Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.

APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials.

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid-targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid-positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non-carriers. Carrier and non-carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) were -0.30 (-0.478, -0.106) and -0.20 (-0.435, 0.042) and AD Assessment Scale-Cognitive subscale (ADAS-Cog) values were -1.01 (-1.577, -0.456) and -0.80 (-1.627, 0.018), respectively. Decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non-carriers to amyloid-targeting therapies and similar or less disease progression with placebo in amyloid-positive trials. HIGHLIGHTS: Amyloid-targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers. Clinical decline is the same/slightly faster in amyloid-positive APOE ε4 non-carriers. Prevalence of non-carriers in trial populations could impact outcomes.

Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial.

Importance: ß-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. Objective: To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures. Design, Setting, and Participants: The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels. Interventions: Donanemab (an antibody specific for the N-terminal pyroglutamate ß-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance. Main Outcomes and Measures: Change in amyloid, tau, and clinical decline after donanemab treatment. Results: The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001). Conclusions and Relevance: Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status. Trial Registration: ClinicalTrials.gov Identifier: NCT03367403.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet ß-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Differences in Patient Screening Mammography Rates Associated With Internist Gender and Level of Training and Change Following the 2009 U.S. Preventive Services Task Force Guidelines.

BACKGROUND: Significant discordance arose between screening mammography clinical practice guidelines published by different national health care organizations following the release of the U.S. Preventive Services Task Force (USPSTF) guidelines in 2009. This allowed for greater interprovider variation in clinical practice while remaining within standard of care. The objective of this study was to determine how differences in patient screening mammography rates between internal medicine physician subgroups defined by gender and level of training changed, if at all, following the release of the new guidelines. METHODS: The study was an observational study including all internists and internal medicine residents at a single academic medical center, Dartmouth-Hitchcock Medical Center. Screening mammography rates were determined for patients of subgroups of internists defined by gender and level of training (attending vs resident physician) for the 2 years before and after the release of the updated screening guidelines. RESULTS: Patients having female attending internists as their primary care provider were more likely to undergo screening mammography than those having male attending or resident internists of either gender both before and after the release of the new guidelines, with the difference in patient screening mammography rates between physician subgroups increasing following their release (rates before and after, respectively, by subgroup: female attending = 67%, 64%; male attending = 56%, 50%; female resident = 58%, 41%; male resident = 55%, 41%; P<.05). CONCLUSIONS: Internist gender and level of training are associated with differences in patient screening mammography rates at one academic medical center, with these differences increasing following the 2009 USPSTF guidelines. These findings suggest that the correlation between provider gender/level of training and a woman's likelihood of undergoing a screening mammogram strengthened as discordance arose between clinical guidelines published by different medical and health care advocacy groups. It is important for providers and patients both to be aware of correlations that exist between provider characteristics and patient cancer screening rates and to take steps to minimize the impact of provider bias on the shared decision-making process.

2014 AAHA weight management guidelines for dogs and cats.

Communicating and implementing a weight management program for dogs and cats can be a challenging endeavor for veterinarians, but a rewarding one. An effective individualized weight loss program provides a consistent and healthy rate of weight loss to reduce risk of disease, prevent malnutrition, and improve quality of life. Weight loss is achieved with appropriate caloric restriction, diet selection, exercise, and strategies to help modify behavior of both the pet and client. This document offers guidelines and tools for the management of weight loss and long-term maintenance of healthy weight.

2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents.

Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.

Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis.

To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.

Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists.

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.

Application of the Dakin-West reaction for the synthesis of oxazole-containing dual PPARalpha/gamma agonists.

An improved method for the preparation of a series of oxazole-containing dual PPARalpha/gamma agonists is described. A synthetic sequence utilizing a Dakin-West reaction was devised that allows for the introduction of the oxazole ring either late in the synthetic sequence via aminomalonate-derived chemistry or in pivotal SAR intermediates derived from aspartic acid.

Greater GNN pattern bias in sequence elements encoding conserved residues of ancient proteins may be an indicator of amino acid composition of early proteins.

The possibility that RNY pattern bias in extant sequences is a remnant of more pronounced bias of this type in early ancestors was investigated. To this end, conserved residues (those residues for which the inferred ancestral and known descendant amino acids are identical) and non-conserved residues of ancient proteins dating to the Last Universal Ancestor were identified within six species: two archaea, two eubacteria and two eukaryotes. Bias within sequence elements encoding each subset of residues, conserved and non-conserved, was then determined. In all species, GNN bias is greater within conserved than non-conserved sequence elements, whereas ANN is not. This difference is statistically significant in all six species examined. Since the relative mutability of the GNN-encoded amino acids does not explain the greater bias in conserved sequences, it is concluded that early sequences probably possessed a strong GNN bias. It is suggested that this bias may be a consequence of the GNN codons being the first introduced into the genetic code. Although NNY bias is also greater within conserved sequence elements of the six species, that difference is statistically significant in only half of them. Therefore, the evidence for early NNY bias remains inconclusive. The findings of this study do not support the proposal of Diaz-Lazcoz et al. (J. Mol. Biol. 250 (1995) 123) that the codons of the TCN four-codon block were the first assigned to serine during the evolution of the genetic code.

Evolution of amino acid frequencies in proteins over deep time: inferred order of introduction of amino acids into the genetic code.

To understand more fully how amino acid composition of proteins has changed over the course of evolution, a method has been developed for estimating the composition of proteins in an ancestral genome. Estimates are based upon the composition of conserved residues in descendant sequences and empirical knowledge of the relative probability of conservation of various amino acids. Simulations are used to model and correct for errors in the estimates. The method was used to infer the amino acid composition of a large protein set in the Last Universal Ancestor (LUA) of all extant species. Relative to the modern protein set, LUA proteins were found to be generally richer in those amino acids that are believed to have been most abundant in the prebiotic environment and poorer in those amino acids that are believed to have been unavailable or scarce. It is proposed that the inferred amino acid composition of proteins in the LUA probably reflects historical events in the establishment of the genetic code.

Increased frequency of cysteine, tyrosine, and phenylalanine residues since the last universal ancestor.

Analysis of extant proteomes has the potential of revealing how amino acid frequencies within proteins have evolved over biological time. Evidence is presented here that cysteine, tyrosine, and phenylalanine residues have substantially increased in frequency since the three primary lineages diverged more than three billion years ago. This inference was derived from a comparison of amino acid frequencies within conserved and non-conserved residues of a set of proteins dating to the last universal ancestor in the face of empirical knowledge of the relative mutability of these amino acids. The under-representation of these amino acids within last universal ancestor proteins relative to their modern descendants suggests their late introduction into the genetic code. Thus, it appears that extant ancient proteins contain evidence pertaining to early events in the formation of biological systems.

A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models.

A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.

Reproducibility of control organism zone diameters for batches of IsoSensitest agar manufactured from 1996 to 2000 using the BSAC disc susceptibility test method.

The BSAC Working Party on Susceptibility Testing has recently suggested that the performance of IsoSensitest agar has changed since 1991. Twenty batches of IsoSensitest agar that had been manufactured between 1996 and 2000 were tested using the BSAC standardized disc susceptibility testing method. Antibiotic discs containing amoxicillin 10 microg, ceftazidime 30 microg, gentamicin 10 microg, ciprofloxacin 1 microg and colistin sulphate 25 microg were tested on each batch of media 12 times against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 where appropriate. There was a small reduction in zone sizes for most antibiotics on batches of media that were near their expiration date, but otherwise zone sizes were remarkably consistent. We could find no evidence to suggest that a change in the performance of IsoSensitest agar for the disc diffusion method had occurred since 1996.