Aggregate IND Safety Reporting for Smaller Companies and Programs.

The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy. Ball et al. (Ball et al. in Ther Innov Regul Sci 55:705-716, 2021) have reported on how the Final Rule has been implemented by large pharmaceutical companies. This paper explores the experiences of small sponsor companies regarding the Final Rule, to understand the current challenges that they have been facing to meet aggregate IND safety reporting requirements.

Validation of a Modified National Eye Institute Grading Scale for Corneal Fluorescein Staining.

Purpose: Validation of the novel Lexitas modified NEI scale for use in assessment of corneal fluorescein staining. Patients and Methods: A series of 18 illustrations and 14 clinical photographs depicting varying severity levels of corneal fluorescein staining were assessed by 3 independent examiners. Regions of the cornea were graded for staining severity based on 3 different grading scales: the original NEI staining scale (density-based scoring; 0-3 scale), a structured version of the NEI scale (dot-count scoring; 0-3 scale), and the Lexitas modified NEI staining scale (0-4 scale with half-point increments). Kappa statistics (simple and weighted) were computed to determine intra-examiner image grading repeatability for each examiner over 2 separate assessments. Inter-examiner assessment reliability utilized the scores from the first read of each examiner, and pairs of examiners to compute kappa statistics. Results: Data was analyzed from the scores provided by the examiners from each gradable corneal region on 32 images (18 illustrations and 14 photographs) for a total of 154 corneal regions across the 3 grading scales for each validation run. The mean intra-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.67/0.72, 0.91/0.94, 0.80/0.92 for the graded illustrations, and 0.83/0.88, 0.76/0.85, 0.77/0.88 for the graded photographs, respectively. The mean inter-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.59/0.65, 0.86/0.90, and 0.78/0.91 for the graded illustrations, and 0.80/0.88, 0.84/0.89, 0.69/0.88 for the graded photographs, respectively. Conclusion: The expanded scale of the Lexitas modified NEI staining scale demonstrated a high degree of reliability and repeatability of grading assessments within and across individual examiners, comparing favorably with the original NEI staining scale. A future investigation into the in-office utility of the Lexitas modified NEI staining scale is warranted.

Safety and Effectiveness of Tenofovir Alafenamide in Usual Clinical Practice Confirms Results of Clinical Trials: TARGET-HBV.

BACKGROUND: Nucleos(t)ide analogues, with a proven record of safety and efficacy, have been the therapy of choice for over a decade for the treatment of chronic hepatitis B. The approval of tenofovir alafenamide (TAF) in 2016 provided an additional treatment option. AIMS: The aim of this study was to evaluate the characteristics and clinical outcomes of patients treated with TAF in usual clinical practice. METHODS: Retrospective data from electronic health records was obtained from those enrolled in TARGET-HBV, a longitudinal observational cohort study of patients with chronic hepatitis B managed according to local practice standards at community and academic medical centers throughout the U.S. RESULTS: Of 500 patients enrolled, most were male (66%) and of Asian race (66%) with median age of 55 years. Cirrhosis was evident in 15%. Most patients (82%) had switched to TAF after treatment with other antivirals. The perceived safety profile of TAF was cited as the primary reason for changing therapy (32%). TAF was well tolerated and only 4 patients discontinued therapy due to adverse event during a median duration of TAF dosing of 74 weeks. Among those with paired laboratory data 12-18 months after switching to TAF, biochemical response and HBV DNA suppression was maintained. Most patients had normal renal function which was essentially unchanged throughout follow-up. CONCLUSIONS: TAF is frequently utilized in routine clinical practice due to the perception of its improved safety profile. The current study supports the growing body of evidence regarding the safety and effectiveness of TAF. Trial Registration ClinicalTrials.gov identifier: NCT03692897, https://clinicaltrials.gov/ct2/show/NCT03692897 .

GEECORR: A SAS macro for regression models of correlated binary responses and within-cluster correlation using generalized estimating equations.

BACKGROUND AND OBJECTIVES: Generalized estimating equations (GEE) provide population-averaged model inference for longitudinal and clustered outcomes via a generalized linear model for the effect of explanatory variables on the marginal mean, while intra-cluster correlations are ordinarily treated as nuisance parameters. Software to richly parameterize and conduct inference for complex correlation structures in the marginal modeling framework is scarce. METHODS: A SAS macro, GEECORR, has been developed for the analysis of clustered binary data based on GEE to include additional estimating equations for modeling pairwise correlation between binary variates as a function of covariates. RESULTS: We illustrate the macro in a surveillance study with repeated measures, a longitudinal study, and a study with biological clustering. CONCLUSIONS: This article provides an overview of the GEE method consisting of a pair of estimating equations, describes the features and capabilities of the GEECORR macro including regression diagnostics and finite-sample bias-corrected covariance estimators, and demonstrates the macro usage for three studies.

A Real-World Observational Cohort of Patients with Hepatocellular Carcinoma: Design and Rationale for TARGET-HCC.

This study describes the design of the TARGET-hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET-HCC is a 5-year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient-reported outcome measures and provide biological specimens for future translational studies. The TARGET-HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol-related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET-HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC.

Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor.

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over ß-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.

Patient Characteristics and Outcomes of 11 721 Patients With Coronavirus Disease 2019 (COVID-19) Hospitalized Across the United States.

BACKGROUND: As coronavirus disease 2019 (COVID-19) disseminates throughout the United States, a better understanding of the patient characteristics associated with hospitalization, morbidity, and mortality in diverse geographic regions is essential. METHODS: Hospital chargemaster data on adult patients with COVID-19 admitted to 245 hospitals across 38 states between 15 February and 20 April 2020 were assessed. The clinical course from admission, through hospitalization, and to discharge or death was analyzed. RESULTS: A total of 11 721 patients were included (majority were >60 years of age [59.9%] and male [53.4%]). Comorbidities included hypertension (46.7%), diabetes (27.8%), cardiovascular disease (18.6%), obesity (16.1%), and chronic kidney disease (12.2%). Mechanical ventilation was required by 1967 patients (16.8%). Mortality among hospitalized patients was 21.4% and increased to 70.5% among those on mechanical ventilation. Male sex, older age, obesity, geographic region, and the presence of chronic kidney disease or a preexisting cardiovascular disease were associated with increased odds of mechanical ventilation. All aforementioned risk factors, with the exception of obesity, were associated with increased odds of death (all P values < .001). Many patients received investigational medications for treatment of COVID-19, including 48 patients on remdesivir and 4232 on hydroxychloroquine. CONCLUSIONS: This large observational cohort describes the clinical course and identifies factors associated with the outcomes of hospitalized patients with COVID-19 across the United States. These data can inform strategies to prioritize prevention and treatment for this disease.

Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI). METHODS: We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type. RESULTS: Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P < .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77). CONCLUSIONS: More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.

High-alert medication administration and intravenous smart pumps: A descriptive analysis of clinical practice.

BACKGROUND: The Institute for Safe Medication Practices (ISMP) describes high alert medications (HAM) as medications that represent a heightened risk of patient harm when used in error. IV smart pumps with dose error reduction systems (DERS) were created to help address medication administration errors. Compliance with DERS provides a measure of how accurately a hospital uses smart pump technology to reduce IV medication error. OBJECTIVE: The primary purpose of this research was to use the REMEDI dataset, an aggregate, multi-hospital database inclusive of smart pump analytics, to improve the current understanding of clinical practices for IV HAM administration. METHODS: Descriptive analyses and analysis of variance (ANOVA) were used to test for differences in the mean DERS alert override rate, and mean DERS alert override to reprogram ratio between non-HAM and HAM overall, by hospital system, and by pump type. RESULTS: High mean override rates for non-HAM (73.8%) and HAM (75.8%) and high override to reprogram ratios for both non-HAM (7.30) and HAM (9.92) were seen. No significant differences were found in override rates (p = 0.23) and override to reprogram ratios (p = 0.06) between non-HAM and HAM. By hospital system, significant variability in override rates and override to reprogram ratios were seen. By pump type, there were no significant differences in the mean override rates (Baxter: p = 0.09; BD p = 0.34; ICU Medical p = 0.18) and the mean override to reprogram ratios (Baxter p = 0.84; BD p = 0.03; ICU Medical p = 0.63) between non-HAM and HAM. CONCLUSIONS: These findings indicate that the majority of alerts generated are bypassed by clinicians at the point of care, a symptom of alert fatigue. Given the potential for significant patient harm with HAM and the high DERS alert override rates that routinely occur during IV medication administration, this study provides further support for clinician-driven IV smart pump innovation to improve alert fatigue.

Fox sightings in a city are related to certain land use classes and sociodemographics: results from a citizen science project.

BACKGROUND: Red foxes (Vulpes vulpes L.) have become successful inhabitants of urban areas in recent years. However, our knowledge about the occurrence, distribution and association with land uses of these urban foxes is poor, partly because many favoured habitats are on private properties and therefore hardly accessible to scientists. We assumed that citizen science, i.e. the involvement of the public, could enable researchers to bridge this information gap. We analysed 1179 fox sightings in the city of Vienna, Austria reported via citizen science projects to examine relationships between foxes and the surrounding land use classes as well as sociodemographic parameters. RESULTS: Conditional probabilities of encountering foxes were substantially higher in gardens, areas with a low building density, parks or squares as compared to agricultural areas, industrial areas or forests. Generalized linear model analyses showed that sociodemographic parameters such as education levels, district area, population density and average household income additionally improved the predictability of fox sightings. CONCLUSIONS: Reports of fox sightings by citizen scientists might help to support the establishment of wildlife management in cities. Additionally, these data could be used to address public health issues in relation with red foxes as they can carry zoonoses that are also dangerous to humans.

Understanding the influence of individual variables contributing to multivariate outliers in assessments of data quality.

Mahalanobis distance is often recommended to identify patients or clinical sites that are considered unusual in clinical trials. Patients extreme in one or more covariates may be considered outliers in that they reside some distance from the multivariate mean, which can be thought of as the center of the data cloud. Less often discussed, patients whose data are believed to be "too good to be true" are located near the centroid as inliers. In order to efficiently investigate these anomalies for potential lapses in data quality, it is important to understand how the individual variables contribute to each multivariate outlier. There is a lack of literature describing a reasonable workflow for identification of outliers and their subsequent investigation to understand how each variable contributes to an observation being considered extreme. We describe how to identify multivariate inliers and outliers, classify outliers according to varying levels of severity, and summarize the contributions of variables using principal components in a manner that is accessible to a wide audience with straightforward interpretation. We illustrate how numerous data visualizations, including Pareto plots, can facilitate further review even in studies containing numerous observations and variables. We illustrate these methodologies using data from a multicenter clinical trial.

The insensitive dormouse: reproduction skipping is not caused by chronic stress in Glis glis.

Entire populations of edible dormice (Glis glis) can skip reproduction in years without mast seeding of deciduous trees (particularly beech or oak seed), because juveniles require high-calorie seeds for growth and fattening prior to hibernation. We hypothesized that, in mast failure years, female dormice may be forced to spend larger amounts of time foraging for low-quality food, which would increase their exposure to predators, mainly owls. This may lead to chronic stress, i.e. long-term increased secretion of glucocorticoids (GC), which can have inhibitory effects on reproductive function in both female and male mammals. We monitored reproduction in free-living female dormice over 3 years with varying levels of food availability, and performed a supplemental feeding experiment. To measure stress hormone levels, we determined fecal GC metabolite (GCM) concentrations collected during the day, which reflect hormone secretion rates in the previous nocturnal activity phase. We found that year-to-year differences in beech mast significantly affected fecal GCM levels and reproduction. However, contrary to our hypothesis, GCM levels were lowest in a non-mast year without reproduction, and significantly elevated in full-mast and intermediate years, as well as under supplemental feeding. Variation in owl density in our study area had no influence on GCM levels. Consequently, we conclude that down-regulation of gonads and reproduction skipping in mast failure years in this species is not caused by chronic stress. Thus, in edible dormice, delayed reproduction apparently is profitable in response to the absence of energy-rich food in non-mast years, but not in response to chronic stress.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Real World Insights.

BACKGROUND: Although randomized controlled clinical trials provide necessary information and serve as the basis for regulatory decision making, a significant gap exists between the evidence these trials provide and what the biomedical community needs. It is recognized that a wealth of data are routinely collected outside clinical trials. Such real-world data (RWD) are not of comparable quality, it does not have similar immunity from bias and confounding as data collected in randomized clinical trials, but it might offer additional understanding of the benefit-risk, provide new insights to different stakeholders, and aid in regulatory decision making. This can be especially true when rare but serious adverse events are considered because randomized clinical trials are often not large enough and have insufficient duration to address safety concerns fully. Also, the passage of the 21st Century Cures bill passed by Congress in 2016 means that several data sources outside traditional clinical trials will play a greater role in regulatory decision making. This manuscript is third in a series of articles from the American Statistical Association Biopharmaceutical Section Safety Working Group. METHODS: In this manuscript, authors reviewed some RWD sources and shared considerations for statistical strategies and methodologies needed to design and analyze observational safety studies and pragmatic trials. RESULTS: Authors presented case studies and shared recommendations for statistical methods necessary to design and analyze safety trials using RWD. CONCLUSIONS: RWD is an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. However, it is important to determine if such data are fit for purpose.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials.

BACKGROUND: There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. METHODS: In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. RESULTS: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. CONCLUSIONS: Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Postmarket Surveillance.

BACKGROUND: Safety data are continuously evaluated throughout the life cycle of a medical product to accurately assess and characterize the risks associated with the product. The knowledge about a medical product's safety profile continually evolves as safety data accumulate. METHODS: This paper discusses data sources and analysis considerations for safety signal detection after a medical product is approved for marketing. This manuscript is the second in a series of papers from the American Statistical Association Biopharmaceutical Section Safety Working Group. RESULTS: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from passive postmarketing surveillance systems compared to other sources. CONCLUSIONS: Signal detection has traditionally relied on spontaneous reporting databases that have been available worldwide for decades. However, current regulatory guidelines and ease of reporting have increased the size of these databases exponentially over the last few years. With such large databases, data-mining tools using disproportionality analysis and helpful graphics are often used to detect potential signals. Although the data sources have many limitations, analyses of these data have been successful at identifying safety signals postmarketing. Experience analyzing these dynamic data is useful in understanding the potential and limitations of analyses with new data sources such as social media, claims, or electronic medical records data.

Rethinking the Clinically Based Thresholds of TransCelerate BioPharma for Risk-Based Monitoring.

BACKGROUND: The quality of data from clinical trials has received a great deal of attention in recent years. Of central importance is the need to protect the well-being of study participants and maintain the integrity of final analysis results. However, traditional approaches to assess data quality have come under increased scrutiny as providing little benefit for the substantial cost. Numerous regulatory guidance documents and industry position papers have described risk-based approaches to identify quality and safety issues. In particular, the position paper of TransCelerate BioPharma recommends defining risk thresholds to assess safety and quality risks based on past clinical experience. This exercise can be extremely time-consuming, and the resulting thresholds may only be relevant to a particular therapeutic area, patient or clinical site population. In addition, predefined thresholds cannot account for safety or quality issues where the underlying rate of observing a particular problem may change over the course of a clinical trial, and often do not consider varying patient exposure. METHODS: In this manuscript, we appropriate rules commonly utilized for funnel plots to define a traffic-light system for risk indicators based on statistical criteria that consider the duration of patient follow-up. Further, we describe how these methods can be adapted to assess changing risk over time. Finally, we illustrate numerous graphical approaches to summarize and communicate risk, and discuss hybrid clinical-statistical approaches to allow for the assessment of risk at sites with low patient enrollment. RESULTS: We illustrate the aforementioned methodologies for a clinical trial in patients with schizophrenia. CONCLUSIONS: Funnel plots are a flexible graphical technique that can form the basis for a risk-based strategy to assess data integrity, while considering site sample size, patient exposure, and changing risk across time.

Intravenous Smart Pump Drug Library Compliance: A Descriptive Study of 44 Hospitals.

BACKGROUND: Although intravenous (IV) smart pumps with built-in dose-error reduction systems (DERS) can reduce IV medication administration error, most serious adverse events still occur during IV medication administration. Sources of error include overriding DERS and manually bypassing drug libraries and the DERS. METHODS: Our purpose was to use the Regenstrief National Center for Medical Device Informatics data set to better understand IV smart pump drug library and DERS compliance. Our sample consisted of 12 months of data from 7 hospital systems, 44 individual hospitals, and descriptive data from the American Hospital Directory (AHD) for 2015. The aims of the study were (1) to determine whether there are differences in IV smart pump drug library compliance between hospital systems and (2) to provide a broad descriptive overview of relevant trends related to IV smart pump compliance. RESULTS: For aim 1, we found 3 significant relationships among the 7 hospital systems: systems 3 (P < 0.001), 6 (P = 0.003), and 7 (P = 0.002) had significantly higher IV smart compliance as compared with system 4. For aim 2, the number of drug library profiles was positively correlated (P = 0.029) with IV smart pump compliance and the IV smart pump type used was significantly correlated (P = 0.013) with IV smart pump compliance. CONCLUSIONS: Our findings support that there are differences in IV smart pump compliance both within and between hospital systems and that IV smart pump type and the number of drug library profiles may be influencing factors. Further research is required to more accurately identify the impact of these factors in this very important area of patient safety.

Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus.

As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.