonists to inform subsequent investigations. Relevant English-language literature was retrieved from the Science Citation Index Expanded of the Web of Science Core Collection on January 10, 2024. Analyses of countries, institutions, authors, journals, documents, cited references and keywords were performed by the CiteSpace and VOSviewer software. Overall, 498 documents, including 297 articles and 201 reviews, were included and analyzed. The United States (n = 188), Bayer AG (n = 78), and Professor Peter Kolkhof (n = 59) were the most prolific country, institution, and author in this field, respectively. Cluster analysis of cited references identified major clusters like cardiovascular disease, chronic kidney disease, and omecamtiv mecarbil. Keyword analysis indicated that sodium-glucose transport protein (SGLT)-2 inhibitors, pharmacotherapy, clinical trial, and guideline have emerged recently. The field of non-steroidal MR antagonists is gradually gaining momentum as a novel pharmacotherapy in cardiorenal diseases, especially diabetic kidney disease, hypertension, and heart failure. Future studies will focus on add-on pharmacotherapy by combining non-steroidal MR antagonists with SGLT-2 inhibitors and the development and publication of clinical guidelines to facilitate patient management.

Comparison of measured and predicted herbicide concentrations in surface water catchments in Belgium.

In the process of approval of active substances and authorization in the European Union and at the member state level, it must be shown by the applicant that an unacceptable risk for nontarget organisms in the aquatic environment by the active substance can be excluded. To achieve this aim, standardized models, scenarios, and agreed pesticide input parameters have to be used to calculate the exposure as defined by the FOrum for the Co-ordination of pesticide fate models and their Use (FOCUS). During a period of daily surface water sampling lasting 3.5 years, a survey was conducted among farmers in the highly vulnerable catchment of Grote Kemmelbeek in Belgium to collect agronomic data on crops, application dates, and application rates of 12 applied herbicides and one metabolite. Daily surface water concentrations for the same herbicides were measured over 2.5 years for a second, much larger but less vulnerable, catchment of Kleine Aa (KAa). A comparison of realistic worst-case predicted environmental concentrations in surface water (PECsw) according to FOCUS with measured concentrations shows that, in the GKb catchment, the PECsw was never exceeded for six substances, was exceeded on only 1-2 days for five substances, and was exceeded on 9-27 days for two substances. For the KAa catchment, the PECsw was only exceeded on twodays for one compound and never for the other 12 compounds. These numbers correspond to a level of protection of the FOCUS PECsw between 100% and 97% and are much higher than the regulatory protection goal of 90%. These two case studies demonstrate the protectiveness of the FOCUS surface water approach. Integr Environ Assess Manag 2024;20:1447-1462. © 2024 Bayer AG. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial

Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. Bayer AG and Regeneron Pharmaceuticals.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial

Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Modification of the existing maximum residue levels and setting import tolerances for flupyradifurone and difluoroacetic acid (DFA) in various crops.

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG, Crop Science Division submitted a request to the competent national authority in the Netherlands to modify the existing maximum residue levels (MRL) and to set import tolerances for flupyradifurone and its metabolite difluoroacetic acid (DFA) in various plant commodities. The data submitted in support of the request were found to be sufficient to derive MRL proposals for flupyradifurone and DFA in avocados, mangoes, papayas, asparagus, sesame seeds, sunflower seeds, sugar beet roots and chicory roots. Adequate analytical methods for enforcement are available to control the residues of flupyradifurone and DFA in plant matrices under consideration at the validated limits of quantification (LOQs) of 0.01 and 0.007 mg/kg, respectively. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of flupyradifurone and DFA residues resulting from the use of flupyradifurone according to the reported agricultural practices is unlikely to present a risk to consumer health.

Market Share and Purchase Influencing Factors of Various Pesticide Brands in Uttar Pradesh

The worldwide consumption of pesticides is about two million tons per year. Out of which 45 percent is used by Europe alone, 25 percent is consumed in the USA, and 25 percent in the rest of the world. The three most commonly used pesticides are HCH (only gamma-HCH is allowed), DDT and Malathion, and these account for about 70 percent of the total pesticide consumption. India’s consumption of pesticide is only 3 percent of total world’s consumption of pesticides. Among different classes of pesticide, contribution of insecticide (60 percent) is high followed by fungicide (19percent), herbicide (16percent), Bio-Pesticide (3percent) and others (3percent). It is estimated that 18- 20 percent of total pesticides used in the country are applied on vegetables. The Government of India regulates the production, import, Sales, and use of pesticides through the Insecticides Act, 1968. The market in India is highly dominated by the foreign players. Bayer AG is the largest agrochemical producer in the world. Some of the big names include Yara International ASA, BASF, Bayer Crop Science Limited, Indofil Industries Limited, Makhteshim Agan Industries Ltd, Dow Agro Sciences, Monsanto, Syngenta, Aventis, Agrium etc. This study show the market shares of various brands in which 15.15% share in insecticides was Pexalon of Corteva Agriscience, 14.70% chess of Syngenta,13.16% of coragen(FMC India Pvt. Ltd.) and remaining others. In market share 33.09% Indofill Industries, 18.23% UPL and rest in remaining. The retail trade influence was maximum on the farmers and ranked I followed by influence from company representative ranked II. Farmers meeting, distribution of literature and samples, through participation in fairs and wall painting were moderately influencing factors, which were ranked fourth, sixth, and seventh.

Modification of the existing maximum residue level for propamocarb in honey.

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG Crop Science Division submitted a request to the competent national authority in Greece to modify the existing maximum residue level (MRL) for the active substance propamocarb in honey. The data submitted in support of the request were found to be sufficient to derive MRL proposals for honey. Adequate analytical methods for enforcement are available to control the residues of propamocarb on the commodity under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of propamocarb according to the reported agricultural practice is unlikely to present a risk to consumer health.

The effect of an educational animation on knowledge of testicular health and fertility of adolescents.

Does the provision of an educational animation, developed with young people, about testicular health and fertility impact the knowledge of these topics among adolescents? The development and provision of education on testicular health and fertility were welcomed by adolescents and associated with a significant increase in knowledge. Young people may know less than they should about testicular health and male fertility topics. Lack of knowledge can have implications for health including late medical help-seeking for signs and symptoms of scrotal disorders, such as torsion, for which late presentation frequently results in testicular damage. A mixed methods experimental pre- and post-design was used with embedded qualitative data collection. High school students completed a pre-animation questionnaire, watched four animations on testicular health and fertility, and completed a post-animation questionnaire. Data were collected during Personal Social and Health Education lessons across a 2-week period. Four animations on testicular health and fertility, informed by andrologists, academics, designers, boys, and young men, were developed. Eligible participants were boys and girls in the UK school years 8 and 9 (age 13-14 years). Participants completed a Time 1 (T1) survey (fertility knowledge, demographics) prior to watching the animations and a Time 2 (T2) survey (fertility knowledge, perceptions of the animations) immediately after the animations. Perceptions were rated on 10-point response scales (higher scores better). Participants additionally expressed in their own words positive and negative aspects of the animations. ANOVA was used to examine the effects of the animations using a 2 (time: T1, T2)×2 (gender: male, female) design on topic knowledge, perceived importance, usefulness, and style of the animations according to gender. Regression analysis examined the associations between gender, disability, class year, and knowledge at T2 while controlling for knowledge at T1. Qualitative data on perceptions of the animations were analyzed using inductive thematic analysis. Results showed that the animations significantly increased testicular health and fertility-related knowledge from T1 (x̄=41.84 ± 24.72) to T2 (x̄=79.15, ±15.04). Boys had significantly higher levels of knowledge compared to girls at T1 (x̄=44.74, SD = 25.16 versus x̄=37.79 ± 23.49, respectively) and T2 (x̄=80.07, SD = 15.68 versus x̄=77.89 ± 14.30, respectively) but knowledge gain from T1 to T2 was not significantly different according to gender (P = 0.11) as shown by non-significant gender×time interaction. There were no significant gender differences in the perceived usefulness and importance of the animations or liking of the style of the animations, with both genders considering the animations as useful, important, and likable. Regression analysis showed only knowledge at T1 to be significantly associated with knowledge at T2. Qualitative data showed three main themes: accessibility of important and useful information; information engagement and help-seeking behaviour; and inclusivity of information. This was a pre- and post-study with a sample of young people from a selected educational institution without a control group. Only short-term effects of the animations were recorded. Adolescents are interested in and learn from the provision of engaging fertility-related information. Boys and men should be considered as being a relevant target population for fertility education, not just girls and women. This research was carried out in partnership with the British Fertility Society, was financially supported by an Economic and Social Research Council Impact Acceleration Award (520792) and commercial sponsorship from iMediCare Ltd, Bayer AG, Merck Group, Cryos International given to the British Fertility Society, and a financial contribution from Orchid Cancer Appeal. The authors are fully responsible for the content of the animations and this manuscript, and the views and opinions described in the publication reflect solely those of the authors. J.B. reports a grant from Merck Serono Ltd outside the submitted work. C.H., G.G., A.D., E.B., U.G., M.L, B.W., and M.H. declare no conflict of interest. K.M. reports honoraria from Bayer and Merck. A.P. reports paid consultancy for Cryos International, Cytoswim Ltd, Exceed Health, and Merck Serono in the last 2 years, but all monies have been paid to the University of Sheffield. N/A.

THU651 Testosterone Treatment And Sexual Function In Men With Or At Risk Of T2D: The T4DM Study

Abstract Disclosure: G.A. Wittert: Advisory Board Member; Self; Bayer Schering Pharma. Speaker; Self; Bayer Schering Pharma, Besin. K. Robledo: None. M. Grossmann: None. B.B. Yeap: Advisory Board Member; Self; Bayer Schering Pharma. Grant Recipient; Self; Bayer Schering Pharma, Lawley. B.G. Stuckey: None. W.J. Inder: None. K. Bracken: None. D.R. Jesudason: None. C.A. Allan: None. D.J. Handelsman: None. Background: In T4DM (men aged 50 – 74 yrs., waist circumference (WC) ≥95cm cm, prediabetes, or newly diagnosed type 2 diabetes (T2D) and serum testosterone (T) ≤ 14 nmol/L), 2 years treatment with T-undecanoate (1000 mg IM 3 monthly) vs placebo while enrolled in a lifestyle weight management program, decreased fat mass, and reduced the risk of T2D by 40%. Aim: To determine baseline predictors and T treatment effects on sexual function (SF) over time, including interactions with changes in waist circumference (WC), blood pressure (BP), glucose and mood. Methods: Adjusting for baseline sociodemographic, clinical parameters and serum sex steroid (LCMS) concentrations, linear mixed effects models were fitted to assess T treatment effects on measures of SF (erectile function (EF), sexual desire (SD), orgasmic function (OF), intercourse satisfaction (IS) and overall satisfaction (OS) via questionnaire (IIEF)) completed by each participant at baseline and weeks 30, 54, 78, and 102, together with WC, BP, glucose, trough T, estradiol (E), T:E ratio and mood (Center for Epidemiologic Studies Depression Scale (CES-D) at weeks 0, 54 and 102. Results Among men on T (504) or placebo (503) at baseline, age was inversely associated with all SF scales (p &amp;lt;0.001), and WC and CES-D score inversely associated with EF (p=0.041) and SD (p=0.029). There was no effect of baseline T, E or T:E ratio on SF. T treatment improved all SF measures (p&amp;lt;0.001) peaking at 30-54 weeks). The T treatment effect on SD and OF (both p-int=0.014) was greater in older men. Increasing WC over time was inversely associated with EF (p=0.036) and SD (p=0.043) scores, with no interaction with T treatment. SF scores were unaffected by changes in glucose, BP, or trough T, E or T:E ratio. Increase in depression scores corresponded to decreases in all SF scores (p &amp;lt;0.001). T treatment increased SD more in those with higher depression scores (p int=0.026) while not affecting the CES-D scores. Conclusion: Baseline age, WC, and depression scores, but not T were inversely associated with SF measures which improved with T treatment regardless of baseline T, E, or T:E ratio. T treatment improved SD and OF more in older men, and SD in those with more depressive symptoms. Change in WC was inversely associated with EF and SD, independent of T treatment. A pharmacological effect of T treatment to improve SF, particularly in older and depressed men, coexists with benefits from reduced central adiposity. Presentation: Thursday, June 15, 2023

OR25-05 Clinical Predictors Of Symptomatic Benefit In Men With Low Testosterone During Testosterone Treatment Compared With Placebo: Results Of Individual Patient And Aggregate Data Meta-analyses

Abstract Disclosure: J. Hudson: None. M. Cruickshank: None. R. Quinton: Speaker; Self; Bayer Schering Pharma, Besins. L. Aucott: None. F.C. Wu: None. M. Grossmann: None. S. Bhasin: None. P.J. Snyder: None. S. Ellenberg: None. T.G. Travison: None. G.B. Brock: None. E.J. Gianatti: None. Y.T. van der Schouw: None. M.H. Emmelot-Vonk: None. E. Giltay: None. H. Geoff: None. S. Ramachandran: None. J.B. Svartberg: None. K.L. Hildreth: None. K. Groti Antonic: None. J.S. Tenover: None. H. Tan: None. C. Ho Chee Kong: None. T. Wei Shen: None. L.S. Marks: None. R.J. Ross: None. R.S. Schwartz: None. S. Roberts: None. M. Andersen: None. L. Magnussen: None. M. Aceves-Martins: None. S. Bhattacharya: None. W.S. Dhillo: None. M. Brazzelli: None. C.N. Jayasena: Grant Recipient; Self; Logixx Pharma Ltd. Background: Testosterone treatment increases the international index of erectile function 15 (IIEF-15) in young men with pathological hypogonadism. However, testosterone is most frequently prescribed to middle-aged and older men, and men with obesity, whose sexual dysfunction may be unrelated to their low testosterone; prior studies suggest that symptomatic responses to testosterone treatment may be attenuated in older men and those with obesity. To identify subgroups of men with low testosterone experiencing the greatest symptomatic benefit during testosterone therapy, we utilised individual participant data (IPD) from the Testosterone Efficacy and Safety (TestES) Consortium. Methods: Systematic review of randomised controlled trials including IPD meta-analysis (PROSPERO CRD42018111005) identifying clinical efficacy outcomes, and subgroups associated with outcomes in RCTs comparing testosterone with placebo in men with baseline total testosterone &amp;lt;12nmol/L (348ng/dL). One-stage meta-analyses used IPD, and two-stage meta-analyses integrated IPD with aggregate data from studies not providing IPD. Findings: Seventeen of 35 trials provided IPD (3431/5601 participants; mean duration 9.5months; 97% men aged &amp;gt;40years). As expected, testosterone increased IIEF-15 compared with placebo (MD 5.52 (95% CI 3.95, 7.10; τ^2=1.17). However, no significant increment in IIEF-15 during testosterone compared with placebo was observed in smokers (interaction -9.03, 99% CI -48.90, 30.84). Increases in IIEF-15 during testosterone compared with placebo were not associated with patient age, obesity, presence of diabetes, or baseline total testosterone. However, absolute levels of sexual function achieved during testosterone treatment were subject to thresholds in patient age (mean IIEF-15: 46.8 (19.4), &amp;lt;52 years; 38.8 (21.9), 52-70 years; 26.8 (21.1), &amp;gt;70 years; P&amp;lt;0.001), body mass index (BMI) (mean IIEF-15: 40.0 (22.2), &amp;lt;30.6kg/m2; 34.4 (21.9), ≥30.6kg/m2; P&amp;lt;0.001), and baseline serum testosterone (mean IIEF-15: 42.2 (23.9), ≥9.8nmol/L; 30.7 (22.1), &amp;lt;9.8nmol/L; P&amp;lt;0.001). Interpretation: In men aged &amp;gt;40 years with serum baseline testosterone &amp;lt;12nmol/L, we were surprised to observe that increments in IIEF-15 during testosterone treatment are not significantly affected by age, obesity, or baseline testosterone status. However, baseline factors may influence the absolute post-treatment IIEF-15 achieved during testosterone treatment. Funding: National Institute for Health Research Health Technology Assessment programme (NIHR HTA 17/68/01). Presentation Date: Saturday, June 17, 2023

OR20-01 Machine Learning-based Steroid Metabolome Analysis In Women With Polycystic Ovary Syndrome Reveals Three Distinct Androgen Excess Subtypes With Different Metabolic Risk Profiles.

Abstract Disclosure: T.P. Rocha: None. E. Melson: None. R.J. Veen: None. L. Abdi: None. T. McDonnell: None. V. Tandl: None. J. Hawley: None. L. Wittemans: None. A. Anthony: None. L. Gilligan: None. F. Shaheen: None. P. Kempegowda: None. C.D. Gillett: None. L. Cussen: None. C. Missbrenner: None. F. Lajeunesse-Trempe: None. H. Gleeson: None. A. Rees: None. L. Robinson: None. C. Jayasenna: None. H.S. Randeva: None. H.S. Randeva: None. G.K. Dimitriadis: None. L.G. Gomes: None. A. Sitch: None. E. Vradi: Employee; Self; Bayer Schering Pharma. A.E. Taylor: None. M.W. O'Reilly: None. B.M. Obermayer-Pietsch: None. M. Biehl: None. W. Arlt: None. Introduction: Polycystic ovary syndrome affects 10% of women and is associated with an increased risk of type 2 diabetes, hypertension, and fatty liver disease. Androgen excess, a defining feature of PCOS, has been implicated as a driver of metabolic risk. Adrenal-derived 11-oxygenated androgens are a component of PCOS-related androgen excess and are preferentially activated in adipose tissue. Here, we aimed to identify PCOS sub-types with distinct steroid metabolomes and compare their cardiometabolic risk parameters. Methods: We prospectively recruited 488 treatment-naïve women with PCOS fulfilling diagnostic Rotterdam criteria [median age 28 (IQR 24-32) years; BMI 27.5 (22.4-34.6) kg/m2] at eight centres in the UK &amp; Ireland (n=208), Austria (n=242), and Brazil (n=38). Participants underwent a standardised assessment, including insulin sensitivity at baseline (HOMA-IR) and across a 2-h oGTT (Matsuda ISI). We used tandem mass spectrometry to measure 11 androgenic serum steroids, including classic and 11-oxygenated androgens. Results were analysed by unsupervised k-means clustering, followed by a comparison of clinical and metabolic phenotype parameters. Results: Machine learning analysis identified three distinct androgen metabolomes: a cluster with mainly gonadal-derived androgen excess (GAE; testosterone, dihydrotestosterone; 21.5% of women), a cluster with mainly adrenal-derived androgen excess (AAE; 11-oxygenated androgens; 21.7%), and a cluster with comparably mild androgen excess (MAE; 56.8%). Age and BMI were similar between groups. Compared to GAE and MAE, the AAE cluster had the highest rates of hirsutism (76.4% vs 67.6% vs 59.9%) and female pattern hair loss (32.1% vs 14.3% vs 21.7%). The AAE cluster had significantly increased insulin resistance as indicated by higher fasting insulin,120min insulin and HOMA-IR, and lower ISI than GAE and MAE clusters (all p&amp;lt;0.01). The AAE cluster had a 2-3fold higher prevalence of impaired glucose tolerance and newly diagnosed type 2 diabetes. Conclusion: Unsupervised cluster analysis revealed three distinct androgen excess subtypes in PCOS. Women within the adrenal androgen excess cluster had a significantly higher prevalence of insulin resistance, impaired glucose tolerance and type 2 diabetes. These results implicate 11-oxygenated androgens as drivers of metabolic risk in PCOS and provide proof-of-principle for an androgen-based stratification tool to guide preventative and therapeutic strategies in PCOS. Presentation Date: Saturday, June 17, 2023

Finerenone in Black Patients With Type 2 Diabetes and CKD: A Post hoc Analysis of the Pooled FIDELIO-DKD and FIGARO-DKD Trials

In FIDELITY, finerenone improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). This analysis explored the efficacy and safety of finerenone in Black patients. Subanalysis of randomized controlled trials. Patients with T2D and CKD. Finerenone or placebo. Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; composite of kidney failure, sustained≥57% estimated glomerular filtration rate (eGFR) decline from baseline maintained for≥4 weeks, or renal death. Of the 13,026 patients, 522 (4.0%) self-identified as Black. Finerenone demonstrated similar effects on the cardiovascular composite outcome in Black (HR, 0.79 [95% CI, 0.51-1.24]) and non-Black patients (HR, 0.87 [95% CI, 0.79-0.96; P=0.5for interaction]). Kidney composite outcomes were consistent in Black (HR, 0.71 [95% CI, 0.43-1.16]) and non-Black patients (HR, 0.76 [95% CI, 0.66-0.88; P=0.9for interaction]). Finerenone reduced urine albumin-to-creatinine ratio by 40% at month 4 (least-squares mean treatment ratio, 0.60 [95% CI, 0.52-0.69; P<0.001]) in Black patients and 32% at month 4 (least-squares mean treatment ratio, 0.68 [95% CI, 0.66-0.70; P<0.001]) in non-Black patients, versus placebo. Chronic eGFR decline (month 4 to end-of-study) was slowed in Black and non-Black patients treated with finerenone versus placebo (between-group difference, 1.4mL/min/1.73m2 per year [95% CI, 0.33-2.44; P=0.01] and 1.1mL/min/1.73m2 per year [95% CI, 0.89-1.28; P< 0.001], respectively). Safety outcomes were similar between subgroups. Small number of Black patients; analysis was not originally powered to determine an interaction effect based on Black race. The efficacy and safety of finerenone appears consistent in Black and non-Black patients with CKD and T2D. Bayer AG. ClinicalTrials.gov NCT02540993, NCT02545049. Diabetes is a major cause of chronic kidney disease (CKD), affecting more Black adults than White adults. Most adults with CKD ultimately die from heart and vascular complications (eg, heart attack and stroke) rather than kidney failure. This analysis of 2 recent trials shows that the drug finerenone was beneficial for patients with diabetes and CKD. Along with reducing kidney function decline and protein in the urine, it also decreased heart and vascular issues and lowered blood pressure in both Black and non-Black adults with diabetes and CKD. These findings have promising implications for slowing the progression of CKD and protecting against cardiovascular problems in diverse populations.