ScienceInSpotlight

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Science in Spotlight is an internet platform listing scientific publications authored by Bayer employees to increase transparency and visibility of Bayer’s innovative research activities to the external scientific community.

The platform allows keyword search and provides links to the published manuscripts.

JOURNAL OF HYPERTENSION
(2023) Vol. 41, No. 2, pp. 295-302.

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Effect of finerenone on ambulatory blood pressure in chronic kidney disease in type 2 diabetes.

Agarwal Rajiv; Ruilope Luis M; Ruiz-Hurtado Gema; Haller Hermann; Schmieder Roland E; Anker Stefan D; Filippatos Gerasimos; Pitt Bertram; Rossing Peter; Lambelet Marc; Nowack Christina; Kolkhof Peter; Joseph Amer; Bakris George L

OBJECTIVE: Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes. METHODS: ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio >/=30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90. RESULTS: Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval [CI], -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval. CONCLUSIONS: Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.

PULMONARY CIRCULATION
(2022) Vol. 12, No. 4, pp. e12178.

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Pulmonary hypertension in interstitial lung disease: Clinical trial design and endpoints: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension.

Nathan Steven D; Fernandes Peter; Psotka Mitchell; Vitulo Patrizio; Piccari Lucilla; Antoniou Katerina; Nikkho Sylvia M; Stockbridge Norman

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is an attractive target for clinical trials of PH medications. There are many factors that need to be considered to prime such studies for success. The patient phenotype most likely to respond to the intervention requires weighing the extent of the parenchymal lung disease against the severity of the hemodynamic impairment. The inclusion criteria should not be too restrictive, thus enabling recruitment. The trial should be of sufficient duration to meet the chosen endpoint which should reflect how the patient feels, functions, or survives. This paper summarizes prior studies in PH-ILD and provides a framework of the type of studies to be considered. Inclusion criteria, clinical trial endpoints, and pharmacovigilance in the context of PH-ILD trials are also addressed. Through lessons learnt from prior studies, suggestions and guidance for future clinical trials in PH-ILD are also provided.

FRONTIERS IN PUBLIC HEALTH
(2022) Vol. 10, pp. 1037780.

4a9a16f1-5f47-47ac-a292-3845a78e37f5

Dermal measurement of exposure to plant protection products: Actual hand exposure from hand washing vs. wearing cotton gloves.

Kuster Christian J; Hewitt Nicola J; Hamacher Georg

For the authorization of plant protection products, a quantitative non-dietary exposure risk assessment relies on established dermal exposure models, measured mainly using passive dosimetry. Exposure to the hands is determined via hand washing or using cotton gloves as a surrogate for skin. This study compared both methods using operator exposure data available from the Agricultural Operator Exposure Model (AOEM) project report. These data indicate that hand exposure determined using cotton gloves resulted in markedly higher exposure values for all exposure scenarios compared to those determined by hand washes. One explanation for this is that dermal uptake of the residues reduces the amount of residue that can be recovered by hand washing. Uncertainty due to dermal uptake can be addressed by either default assumptions or by specific dermal absorption data. However, this cannot solely account for the large difference observed between the values and is mainly likely to be due to the higher capacity of the cotton gloves vs. human skin to retain residues. The results further indicate that the variability between hand wash samples and cotton glove samples differs between the exposure scenarios. Hence, the level of conservatism related to the use of cotton gloves as surrogate skin remains unknown. In conclusion, this evaluation of the AOEM data indicates that the cotton glove method results in much higher levels of measured hand exposure than the hand wash method. It cannot be excluded that dermal uptake has contributed to that result. However, the findings suggest the higher retention capacity of cotton gloves vs. human skin to be the main impact parameter. The cotton glove method does not provide the results with regards to the protection level that can be expected from the use of protective gloves. Therefore, we believe that the application of the hand wash method is a more accurate measure of exposure levels, if either specific dermal absorption data or, in its absence, default assumptions are applied as adjustment factor.

JOURNAL OF MEDICAL INTERNET RESEARCH
(2023) Vol. 25, pp. e43404.

a33ca7df-b683-4e62-9902-f71472232ffa

Advancing Digital Health Innovation in Oncology: Priorities for High-Value Digital Transformation in Cancer Care.

Patel Smit; Goldsack Jennifer C; Cordovano Grace; Downing Andrea; Fields Karen K; Geoghegan Cindy; Grewal Upinder; Nieva Jorge; Patel Nikunj; Rollison Dana E; Sah Archana; Said Maya; Van De Keere Isabel; Way Amanda; Wolff-Hughes Dana L; Wood William A; Robinson Edmondo J

Although health care delivery is becoming increasingly digitized, driven by the pursuit of improved access, equity, efficiency, and effectiveness, progress does not appear to be equally distributed across therapeutic areas. Oncology is renowned for leading innovation in research and in care; digital pathology, digital radiology, real-world data, next-generation sequencing, patient-reported outcomes, and precision approaches driven by complex data and biomarkers are hallmarks of the field. However, remote patient monitoring, decentralized approaches to care and research, "hospital at home," and machine learning techniques have yet to be broadly deployed to improve cancer care. In response, the Digital Medicine Society and Moffitt Cancer Center convened a multistakeholder roundtable discussion to bring together leading experts in cancer care and digital innovation. This viewpoint highlights the findings from these discussions, in which experts agreed that digital innovation is lagging in oncology relative to other therapeutic areas. It reports that this lag is most likely attributed to poor articulation of the challenges in cancer care and research best suited to digital solutions, lack of incentives and support, and missing standardized infrastructure to implement digital innovations. It concludes with suggestions for actions needed to bring the promise of digitization to cancer care to improve lives.

HEALTH SCIENCE REPORTS
(2023) Vol. 6, No. 1, pp. e1033.

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Evaluation of a 5% dexpanthenol-containing ointment for the treatment of infant irritant diaper dermatitis through the lens of the caregiver-A real-world data observational study.

Peltier Erwan; de Salvo Raffaella; Ehret Andreas; Trapp Sonja; Lakomsky Didier; El Shazly Maged A

BACKGROUND AND AIMS: Irritant diaper dermatitis (IDD) is very common in infants and usually managed by the caregiver. Dexpanthenol-containing ointment (DCO) is a decades-long established product that has demonstrated efficacy and tolerability in the treatment and prevention of infant IDD in controlled clinical settings. The aim of this study was to evaluate the effectiveness of DCO in the treatment of infant IDD from the perspective of the caregiver by collecting data not explored in clinical trials, such as infant quality of life and the speed of action. METHODS: A retrospective observational real-world data (RWD) study was conducted with French adult caregivers who had used a DCO to treat IDD in their infants within the past 6 months and consented to participate to the study completed a web-based survey answering questions regarding the severity of their infants' symptoms (intensity/extent of redness and discomfort, rated using Likert scales) before and after DCO application. The speed of onset of symptom relief and product acceptability were also collected. RESULTS: A total of 500 caregivers of 564 infants completed the survey. Of these, 80% reported that DCO visibly treats IDD. In terms of speed of action, 83% declared that the first signs of symptom relief appeared after 1 day of application and 78% reported full symptom resolution within 2 days of application. Additionally, >/=77% of caregivers agreed that DCO provided overnight relief from the discomfort caused by IDD and reduced sleep disturbance in their children. Finally, 85% of caregivers declared being satisfied with the product overall and considered the product pleasant to use. CONCLUSION: This evidence from caregivers' experience confirms that DCO can be considered an adequate medication to self-manage IDD episode as it provides rapid relief of the signs and symptoms of inflammation, while by being pleasant to be use.

JOURNAL OF MANAGED CARE & SPECIALTY PHARMACY
(2023) Vol. 29, No. 1, pp. 80-89.

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Descriptive study of the economic burden among patients with type 2 diabetes mellitus, chronic kidney disease, and chronic kidney disease and type 2 diabetes mellitus in a large US commercially insured population.

Chung Haechung; Crowe Christopher L; Kong Sheldon X; Singh Rakesh; Farej Ryan; Elliott Jay; Williamson Todd; Willey Vincent J

BACKGROUND: Chronic kidney disease (CKD) is a major public health concern that affects 37 million adults in the United States. It is well known that CKD presents a large economic burden, especially in the Medicare population. However, studies of the economic burden of CKD in younger populations are scarce. In particular, there is a gap in understanding how the presence of type 2 diabetes mellitus (T2DM) affects the burden of CKD in commercially insured populations. OBJECTIVE: To describe the economic and health care resource utilization (HCRU) burden of CKD within 3 patient groups (T2DM only, CKD only, and CKD and T2DM) aged 45-64 years overall and by Kidney Disease Improving Global Outcomes (KDIGO) CKD estimated glomerular filtration rate-based stage categories. METHODS: A descriptive, observational retrospective cohort study was conducted using administrative medical and pharmacy claims integrated with laboratory results data available in the HealthCore Integrated Research Database from January 1, 2017, to December 31, 2019. Three mutually exclusive groups of commercially insured patients aged 45-64 years were identified: T2DM only, CKD only, and CKD and T2DM. All-cause and disease-specific HCRU and costs in total, by medical and pharmacy benefits and across all places of service, were described for each of these groups 12 months after index date. For the CKD only and CKD and T2DM groups, costs were also described by KDIGO CKD stage. RESULTS: The CKD and T2DM group (n = 13,052) had numerically higher 12-month post-index all-cause and CKD/T2DM-related HCRU across all places of service. Mean 12-month all-cause costs for this group were $35,649, whereas costs for the CKD only group (n = 7,876) were $25,010 and costs for the T2DM only group (n = 120,364) were $16,121. Costs also tended to increase as CKD stage increased, with the greatest increases beginning at KDIGO stage 3b and higher. Mean 12-month all-cause costs for the CKD and T2DM group ranged from $29,993 to $41,222 for stages 1 to 3a and from $46,796 to $119,944 for stages 3b to 5. CONCLUSIONS: Commercially insured patients aged 45-64 years with CKD, especially those who also have T2DM, present a substantial burden in terms of elevated HCRU and costs. Costs tend to increase across KDIGO CKD stages and increase most rapidly at stage 3b and later. Therefore, there is an opportunity to reduce the burden of CKD in this population by investing in interventions to prevent or delay CKD disease progression. DISCLOSURES: HealthCore, Inc, received funding to perform this research, as well as funding from multiple pharmaceutical companies to perform various research studies outside of the submitted work. Mr Crowe and Dr Willey are employees of HealthCore, Inc., a wholly owned subsidiary of Elevance Health, Inc. Ms Chung was an employee of HealthCore, Inc., a wholly owned subsidiary of Elevance Health, Inc, at the time of study performance. Ms Chung and Dr Willey are shareholders of Elevance Health, Inc. Dr Kong, Dr Singh, Mr Farej, Dr Elliot, and Dr Williamson are employees of Bayer US, LLC. Dr Singh is a shareholder of Bayer US, LLC.

NATURE COMMUNICATIONS
(2023) Vol. 14, No. 1, pp. 58.

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Author Correction: Selective optogenetic control of Gq signaling using human Neuropsin.

Wagdi Ahmed; Malan Daniela; Sathyanarayanan Udhayabhaskar; Beauchamp Janosch S; Vogt Markus; Zipf David; Beiert Thomas; Mansuroglu Berivan; Dusend Vanessa; Meininghaus Mark; Schneider Linn; Kalthof Bernd; Wiegert J Simon; Konig Gabriele M; Kostenis Evi; Patejdl Robert; Sasse Philipp; Bruegmann Tobias

THROMBOSIS AND HAEMOSTASIS
(2023) Vol. 123, No. 1, pp. 27-39.

446e5a71-8ca3-4962-bfc9-52a33dac1114

BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial.

Ljung Rolf; Chan Anthony K C; Glosli Heidi; Afonja Olubunmi; Becker Bastian; Tseneklidou-Stoeter Despina; Mancuso Maria Elisa; Saulyte-Trakymiene Sonata; Kenet Gili

INTRODUCTION: BAY 81-8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials. AIM: To assess BAY 81-8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs). METHODS: In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs (<6 years old) with severe hemophilia A received BAY 81-8973 (15-50 IU/kg) at least once weekly as prophylaxis. Primary efficacy endpoint was the annualized bleeding rate (ABR) within 48 hours after prophylaxis infusion. Adverse events and immunogenicity were assessed. Patients who developed inhibitors were offered immune tolerance induction (ITI) treatment in an optional extension phase. RESULTS: Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0-1.8) among patients without inhibitors (n = 20) and 0.0 (0.0-2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [n = 5], low titer [n = 1]) achieved a negative inhibitor titer. CONCLUSION: BAY 81-8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81-8973 benefit-risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81-8973.

BMC PLANT BIOLOGY
(2023) Vol. 23, No. 1, pp. 18.

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Genetic architecture of fresh-market tomato yield.

Bhandari Prashant; Kim Juhee; Lee Tong Geon

BACKGROUND: The fresh-market tomato (Solanum lycopersicum) is bred for direct consumption and is selected for a high yield of large fruits. To understand the genetic variations (distinct types of DNA sequence polymorphism) that influence the yield, we collected the phenotypic variations in the yields of total fruit, extra-large-sized fruit, small-sized fruit, or red-colored fruit from 68 core inbred contemporary U.S. fresh-market tomatoes for three consecutive years and the genomic information in 8,289,741 single nucleotide polymorphism (SNP) positions from the whole-genome resequencing of these tomatoes. RESULTS: Genome-wide association (GWA) mapping using the SNP data with or without SNP filtering steps using the regularization methods, validated with quantitative trait loci (QTL) linkage mapping, identified 18 significant association signals for traits evaluated. Among them, 10 of which were not located within genomic regions previously identified as being associated with fruit size/shape. When mapping-driven association signals [558 SNPs associated with 28 yield (component) traits] were used to calculate genomic estimated breeding values (GEBVs) of evaluated traits, the prediction accuracies of the extra-large-sized fruit and small-sized fruit yields were higher than those of the total and red-colored fruit yields, as we tested the generated breeding values in inbred tomatoes and F(2) populations. Improved accuracy in GEBV calculation of evaluated traits was achieved by using 364 SNPs identified using the regularization methods. CONCLUSIONS: Together, these results provide an understanding of the genetic variations underlying the heritable phenotypic variability in yield in contemporary tomato breeding and the information necessary for improving such economically important and complex quantitative trait through breeding.

ALZHEIMER'S RESEARCH & THERAPY
(2023) Vol. 15, No. 1, pp. 13.

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Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer's disease: results from the DELCODE study.

Brosseron Frederic; Maass Anne; Kleineidam Luca; Ravichandran Kishore Aravind; Kolbe Carl-Christian; Wolfsgruber Steffen; Santarelli Francesco; Hasler Lisa M; McManus Roisin; Ising Christina; Roske Sandra; Peters Oliver; Cosma Nicoleta-Carmen; Schneider Luisa-Sophie; Wang Xiao; Priller Josef; Spruth Eike J; Altenstein Slawek; Schneider Anja; Fliessbach Klaus; Wiltfang Jens; Schott Bjorn H; Buerger Katharina; Janowitz Daniel; Dichgans Martin; Perneczky Robert; Rauchmann Boris-Stephan; Teipel Stefan; Kilimann Ingo; Gorss Doreen; Laske Christoph; Munk Matthias H; Duzel Emrah; Yakupow Renat; Dobisch Laura; Metzger Coraline D; Glanz Wenzel; Ewers Michael; Dechent Peter; Haynes John Dylan; Scheffler Klaus; Roy Nina; Rostamzadeh Ayda; Spottke Annika; Ramirez Alfredo; Mengel David; Synofzik Matthis; Jucker Mathias; Latz Eicke; Jessen Frank; Wagner Michael; Heneka Michael T

BACKGROUND: Neuroinflammation constitutes a pathological hallmark of Alzheimer's disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD. METHODS: Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer's Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance. RESULTS: Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes. CONCLUSIONS: Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein's specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.

JOURNAL OF CHEMINFORMATICS
(2023) Vol. 15, No. 1, pp. 2.

182a0800-1337-4ea0-a5fa-cc1eafd417b5

XSMILES: interactive visualization for molecules, SMILES and XAI attribution scores.

Heberle Henry; Zhao Linlin; Schmidt Sebastian; Wolf Thomas; Heinrich Julian

BACKGROUND: Explainable artificial intelligence (XAI) methods have shown increasing applicability in chemistry. In this context, visualization techniques can highlight regions of a molecule to reveal their influence over a predicted property. For this purpose, some XAI techniques calculate attribution scores associated with tokens of SMILES strings or with atoms of a molecule. While an association of a score with an atom can be directly visually represented on a molecule diagram, scores computed for SMILES non-atom tokens cannot. For instance, a substring [N+] contains 3 non-atom tokens, i.e., [, [Formula: see text], and ], and their attributions, depending on the model, are not necessarily revealing an influence of the nitrogen atom over the predicted property; for that reason, it is not possible to represent the scores on a molecule diagram. Moreover, SMILES's notation is complex, foregrounding the need for techniques to facilitate the analysis of explanations associated with their tokens. RESULTS: We propose XSMILES, an interactive visualization technique, to explore explainable artificial intelligence attributions scores and support the interpretation of SMILES. Users can input any type of score attributed to atom and non-atom tokens and visualize them on top of a 2D molecule diagram coordinated with a bar chart that represents a SMILES string. We demonstrate how attributions calculated for SMILES strings can be evaluated and better interpreted through interactivity with two use cases. CONCLUSIONS: Data scientists can use XSMILES to understand their models' behavior and compare multiple modeling approaches. The tool provides a set of parameters to adapt the visualization to users' needs and it can be integrated into different platforms. We believe XSMILES can support data scientists to develop, improve, and communicate their models by making it easier to identify patterns and compare attributions through interactive exploratory visualization.

BMJ OPEN DIABETES RESEARCH & CARE
(2023) Vol. 11, No. 1.

ee4a227d-74e5-45d1-bbf3-a84a44a06e97

Cardiovascular and renal outcomes among patients with type 2 diabetes using SGLT2 inhibitors added to metformin: a population-based cohort study from the UK.

Gonzalez Perez Antonio; Vizcaya David; Saez Maria E; Lind Marcus; Garcia Rodriguez Luis A

INTRODUCTION: Large numbers of patients with type 2 diabetes receive treatment with a sodium-glucose co-transporter-2 inhibitor (SGLT2i). We investigated whether the cardiorenal preventative effects found in clinical trials are also seen in clinical practice where patient characteristics and adherence to treatment differ. RESEARCH DESIGN AND METHODS: Using UK primary care electronic health records, we followed two cohorts of patients with type 2 diabetes prescribed metformin: SGLT2is (N=12 978) and a matched comparator of patients not using an SGLT2i at the start of follow-up (N=44 286). Independent follow-ups were performed to identify the study outcomes: cardiovascular (CV) composite (comprising non-fatal myocardial infarction (MI)/ischemic stroke (IS) requiring hospitalization and CV death), severe renal disease, and all-cause mortality. Cox regression was used to estimate adjusted HRs. RESULTS: Mean follow-up was 2.3 years (SGLT2i cohort) and 2.1 years (comparison cohort). Mean age was 59.6 years (SD +/-10.2, SGLT2i cohort) and 60.4 years (SD +/-10.0, comparison cohort). SGLT2i new users were associated with a reduced risk of the CV composite (HR 0.75, 95% CI: 0.61 to 0.93), severe renal disease (HR 0.55, 95% CI: 0.46 to 0.67), and all-cause mortality (HR 0.56, 95% CI: 0.49 to 0.63), with risk reductions similar irrespective of baseline chronic kidney disease. Reduced risks were seen for IS (HR 0.51, 95% CI: 0.36 to 0.74) but not MI (HR 0.98, 95% CI: 0.74 to 1.28). Results were consistent in sensitivity analyses. CONCLUSIONS: In this population-based study, SGLT2is were associated with significant CV, renal and survival benefits among individuals with type 2 diabetes on metformin; the CV benefit was driven by a reduced risk of ischemic stroke.

EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY
(2023)

6317637a-29bd-4571-97e6-6608159a79c9

Finerenone and effects on mortality in chronic kidney disease and type 2 diabetes: a FIDELITY analysis.

Filippatos Gerasimos; Anker Stefan D; August Phyllis; Coats Andrew J S; Januzzi James L; Mankovsky Boris; Rossing Peter; Ruilope Luis M; Pitt Bertram; Sarafidis Pantelis; Teerlink John R; Kapelios Chris J; Gebel Martin; Brinker Meike; Joseph Amer; Lage Andrea; Bakris George; Agarwal Rajiv

AIMS: Finerenone reduces the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We investigated the causes of mortality in the FIDELITY population. METHODS AND RESULTS: The FIDELITY prespecified pooled data analysis from FIDELIO-DKD and FIGARO-DKD excluded patients with heart failure and reduced ejection fraction. Outcomes included intention-to-treat and prespecified on-treatment analyses of the risk of all-cause and cardiovascular mortality. Of 13 026 patients [mean age, 64.8 years; mean estimated glomerular filtration rate (eGFR), 57.6 mL/min/1.73 m2], 99.8% were on renin-angiotensin system inhibitors. Finerenone reduced the incidence of all-cause and cardiovascular mortality vs. placebo (8.5% vs. 9.4% and 4.9% vs. 5.6%, respectively) and demonstrated significant on-treatment reductions [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70-0.96; P = 0.014 and HR, 0.82; 95% CI, 0.67-0.99; P = 0.040, respectively]. Cardiovascular-related mortality was most common, and finerenone lowered the incidence of sudden cardiac death vs. placebo [1.3% (incidence rate 0.44/100 patient-years) vs. 1.8% (0.58/100 patient-years), respectively; HR, 0.75; 95% CI, 0.57-0.996; P = 0.046]. The effects of finerenone on mortality were similar across all Kidney Disease: Improving Global Outcomes risk groups. Event probability with finerenone at 4 years was consistent irrespective of baseline urine albumin-to-creatinine ratio, but seemingly more pronounced in patients with higher baseline eGFR. CONCLUSION: In FIDELITY, finerenone significantly reduced the risk of all-cause and cardiovascular mortality vs. placebo in patients with T2D across a broad spectrum of CKD stages while on treatment, as well as sudden cardiac death in the intention-to-treat population. CLINICAL TRIALS REGISTRATION: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

INTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT
(2023)

32828010-2803-46f6-ab7a-6d214dc2291a

CURRENT TESTING PROGRAMS FOR PESTICIDES ADEQUATELY CAPTURE ENDOCRINE ACTIVITY AND ADVERSITY FOR PROTECTION OF VERTEBRATE WILDLIFE.

Staveley Jane P; Freeman Elaine L; McArdle Margaret E; Ortego Lisa S; Coady Katherine K; Bone Audrey; Lagadic Laurent; Weltje Lennart; Weyers Arnd; Wheeler James R

The toxicity and ecotoxicity of pesticide active ingredients are evaluated by a number of standardized test methods using vertebrate animals. These standard test methods are required under various regulatory programs for the registration of pesticides. Over the past two decades, additional test methods have been developed with endpoints that are responsive to endocrine activity and subsequent adverse effects. This article examines the available test methods and their endpoints that are relevant to an assessment of endocrine-disrupting properties of pesticides. Furthermore, the article highlights how weight-of-evidence approaches should be applied to determine whether an adverse response in (eco)toxicity tests is caused by an endocrine mechanism of action. The large number of endpoints in the current testing paradigms for pesticides make it unlikely that endocrine activity and adversity is being overlooked. Integr Environ Assess Manag 2023;00:1-21. (c) 2023 Bayer CropScience and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

AMERICAN JOURNAL OF CARDIOVASCULAR DRUGS : DRUGS, DEVICES, AND OTHER INTERVENTIONS
(2023)

dfb07aee-a4a9-4111-b5fd-567cfbec28e8

Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes.

Bottcher Michael; Dungen Hans-Dirk; Corcea Vasile; Donath Frank; Fuhr Rainard; Gal Pim; Mikus Gerd; Trenk Dietmar; Coenen Martin; Pires Philippe Vieira; Maschke Claudia; Aliprantis Antonios Othon; Besche Nina; Becker Corina

BACKGROUND: Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. OBJECTIVE: To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS). METHODS: This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat. RESULTS: In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns. CONCLUSIONS: As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03504982.

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