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Marie T Borin,1 Arthur Lo,2 Chris N Barnes,3 Srikanth Pendyala,4 David L Bourdet2 1Department of Clinical and Translational Pharmacology, Theravance Biopharma US, Inc., South San Francisco, CA, USA; 2Department of Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., South San Francisco, CA, USA; 3Department of Biostatistics, Theravance Biopharma US, Inc., South San Francisco, CA, USA; 4Department of Clinical Development, Inflammation and Immunology, Theravance Biopharma US, Inc., South San Francisco, CA, USACorrespondence: David L BourdetDepartment of Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USATel +1 650 808 3755Email dbourdet@theravance.comPurpose: Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592).Subjects and methods: The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate

Background: Dietary Approaches to Stop Hypertension (DASH) is a recommended first-line treatment for adults with hypertension, yet adherence to DASH is low., Purpose: To evaluate the efficacy of a digital health intervention (DHI), compared with attention control, on changes in DASH adherence and blood pressure among adults with hypertension., Methods: Nourish was a 12-month, parallel, 2-arm, randomized controlled trial of a virtually delivered DHI. Participants had a previous diagnosis of hypertension. The primary outcome was a 6-month change in DASH adherence. The secondary outcome was a change in blood pressure. We used linear mixed models to compare 6 and 12-month changes in DASH adherence, systolic blood pressure, and diastolic blood pressure., Results: Nourish randomized 301 adults who averaged 54.4 (SD, 13.4) years and predominately identified as female (65%), White (53%), or Black (31%). Adjusted mean baseline DASH score was 2.30 (95% CI, 2.03-2.58). The adjusted mean baseline systolic blood pressure and diastolic blood pressure were 123.2 (95% CI, 119.5-126.9) and 77.1 (95% CI, 74.6-79.6) mm Hg. DASH score change was not significantly different between arms at 6 months ( M diff , 0.02 [95% CI, -0.37 to 0.40]). Yet, DHI participants had significantly greater 12-month changes in DASH score, relative to control ( M diff , 0.62 [95% CI, 0.16-1.08]). Between-group differences in 6-month changes were insignificant for systolic blood pressure and marginally significant for diastolic blood pressure, despite the DHI group showing significant blood pressure reductions from baseline., Conclusions: A DHI led to modest improvements in DASH and blood pressure among adults with hypertension but did not outperform the attention control. Further research is needed to understand the utility of DHIs to promote DASH and identify intervention components that support long-term behavior change.

Rationale : Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (TGF-β) activation mediated by α v integrins is central to the pathogenesis of IPF. Bexotegrast (PLN 74809) is an oral, once-daily, dual-selective inhibitor of α v β 6 and α v β 1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an α v β 6 -specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives : This Phase 2 study (NCT04072315) evaluated α v β 6 receptor occupancy in the lung, as assessed by changes from baseline in α v β 6 PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods : In this open-label, single-center, single-arm study, adults with IPF received up to 2 single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET/CT scan was conducted following administration of an α v β 6 -specific PET probe ([ 18 F]FP-R 0 1-MG-F2). α v β 6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results : Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (V T ) values decreased in a dose- and concentration-dependent manner. The V T data fit a simple saturation model, producing an unbound bexotegrast EC 50 estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions : Dose- and concentration-dependent α v β 6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160 to 320 mg dosing to evaluate efficacy in clinical trials of IPF. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

What is this summary about? This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone , which may decrease the pace of disease progression.The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib .

Nuclear energy, already a practical solution for supplying energy on a scale similar to fossil fuels, will likely increase its footprint over the next several decades to meet current climate goals. Gamma radiation is produced during fission in existing nuclear reactors and thus the need to detect leakage from nuclear plants, and effects of such leakage on ecosystems will likely also increase. At present, gamma radiation is detected using mechanical sensors that have several drawbacks, including: (i) limited availability; (ii) reliance on power supply; and (iii) requirement of human presence in dangerous areas. To overcome these limitations, we have developed a plant biosensor (phytosensor) to detect low-dose ionizing radiation. The system utilizes synthetic biology to engineer a dosimetric switch into potato utilizing the plant's native DNA damage response (DDR) machinery to produce a fluorescent output. In this work, the radiation phytosensor was shown to respond to a wide range of gamma radiation exposure (10-80 Grey) producing a reporter signal that was detectable at >3 m. Further, a pressure test of the top radiation phytosensor in a complex mesocosm demonstrated full function of the system in a 'real world' scenario., (© 2023 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: This study assessed the efficacy and safety of velusetrag-a 5-HT 4 agonist with pan-gastrointestinal prokinetic activity-for gastroparesis symptom management and gastric emptying (GE)., Methods: In this multicenter, double-blind, randomized, placebo-controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7-day mean Gastroparesis Cardinal Symptom Index 24-h composite score (GCSI-24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs)., Key Results: 232 subjects (183 females; 113 idiopathic gastroparesis) received treatment from February 2015 through June 2017. Least-squares mean improvement from baseline GCSI-24H (primary endpoint) at week 4 was -1.5 following velusetrag 5 mg vs -1.1 following placebo (treatment difference, -0.4; 95% confidence interval, -0.75 to -0.03; nominal p = 0.0327; Hochberg-adjusted p = 0.0980 [not significant]). Symptom improvement from baseline was achieved only with velusetrag 5 mg, which resulted in greater improvement from baseline vs placebo in all gastroparesis core symptoms, especially in subjects with idiopathic gastroparesis. Improvement from baseline GE by GES was greater in subjects receiving velusetrag (all doses) vs placebo; >70% of subjects receiving velusetrag 30 mg had GE normalization at 4 h. Treatment-emergent AEs were generally mild., Conclusions and Inferences: Velusetrag treatment was generally well-tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short-term improvement in gastroparesis symptoms., Clinicaltrials: GOV: NCT02267525., (© 2023 John Wiley & Sons Ltd.)

Phytosensors are genetically engineered plant-based sensors that feature synthetic promoters fused to reporter genes to sense and report the presence of specific biotic and abiotic stressors on plants. However, when induced reporter gene output is below detectable limits, owing to relatively weak promoters, the phytosensor may not function as intended. Here, we show modifications to the system to amplify reporter gene signal by using a synthetic transcription factor gene driven by a plant pathogen-inducible synthetic promoter. The output signal was unambiguous green fluorescence when plants were infected by pathogenic bacteria. We produced and characterized a phytosensor with improved sensing to specific bacterial pathogens with targeted detection using spectral wavelengths specific to a fluorescence reporter at 3 m standoff detection. Previous attempts to create phytosensors revealed limitations in using innate plant promoters with low-inducible activity since they are not sufficient to produce a strong detectable fluorescence signal for standoff detection. To address this, we designed a pathogen-specific phytosensor using a synthetic promoter-transcription factor system: the S-Box cis -regulatory element which has low-inducible activity as a synthetic 4xS-Box promoter, and the Q-system transcription factor as an amplifier of reporter gene expression. This promoter-transcription factor system resulted in 6-fold amplification of the fluorescence after infection with a potato pathogen, which was detectable as early as 24 h post-bacterial infection. This novel bacterial pathogen-specific phytosensor potato plant demonstrates that the Q-system may be leveraged as a powerful orthogonal tool to amplify a relatively weak synthetic inducible promoter, enabling standoff detection of a previously undetectable fluorescence signal. Pathogen-specific phytosensors would be an important asset for real-time early detection of plant pathogens prior to the display of disease symptoms on crop plants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Persad-Russell, Mazarei, Schimel, Howe, Schmid, Kakeshpour, Barnes, Brabazon, Seaberry, Reuter, Lenaghan and Stewart.)

Premise: Epiphytes are abundant in ecosystems such as tropical montane cloud forests where low-lying clouds are often in contact with vegetation. Climate projections for these regions include more variability in rainfall and an increase in cloud base heights, which would lead to drier conditions in the soil and atmosphere. While recent studies have examined the effects of drought on epiphytic water relations, the influence that atmospheric moisture has, either alone or in combination with drought, on the health and performance of epiphyte communities remains unclear., Methods: We conducted a 10-week drought experiment on seven vascular epiphyte species in two shadehouses, one with warmer and drier conditions and another that was cooler and more humid. We measured water relations across control and drought-treatment groups and assessed functional traits of leaves produced during drought conditions to evaluate trait plasticity., Results: Epiphytes exposed to drought and drier atmospheric conditions had a significant reduction in stomatal conductance and leaf water potential and an increase in leaf dry matter. Nonsucculent epiphytes from the drier shadehouse had the greatest shifts in functional traits, whereas succulent epiphytes released stored leaf water to maintain water status., Conclusions: Individuals in the drier shadehouse had a substantial reduction in performance, whereas drought-treated individuals that experienced cloud immersion displayed minimal changes in water status. Our results indicate that projected increases in the cloud base height will reduce growth and performance of epiphytic communities and that nonsucculent epiphytes may be particularly vulnerable., (© 2022 Botanical Society of America.)

High-fat diets are linked with obesity and changes in dopamine neurotransmission. Mounting evidence shows that saturated fat impacts dopamine neurons and their terminal fields, but little is known about the effect a diet high in unsaturated fat has on the dopamine system. This study sought to determine whether fat type, saturated vs. unsaturated, differentially affected body weight, blood glucose regulation, locomotor behavior, and control of dopamine release and uptake at dopamine neuron terminals in the nucleus accumbens (NAc). C57BL/6 mice were fed a control diet or a nutrient-matched diet high in saturated fat (SF), unsaturated flaxseed oil (Flax) or a blend of the two fats. After 6-weeks, mice from each high-fat diet group gained significantly more weight than Controls, but the group fed Flax gained less weight than the SF group and had fasting blood glucose levels similar to Controls. Ex-vivo fast scan cyclic voltammetry revealed the SF group also had significantly slower synaptic dopamine clearance and a reduced capacity for phasic dopamine release in the nucleus accumbens (NAc), but the Flax and Blend groups resembled Controls. These data show that different types of dietary fat have substantially different effects on metabolic phenotype and influence how dopamine terminals in the NAc regulate dopamine neurotransmission. Our data also suggests that a diet high in unsaturated fat may preserve normal metabolic and behavioral parameters as well as dopamine signaling in the NAc.

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction., Objective: Assess tildacerfont safety and efficacy., Design and Setting: Two Phase 2 open-label studies., Patients: Adults with 21OHD., Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2)., Main Outcome Measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments., Results: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%)., Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Over 100 million adults in the United States have hypertension. The DASH (Dietary Approaches to Stop Hypertension) eating pattern is an evidence-based first-line treatment option for hypertension; however, adherence to the DASH eating pattern at a population level remains low. To address this gap, we will implement Nourish, a randomized controlled efficacy trial that will leverage a commercially-available smartphone application and evidence-based behavior change principles to improve adherence to the DASH eating pattern among adults with hypertension., Methods: The Nourish trial is a two-arm, 12-month randomized control trial that will enroll adults (N = 300) with hypertension, defined as a systolic blood pressure of 120-159 mmHg; a diastolic blood pressure of 80-99 mmHg; and/or adults on blood pressure-lowering medication. Nourish will test the efficacy of a digital health intervention, as compared to the attention control arm, on DASH eating pattern adherence and blood pressure. Intervention components will include skills training, self-monitoring, personalized feedback, and responsive coaching. The primary outcome of the trial is 6-month changes in adherence to the DASH eating pattern, as measured by 24-h dietary recalls., Discussion: Millions of Americans remain in need of effective behavioral interventions to manage and improve their hypertension and its adverse consequences. The ubiquity of smartphones offers a promising approach to disseminate the DASH eating pattern. By leveraging these widely used smartphone applications, combined with evidence-based behavior change principles and the DASH eating plan, Nourish will demonstrate the effectiveness of a digital health intervention to improve DASH adherence, and ultimately, to reduce blood pressure. Trial Number: NCT03875., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag-a potent, selective, pan-gastrointestinal 5-hydroxytryptamine type 4 receptor agonist-is under investigation for treatment of GI motility disorders including gastroparesis., Aims: To assess the efficacy and safety of velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis., Methods: In this multicentre, randomised, double-blind, placebo-controlled, three-period fixed-sequence crossover phase 2 study, subjects with diabetic or idiopathic gastroparesis received oral velusetrag (5, 15 or 30 mg) or placebo once daily for 7 days each. The primary outcome was proportion of subjects achieving ≥20% reduction in GE half-time (GE t 1/2 ) from each treatment period baseline on day 7. Absolute and percent changes from baseline GE t 1/2 were also assessed. GE was measured using a [ 13 C]-octanoate breath test. Safety was evaluated from treatment-emergent adverse events (TEAEs)., Results: Thirty-four subjects (67.6% female; mean age, 46.3 years; 52.9% with diabetic gastroparesis) were included. Treatment with velusetrag 30 mg significantly increased the proportion of subjects with ≥20% reduction from baseline GE t 1/2 compared with placebo (52% vs 5%, P = 0.002), and GE t 1/2 was numerically reduced following all three doses of velusetrag relative to placebo treatment. Efficacy was similar between subjects with diabetic and idiopathic gastroparesis. Velusetrag treatment was generally well tolerated; most TEAEs were mild and related to GI transit acceleration., Conclusions: Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938)., (© 2021 John Wiley & Sons Ltd.)

At institutions with an emphasis on authentic research experiences as an integral part of the biology curriculum, COVID created a huge challenge for course instructors whose learning objectives were designed for such experiences. Moving such laboratory experiences online when remote learning became necessary has resulted in a new model for CUREs that utilizes free online databases to provide not only a novel research experience for students, but also the opportunity to engage in big data analysis. Cancer BioPortal (cBioPortal) is an open-access collective cancer research resource for storing and exploring clinical, genomic, proteomic, and transcriptomic data. cBioPortal eliminates the computational barrier of interpreting complex genomic data by providing easily understandable visualization that can be interpreted and translated into relevant biological insights. Because no prior computational knowledge is required, cBioPortal is an ideal educational tool for either in-person or distance learning environments. We developed a pedagogical approach, video tutorials, and data analysis workflows centered on using cBioPortal. Pedagogically, students develop an initial research outline that is continually updated and graded throughout the project. Progress during the project or course is assessed by a series of student presentations that are 5 to 15 minutes in length and are aimed at explaining the approach used in data acquisition, interpretation of the data, and relevance to the initial hypothesis. While cancer-specific, this analysis platform appeals to a wide range of classes and student interests. Further, the project has been successfully done both as an independent research experience and as part of a virtual class-based research project., (©2021 Author(s). Published by the American Society for Microbiology.)

Background: Delayed gastric emptying is the leading cause of enteral feeding intolerance (EFI) in critical illness. This phase 2a study compared TAK-954, a selective agonist of 5-hydroxytryptamine type 4 receptors, with metoclopramide in critically ill patients with EFI (NCT01953081)., Methods: A blinded, double-dummy trial was conducted in mechanically ventilated patients with EFI (>200 mL gastric residual volume within 24 hours before randomization). Patients were randomized to receive either 0.5 mg intravenous TAK-954 over 1 hour then 0.9% saline injection 4 times/d (sham metoclopramide) or the active comparator 10 mg intravenous metoclopramide 4 times/d and a 1-hour 0.9% saline infusion. After initial dosing, participants received a radiolabeled meal of liquid nutrient (Ensure; 106 kcal), and gastric emptying was measured (scintigraphy). Adverse events (AEs) were recorded from the time of consent through to day 5; serious AEs were collected to day 30., Results: Thirteen patients (TAK-954, n = 7; metoclopramide, n = 6) participated. Five patients in the TAK-954 group and 4 in the metoclopramide group experienced AEs (2 and 3, respectively, were serious). All AEs except 1 (diarrhea in the metoclopramide group) were considered unrelated to study drug. Following treatment, a greater proportion of patients receiving TAK-954 had normal gastric retention (<13% retention at 180 minutes) than those receiving metoclopramide (6/7 vs 3/6 patients, respectively)., Conclusion: A single dose of 0.5 mg intravenous TAK-954 appears to have at least similar efficacy in accelerating gastric emptying to multiple doses of 10 mg metoclopramide and was not associated with increased AEs., (© 2020 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals, Inc. on behalf of American Society for Parenteral and Enteral Nutrition.)

Revefenacin inhalation solution is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. Mass balance, pharmacokinetics, and metabolism of revefenacin were evaluated after intravenous and oral administration of [ 14 C]-revefenacin in healthy subjects. Pharmacological activity of the major revefenacin metabolite was also assessed. Adult males ( n = 9) received 20 μg intravenously of approximately 1 μCi [ 14 C]-revefenacin and/or a single 200-μg oral solution of approximately 10 μCi [ 14 C]-revefenacin. Mean recovery of radioactive material was 81.4% after intravenous administration (54.4% in feces; 27.1% in urine) and 92.7% after oral dosing (88.0% in feces, 4.7% in urine). Mean absolute bioavailability of oral revefenacin was low (2.8%). Intact revefenacin accounted for approximately 52.1% and 13.1% of the total radioactivity in plasma after intravenous and oral administration, respectively. Two main circulating metabolites were observed in plasma. After an intravenous dose, a hydrolysis product, THRX-195518 (M2) was observed that circulated in plasma at 14.3% of total radioactivity. After an oral dose, both THRX-195518 and THRX-697795 (M10, N-dealkylation and reduction of the parent compound) were observed at 12.5% of total circulating radioactivity. THRX-195518 was the major metabolite excreted in feces and comprised 18.8% and 9.4% of the administered intravenous and oral dose, respectively. The major metabolic pathway for revefenacin was hydrolysis to THRX-195518. In vitro pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M 3 receptor relative to revefenacin. Receptor occupancy analysis suggested that THRX-195518 has minimal contribution to systemic pharmacology relative to revefenacin after inhaled administration. SIGNIFICANCE STATEMENT: The major metabolic pathway for revefenacin was hydrolysis to the metabolite THRX-195518 (M2), and both revefenacin and THRX-195518 underwent hepatic-biliary and fecal elimination after oral or intravenous administration with negligible renal excretion. Pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M 3 muscarinic receptor relative to revefenacin and that THRX-195518 has minimal contribution to systemic pharmacology after inhaled administration., Competing Interests: All authors had access to the data included in the manuscript. The data sets generated during the current study are not publicly available but can be requested from the corresponding author. D.L.B., S.Y., P.-J.C. are employees of Theravance Biopharma US, Inc. C.N.B. and S.S.H. are former employees of Theravance Biopharma US, Inc. M.T.B. is consultant for and received financial support from Theravance Biopharma US, Inc., (Copyright © 2020 The Author(s).)

Background: Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient's ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking., Research Questions: What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIF D ) and HandiHaler (Boehringer Ingelheim; PIF HH ) resistances?, Study Design and Methods: Data from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIF D and PIF HH was defined using data from two randomized, controlled, phase 3 trials (studies 0128 and 0149)., Results: In study 0128, the mean values (SD) for PIF at zero resistance and PIF HH were 84.6 (33.4) and 57.3 (26.1) L/min, respectively. In study 0149, the mean values (SD) for PIF D and PIF HH were 42.4 (11.2) and 29.0 (8.3) L/min, respectively. At the mean level, the mean difference between measurement attempts for PIF D and PIF HH was small, < 5 and < 3 L/min, respectively. The repeatability limit was determined as 10 and 5 L/min for PIF D and PIF HH , respectively. Modeling the relationship between PIF D and PIF HH , after controlling for significant covariates, demonstrated that a PIF D value of 60 L/min was approximately equivalent to PIF HH of 40 L/min., Interpretations: This analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies., Clinical Trial Registration: ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV 1 ) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD., Methods: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV 1 , St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 μg and placebo: severe and very severe airflow limitation (percent predicted FEV 1 30%-< 50% and < 30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥ 12% and ≥ 200 mL increase in FEV 1 ) to short-acting bronchodilators, concurrent use of long-acting β agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors., Results: Revefenacin demonstrated significant improvements in FEV 1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years., Conclusions: Revefenacin showed significantly greater improvements in FEV 1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD., Trial Registration: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

Although no nebulized, dual mechanism, long-acting bronchodilator is currently marketed, with the approval of once-daily long-acting muscarinic antagonist (LAMA) revefenacinefenacin, it is theoretically possible to deliver a LAMA and long-acting beta2-agonist via standard jet nebulizer. The primary and secondary objectives of our study were to characterize the safety profile of revefenacin administered sequentially before or in combination with formoterol, via standard jet nebulizer in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, 42-day trial (NCT03573817), patients received revenacin 175 µg (n=63) or placebo (n=59), followed by formoterol 20 µg in the morning and formoterol alone in the evening formoterol 21 days via standard jet nebulizer (sequential administration). For another 21 days, revefenacin/placebo and formoterol, were administered as mixed solutions via single nebulization in the morning (combined administration), and formoterol alone in the evening. The adverse events' (AEs) incidence was higher in the placebo + formoterol arms (11%-12%) than in the revefenacin + formoterol arms (5%-8%). The most common AEs were worsening/exacerbation of COPD, cough, and dizziness. There were no serious AEs or deaths reported in any arm. The least squares mean in trough forced expiratory volume in 1 second (FEV 1 ) versus baseline was higher in the revefenacin + formoterol arms (116-157 mL) than in the placebo + formoterol arms (35-53 mL). Revefenacin had a safety profile similar to formoterol alone when delivered sequentially or combined. Trough FEV 1 was similar when revefenacin was delivered sequentially or combined with formoterol, with revefenacin providing an additional 81-104 mL improvements over formoterol alone., Competing Interests: TMS received research support from West-Ward Pharmaceuticals, Theravance Biopharma US, Inc., GlaxoSmithKline, Pearl Therapeutics, Chiesi, AstraZeneca, Novartis, Boehringer Ingelheim, Forest, Compleware, Evidera, Novartis, Oncocyte, Teva, Vapotherm, Sunovion, Proterix BioPharma, Seer and Sanofi. He has also received speaker fees from GlaxoSmithKline, Mylan Inc./Theravance Biopharma US, Inc., and Sunovion, and consulting fees from Vapotherm. EJM and GDC are current employees of Theravance Biopharma US, Inc. CNB was an employee of Theravance Biopharma US, Inc., at the time this study was conducted., (JCOPDF © 2020.)

Background: Combinations of a long-acting muscarinic receptor antagonist (LAMA), long-acting β-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstructive pulmonary disease (COPD) exacerbations on bronchodilator monotherapy. In this prespecified subgroup analysis, we assessed the efficacy and safety of the LAMA revefenacin in patients with COPD taking concomitant LABA, including ICS/LABA (LABA subgroup)., Methods: Efficacy data were obtained from two 12-week, replicate, placebo-controlled trials and safety data were pooled from the 12-week and a 52-week tiotropium-controlled trial. Patients received revefenacin 175 µg or placebo in the 12-week or tiotropium 18 µg in the 52-week studies. The efficacy endpoint was least squares (LS) mean change from baseline in trough forced expiratory volume in 1 second (FEV 1 ). Clinical health outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ)., Results: Revefenacin produced similar improvements from baseline in trough FEV 1 in the non-LABA and LABA subgroups [placebo-adjusted LS mean change (95% confidence interval) in day 85 trough FEV 1 , 150.9 (110.3-191.6) ml and 139.2 (82.9-195.5) ml; p  < 0.0001 versus placebo]. Similar improvements were observed in SGRQ scores in the non-LABA and LABA subgroups [-3.3 (-5.4 to -1.2) and -3.4 (-6.3 to -0.6)]. Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse events reported in the LABA than the non-LABA subgroup., Conclusions: Once daily revefenacin for nebulization can be an effective and well-tolerated treatment for patients who require concomitant use of LABA with or without ICS., Clinicaltrials.gov Identifiers: NCT02512510, NCT02459080, NCT02518139 The reviews of this paper are available via the supplemental material section.

Revefenacin is a novel once-daily, lung-selective, long-acting muscarinic antagonist developed as a nebulized inhalation solution for the maintenance treatment of chronic obstructive pulmonary disease. In a randomized, 4-way crossover study, healthy subjects received a single inhaled dose of revefenacin 175 µg (therapeutic dose), revefenacin 700 µg (supratherapeutic dose), and placebo via standard jet nebulizer, and a single oral dose of moxifloxacin 400 mg (open-label) in separate treatment periods. Electrocardiograms were recorded, and pharmacokinetic samples were collected serially after dosing. The primary end point was the placebo-corrected change from baseline QT interval corrected for heart rate using Fridericia's formula, analyzed at each postdose time. Concentration-QTc modeling was also performed. Following administration of revefenacin 175  and 700 µg, placebo-corrected change from baseline QTcF (ΔΔQTcF) values were close to 0 at all times, with the largest mean ΔΔQTcF of 1.0 millisecond (95% confidence interval [CI], -1.2 to 3.1 milliseconds) 8 hours postdose and 1.0 millisecond (95%CI, -1.1 to 3.1 milliseconds) 1 hour postdose after inhalation of revefenacin 175 and 700 µg, respectively. Revefenacin did not have a clinically meaningful effect on heart rate (within ±5 beats per minute of placebo), or PR and QRS intervals (within ±3 and ±1 milliseconds of placebo, respectively). Using concentration-QTc modeling, an effect of revefenacin > 10 milliseconds can be excluded within the observed plasma concentration range of up to ≈3 ng/mL. Both doses of revefenacin were well tolerated. These results demonstrate that revefenacin does not prolong the QT interval., (© 2019 Theravance Biopharma. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: Telavancin-a lipoglycopeptide antibacterial agent active against Gram-positive pathogens including methicillin-sensitive and -resistant Staphylococcus aureus (MRSA)-is approved in the USA for once-daily intravenous use. This registry study captured patient characteristics, prescribing patterns, and treatment outcomes associated with telavancin use in real-world clinical practice., Objective: This prospective, multicenter, observational study will characterize current real-world practice patterns for the use of telavancin in the USA by describing demographic and clinical conditions, examining the process of care and rationale for use, and describing the clinical effectiveness and selected safety outcomes among patients treated with telavancin., Methods: The Telavancin Observational Use Registry (TOUR™) is an observational multicenter registry study. Clinical data-including patient demographics, pathogens, telavancin dosing and treatment duration, and adverse events-along with investigators' assessments of outcome, were collected through retrospective medical chart review., Results: Data from 1063 patients were collected from 45 US sites. Of these patients, 29.4% were ≥ 65 years of age [mean age ± standard deviation, 55.2 ± 15.4 years; median age (interquartile range), 57.0 (46.0-66.0)], 53.4% were male, and 83.4% were White. The primary infections in these patients included complicated skin and skin-structure infection (48.7%), bone and joint infections (27.4%), bacteremia and endocarditis (14.2%), and lower respiratory tract infections (8.5%). The predominant pathogen identified was MRSA (37.7%). The mean telavancin dose and duration of treatment were 741.7 ± 194.3 mg and 17 ± 17 days, respectively. Of the 964 (90.7%) patients for whom an end-of-treatment assessment was available, 77.7% had a positive clinical response, 10.1% failed treatment, and 12.2% had indeterminate outcomes., Conclusions: Real-world data collected from the TOUR study show once-daily telavancin is being used for the treatment of a variety of Gram-positive infections with generally positive clinical outcomes.

Background: Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 μg or 88 μg daily during the 52-week trial., Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 μg or 88 μg in a double-blind manner, or open-label active control tiotropium., Results: Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV 1 ). The trough FEV 1 profile (least squares mean change from baseline) for revefenacin 175 μg ranged from 52.3-124.3 mL and the trough FEV 1 profile for tiotropium ranged from 79.7-112.8 mL. In subgroup comparisons, the effect of revefenacin on trough FEV 1 was comparable in patients taking concomitant long-acting β-agonists, with or without inhaled corticosteroids, with patients who were not taking these medications. There were statistically significant (p < 0.05) improvements in all measured health status outcomes (evaluated using St. George's Respiratory Questionnaire, COPD Assessment Test, Clinical COPD Questionnaire and Baseline and Transition Dyspnea Index) from 3 months onward, in all treatment arms., Conclusions: Significant sustained improvements from baseline in trough FEV 1 and respiratory health outcomes were demonstrated for 175-μg revefenacin over 52 weeks, further supporting its use as a once-daily bronchodilator for the nebulized treatment of patients with COPD., Trial Registration: NCT02518139 ; Registered 5 August 2015.

Background: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus®)., Methods: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV 1 ) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler® DPI., Results: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV 1 , 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV 1 from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV 1 < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3-91.9) mL in trough FEV 1 and 103.5 (7.7-199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV 1 in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV 1 < 50% predicted populations., Conclusions: Revefenacin did not produce significant improvements in FEV1 versus tiotropium in the ITT population, but increased trough FEV 1 in patients with FEV 1 < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456)., Competing Interests: DAM has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc, Grifols SA, Sunovion Pharmaceuticals Inc., Theravance Biopharma, Inc., and Trevi and is on the speaker’s bureau for AstraZeneca, Boehringer Ingelheim, and Sunovion Pharmaceuticals Inc. JAO has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc, Mylan Inc, Reckitt Benckiser Group plc, Sunovion Pharmaceuticals Inc., and Theravance Biopharma, Inc. EJM and GDC are employees of Theravance Biopharma US, Inc. CNB and SP were employees of Theravance Biopharma US, Inc. at the time this study was conducted., (JCOPDF © 2019.)

Introduction: The efficacy and safety of telavancin versus vancomycin in microbiologically evaluable patients with hospital-acquired or ventilator-associated pneumonia (HAP/VAP) caused by Staphylococcus aureus with vancomycin minimum inhibitory concentration (MIC) ≥ 1.0 µg/mL was analyzed using data derived from previously reported Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials., Methods: This post hoc subgroup analysis of two randomized, double-blind, comparator-controlled, parallel-group phase 3 trials conducted at 274 sites in 38 countries included 194 microbiologically evaluable patients with HAP/VAP caused by monomicrobial S. aureus with vancomycin MIC ≥ 1.0 µg/mL. Patients received intravenous telavancin (10 mg/kg every 24 h) or intravenous vancomycin (1 g every 12 h with site-specific modifications) for 7-21 days. Efficacy was assessed by clinical cure, defined as improvement or non-progression of radiographic findings at end of treatment and resolution of pneumonia signs and symptoms at follow-up/test-of-cure visits, and survival 28 days post-randomization. Safety was assessed from categorical shifts in creatinine clearance during therapy and adverse events (AEs)., Results: Clinical cure rates were numerically greater following telavancin versus vancomycin treatment overall (85.4% vs. 74.3%; treatment difference [95% confidence interval (CI)], 11.1% [- 0.002%, 22.2%]) and in patients aged ≥ 65 years (81.6% vs. 66.2%; treatment difference [95% CI], 15.5% [- 0.9%, 30.2%]) patients with VAP (92.3% vs. 47.6%; treatment difference [95% CI], 44.7% [18.1%, 64.9%]), and patients with baseline Acute Physiology And Chronic Health Evaluation II score ≥ 20 (71.4% vs. 55.6%; treatment difference [95% CI], 15.9% [- 11.7%, 40.5%]). Renal function declined in 7 (7.9%) patients receiving telavancin and 6 (5.7%) patients receiving vancomycin. Survival proportion was numerically higher (85.2% vs. 80.2%; treatment difference [95% CI], 5.0% [- 5.8%, 15.8%]) and AEs were comparable in patients treated with telavancin versus vancomycin., Conclusion: Telavancin is an alternative to vancomycin for HAP/VAP caused by S. aureus with vancomycin MIC ≥ 1 µg/mL., Funding: Theravance Biopharma R&D, Inc., South San Francisco, CA, USA.

This article contains information on the experimental design and methods on how the safety and tolerability data concerning patients with moderate to very severe chronic obstructive pulmonary disease (COPD) were obtained. This is in addition to our original research article. [1] We have also provided information on the clinical laboratory tests that were conducted. Further interpretation and discussion of the data are demonstrated in the article "Revefenacin, a Once-daily, Lung-selective, Long-acting Muscarinic Antagonist for Nebulized Therapy: Safety and Tolerability Results of a 52-week Phase 3 Trial in Moderate to Very Severe Chronic Obstructive Pulmonary Disease." [1].

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 μg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 μg (n = 23, 5.6%) and revefenacin 175 μg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 μg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 μg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 μg, and revefenacin 175 μg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 μg, revefenacin 175 μg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 μg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 μg and 175 μg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 μg and 175 μg over 52 weeks of treatment., Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 μg or 175 μg in a double-blind manner, or open-label active control tiotropium., Results: Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74.7%]; 175 μg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 μg (73 [21.8%]) than with 88 μg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 μg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 μg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 μg or tiotropium with a concurrent long-acting β-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 μg., Conclusions: Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Revefenacin, a novel, lung-selective, long-acting muscarinic antagonist, has been developed for nebulized therapy for chronic obstructive pulmonary disease (COPD). We present the results of replicate Phase III efficacy and safety studies of revefenacin in patients with moderate to very severe COPD., Methods: In 2 double-blind, parallel-group studies, (Study 0126 and Study 0127), patients ≥ 40 years old were randomized to revefenacin 88 μg, revefenacin 175 μg or placebo administered once daily by standard jet nebulizer for 12 weeks. The primary endpoint was 24-hour trough forced expiratory volume in 1 second (FEV 1 ) on day 85. Secondary efficacy endpoints included overall treatment effect (OTE) on trough FEV 1 and peak FEV 1 (0-2 hours after first dose). Safety assessments included treatment-emergent adverse events., Results: At day 85, revefenacin 88 µg and 175 µg improved trough FEV 1 versus placebo in Study 0126 (by 79 mL [ p =0.0003] and 146 mL [ p <0.0001]) and Study 0127 (by 160 mL and 147 mL; both p <0.0001). Compared with placebo, pooled data of revefenacin 88 µg and 175 µg increased OTE trough FEV 1 by 115 mL and 142 mL (both p <0.001) and increased peak FEV 1 by 127 mL and 129 mL (both p <0.0001). Revefenacin 175 µg demonstrated greater improvements in FEV 1 in concomitant long-acting beta2-agonist patients and in more severe patients than revefenacin 88 µg. Adverse events were minor., Conclusion: Revefenacin, administered once daily for 12 weeks to patients with moderate to very severe COPD, demonstrated clinically significant improvements in trough FEV 1 and OTE FEV 1 . Revefenacin was generally well tolerated with no major safety concerns., Competing Interests: GTF has received grants, served on advisory boards, received consulting fees and/or received speaking fees from AstraZeneca, Boehringer Ingelheim, Circassia, Forest, GlaxoSmithKline, Innoviva, Meda, Mylan, Novartis, Pearl Therapeutics, Sanofi, Sunovion, Theravance Biopharma and Verona. GF and KKP have nothing to declare. CNB, EJM, BH, SP and GC are employees of Theravance Biopharma US, Inc. Mylan Inc., (Canonsburg, Pennsylvania) and Theravance Biopharma US, Inc., (South San Francisco, California) funded medical writing support., (JCOPDF © 2019.)

Background: Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD., Methods: In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 μg), active control ipratropium (500 μg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 μg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0-6 h) forced expiratory volume in 1 s (FEV 1 ) in Study 0059, and trough FEV 1 after the final dose (Day 7) in Study 0091. In both studies, secondary endpoints included area under the FEV 1 -time curve (FEV 1 AUC) values from time 12-24 h post dose and FEV 1 AUC values from time zero to 24 h post dose., Results: Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV 1 was significantly higher (p < 0.001) for revefenacin and ipratropium compared to placebo, with differences of 176.8 mL for 350 μg revefenacin, 162.2 mL for 700 μg revefenacin and 190.6 mL for ipratropium. In Study 0091, mean trough FEV 1 on Day 7 was significantly higher (p < 0.006) for all revefenacin doses compared to placebo, with differences ranging from 53.5 mL (22 μg dose) to 114.2 mL (175 μg dose). The results for the other spirometry endpoints were consistent with the primary endpoint for each study, demonstrating that the bronchodilator effect of revefenacin lasted more than 24 h following nebulized administration. Revefenacin was rapidly absorbed and extensively metabolized, followed by a slow apparent terminal elimination and minimal accumulation with repeated dosing. In both studies, adverse events were generally mild and occurred with similar frequencies in all groups, with no indication of significant systemic anti-muscarinic activity at any dose., Conclusions: Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Revefenacin is a once-daily long-acting muscarinic antagonist (LAMA) in clinical development for the treatment of patients with chronic obstructive pulmonary disease (COPD). In a dose-ranging study, nebulized once-daily revefenacin had a long duration of action in patients after 7 days' administration of doses up to 700 μg. In this multiple-dose study, the bronchodilation efficacy and adverse events profile were characterized in patients administered nebulized revefenacin once daily for 28 days., Methods: A total of 355 COPD patients (mean age 62 years, mean forced expiratory volume in 1 s [FEV 1 ] 44% of predicted) were randomized in a double-blind, placebo-controlled parallel group study. Inhaled corticosteroids as well as short-acting bronchodilators were permitted. Once-daily treatments (44, 88, 175 or 350 μg revefenacin or matching placebo) were administered by a standard jet nebulizer, for 28 days. The primary endpoint was change from baseline in D28 trough FEV 1 , and secondary endpoints included weighted mean FEV 1 over 0 to 24 h and rescue medication (albuterol) use. Safety evaluations included adverse events, laboratory assessments, electrocardiograms and 24-h Holter profiles., Results: Revefenacin (88, 175 and 350 μg) significantly improved D28 trough FEV 1 over placebo (187.4, 166.6 and 170.6 mL, respectively, all p < 0.001); 44 μg produced a sub-therapeutic response. At doses ≥88 μg, more than 80% of patients achieved at least a 100-mL increase from baseline FEV 1 in the first 4 h post dose compared with 33% of placebo patients. For doses ≥88 μg, D28 24 h weighted mean differences from placebo for FEV 1 were numerically similar to respective trough FEV 1 values, indicating bronchodilation was sustained for 24 h post dose. Doses ≥88 μg reduced the average number of albuterol puffs/day by more than one puff/day. The 350 μg dose did not demonstrate additional efficacy over that observed with 175 μg revefenacin. Revefenacin was generally well tolerated, with minimal reports of systemic anti-cholinergic effects., Conclusions: These data suggest that 88 and 175 μg revefenacin are appropriate doses for use in longer-term safety and efficacy trials. Revefenacin offers the potential for the first once-daily LAMA for nebulization in patients with COPD who require or prefer a nebulized drug delivery option., Trial Registration: ClinicalTrials.gov NCT02040792 . Registered January 16, 2014.

Aims: To examine the association between health insurance coverage, insulin management plans, and their impact on diabetes control in a pediatric type 1 diabetes mellitus clinic population., Methods: Retrospective cohort design drawn from the medical records of the Pediatric Endocrinology Clinic at the University of Louisville, Kentucky., Results: Out of 701 patients, 223 had public insurance, and 478 had private insurance. 77% of publically insured used two or three injections per day vs. 40% private. Conversely, 58% of privately insured used a multiple daily injection (MDI) plan or insulin pump (vs. 21%). 84% of MDI patients had private insurance with 93% using insulin pens compared with 38% of publically insured. Mean HbA1c was 8.6% for privately insured vs. 9.8% public, p<0.0001. Privately insured MDI and pump patients had the lowest HbA1cs., Conclusions: Insurance type had a significant effect on the insulin management plan used and was the most significant factor in overall diabetes control. Limitations on insulin pen use and number of glucose test strips may play a role in the decreased use of MDI/insulin pumps by publicly insured patients. Addressing factors related to insurance type, including availability of resources, could substantially improve diabetes control in those with public insurance.

Lung cancer remains a devastating disease associated with substantial morbidity and mortality. Recent research has suggested that lung cancer screening with spiral computed tomography scans might reduce lung cancer mortality. Studies of lung cancer screening have also suggested that significant numbers of participants quit smoking after screening. However, most have relied solely on self-reported smoking behavior, which may be less accurate among participants in lung cancer screening. To assess the validity of self-reported smoking status among participants in a lung cancer screening trial, this study compared self-reported smoking status against urinary cotinine levels. The sample included 55 consecutive participants enrolled in a randomized clinical trial comparing annual spiral computed tomography and chest X-ray for lung cancer screening. Participants were a mean of 59 years of age and predominantly Caucasian (96%) and male (55%). Self-reported smoking status was assessed before and after participants learned of the purpose of the biochemical verification study. Using urinary cotinine as the "gold standard," the sensitivity and specificity of self-reported smoking status were 91% and 95%, respectively (kappa = 0.85, P < 0.001, 95% confidence interval = 0.71-0.99). Total misclassification rate was 7%. However, three of the four misclassified participants reported concurrent use of nicotine replacement strategies. Eliminating these cases from the analysis revealed sensitivity of 100% and specificity of 95% (kappa = 0.96, P < 0.001, 95% confidence interval = 0.88-1.00). In conclusion, self-reported smoking status among participants in a lung cancer screening trial was highly consistent with urinary cotinine test results.

Study Design: Hyper-reflexia, measured as a decrease of low frequency-dependent depression of the H-reflex, is known to occur in both humans and animals after spinal cord injury (SCI). Previous studies have shown that passive exercise for 3 months could be used to restore low frequency-dependent depression of the H-reflex after SCI., Objective: To determine the effects of various periods of time on the ability of passive exercise to restore low frequency-dependent depression of the H-reflex., Setting: Spinal Cord Injury Mobilization Program of the Center for Translational Neuroscience, the research arm of the Jackson T Stephens Spine and Neuroscience Institute, Little Rock, AR, USA., Methods: Adult rats underwent complete spinal cord transection at the T10 level. The hindlimbs were passively exercised in different groups of rats for 1 h/day, 5 days/week for 15, 30, 45, 60, or 90 days, and low frequency-dependent depression of the H-reflex was tested., Results: Statistically significant low frequency-dependent depression of the H-reflex was evident by 30 days of exercise, although numerical reductions were seen even at 15 days. There was a linear decrease in low frequency-dependent depression of the H-reflex with duration of passive exercise., Conclusions: Passive exercise can restore frequency-dependent depression of spinal reflexes in a time-dependent manner if used following complete spinal transection.

The crude product of deamination of the commercially available L-homoserine was acetylated and the 2-O-acetyl-3-deoxy-L-glycero-tetronolactone (18) formed was used to N-acylate methyl perosaminide (methyl 4-amino-4,6-dideoxy-alpha-D-mannopyranoside, 12) and its 2,3-O-isopropylidene derivative. The major product isolated from the reaction was the crystalline methyl 4-(4-O-acetyl-3-deoxy-L-glycero-tetronamido)-4,6-dideoxy-alpha-D-+ ++mannopyranoside (1, 70-75%) resulting from acetyl group migration in the initially formed 2'-O-acetyl derivative. O-Deacetylation of 1 gave the title amide 2. Compound 2, obtained crystalline for the first time, was fully characterized, and its crystal structure was determined. Deoxytetronamido derivatives diastereomeric with 1 and 2, respectively, were obtained by the acylation of 12 with 2-O-acetyl-3-deoxy-D-glycero-tetronolactone (prepared from D-homoserine), and subsequent deacetylation. Structures of several byproducts of the reaction of 12 with 18 have been deduced from their spectral characteristics. Since these byproducts were various O-acetyl derivatives of 2, the title compound could be obtained in approximately 90% yield by deacetylating (Zemplén) the crude mixture of N-acylation products, followed by chromatography.