Donanemab in Early Alzheimer's Disease.

BACKGROUND: A hallmark of Alzheimer's disease is the accumulation of amyloid-ß (Aß) peptide. Donanemab, an antibody that targets a modified form of deposited Aß, is being investigated for the treatment of early Alzheimer's disease. METHODS: We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET. RESULTS: A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab. CONCLUSIONS: In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).

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.

Fractional CO2 laser therapy for genitourinary syndrome of menopause for breast cancer survivors.

PURPOSE: Fractional CO2 laser therapy is an emerging treatment for genitourinary syndrome of menopause (GSM). The objective of this study was to determine the feasibility and preliminary efficacy of fractional CO2 laser therapy in breast cancer survivors. METHODS: This was a single arm feasibility study of breast cancer survivors with dyspareunia and/or vaginal dryness. Participants received three treatments of fractional CO2 laser therapy at 30-day intervals and returned for a 1-month follow-up. Feasibility was defined as treatment completion without serious adverse events (SAE) in 80% of patients. We collected data on the Vaginal Assessment Scale (VAS), the Female Sexual Function Index (FSFI), the Urinary Distress Index (UDI), and SAE. RESULTS: A total of 64 patients participated in the study. The majority of women had Estrogen receptor/Progesterone receptor (ER/PR) positive/Her2neu negative (n = 37; 63%), stage I (n = 32, 54%) or II (n = 19, 32%) breast cancer. Most were receiving endocrine therapy (n = 54, 92%), most commonly aromatase inhibitors (AI; n = 40, 68%). Fifty-nine (88.1%) of those enrolled completed all treatments according to protocol with no reported SAE. No patient withdrew due to SAE. The scores of the VAS (mean Δ - 0.99; 95% CI [- 1.19, - 0.79], p < 0.001)), FSFI (mean Δ 9.67; 95% CI [7.27, 12.1], p < 0.001), and UDI (mean Δ - 8.85; 95% CI [- 12.75, - 4.75], p < 0.001)) improved from baseline to follow-up. CONCLUSION: Fractional CO2 laser treatment for breast cancer survivors is feasible and appears to reduce GSM symptoms across treatment and follow-up.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. METHODS: Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. RESULTS: PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). DISCUSSION: These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Highlights: Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

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.

Long-Term Follow-Up of Fractional CO2 Laser Therapy for Genitourinary Syndrome of Menopause in Breast Cancer Survivors.

(1) Background: The objective of this study was to determine the long-term efficacy of fractional CO2 laser therapy in breast cancer survivors. (2) Methods: This was a single-arm study of breast cancer survivors. Participants received three treatments of fractional CO2 laser therapy and returned for a 4 week follow-up. Participants were contacted for follow-up at annual intervals. The Vaginal Assessment Scale (VAS), the Female Sexual Function Index (FSFI), the Female Sexual Distress Scare Revised (FSDS-R), the Urinary Distress Inventory (UDI), and adverse events were collected and reported for the two-year follow-up. The changes in scores were compared between the four-week and two-year and the one-year and two-year follow-ups using paired t-tests. (3) Results: In total, 67 BC survivors were enrolled, 59 completed treatments and the four week follow-up, 39 participated in the one-year follow-up, and 33 participated in the two-year follow-up. After initial improvement in the VAS from baseline to the four week follow-up, there was no statistically significant difference in the VAS score (mean Δ 0.23; 95% CI [-0.05, 0.51], p = 0.150) between the four week follow-up and the two-year follow-up. At the two-year follow-up, the FSFI and FSDS-R scores remained improved from baseline and there was no statistically significant change in the FSFI score (mean Δ -0.83; 95% CI [-3.07, 2.38] p = 0.794) or the FSDS-R score (mean Δ -2.85; 95% CI [-1.88, 7.59] p = 0.227) from the one to two-year follow-up. The UDI scores approached baseline at the two-year follow-up; however, the change between the one- and two-year follow-ups was not statistically significant (mean Δ 4.76; 95% CI [-1.89, 11.41], p = 0.15). (4) Conclusions: Breast cancer survivors treated with fractional CO2 laser therapy have sustained improvement in sexual function two years after treatment completion, suggesting potential long-term benefit.

Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer's Disease Dementia.

BACKGROUND: LY3202626 is a small molecule inhibitor of ß-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-ß (Aß)1-40 and Aß1-42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer's disease (AD). OBJECTIVE: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. METHODS: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. RESULTS: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. CONCLUSION: LY3202626 tested at doses generating 70-90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

Patient-reported sexual function of breast cancer survivors with genitourinary syndrome of menopause after fractional CO2 laser therapy.

OBJECTIVE: The objective of this pilot study was to evaluate the change in sexual function following treatment with fractional CO2 laser therapy in breast cancer (BC) survivors with genitourinary syndrome of menopause (GSM). METHODS: A single-arm feasibility study of BC survivors with symptoms of GSM, including dyspareunia and/or vaginal dryness, was conducted. Participants who received three treatments with fractional CO2 laser and 4-week follow-up were contacted for patient-reported outcomes and adverse events at 12 months. Sexual function was measured using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale Revised (FSDS-R). Descriptive statistics were calculated for patient demographics and disease characteristics for the set of participants who agreed to long-term follow-up and those who were lost to follow-up. FSFI and FSDS-R scores were summarized at baseline, 4 weeks and 12 months, as well as the change from baseline, and were compared using a Wilcoxon signed rank test. RESULTS: A total of 67 BC survivors enrolled, 59 completed treatments and 4-week follow-up; 39 participated in the 12 month follow-up. The overall FSFI score improved from baseline to 4-week follow-up (median Δ 8.8 [Q1, Q3] (QS) (2.2, 16.7)], P < 0.001). There were improvements at 4 weeks in all domains of the FSFI (P < 0.001 for each) including desire (median Δ 1.2; QS [0.6, 1.8]), arousal (median Δ 1.2; QS [0.3, 2.7]), lubrication (median Δ 1.8 (0, 3.3), orgasm (median Δ 1.2; QS [0, 3.6]), satisfaction (median Δ 1.6 (0.4, 3.2)), and pain (median Δ 1.6 (0, 3.6). The FSDS-R score also improved from baseline to 4-week follow-up (median Δ -10.0; QS [-16, -5] P < 0.001) indicating less sexually related distress. The scores of the FSFI and FSDS-R remained improved at 12 months and there were no serious adverse events reported. CONCLUSIONS: In BC survivors with GSM, the total and individual domain scores of the FSFI and the FSDS-R improved after fractional CO2 laser therapy.

Video Summary:http://links.lww.com/MENO/A711 .

Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration.

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid ß positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid ß-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Treatment of myelodysplastic syndromes with 5-azacytidine.

Patients with myelodysplastic syndromes (MDS) who were anemic and/or thrombocytopenic were treated with 5-azacytidine (5-AZA) at a dose of 75 mg/m(2) per day SQ x 7 days. This cycle was repeated every 28 days. Forty-eight patients who received at least one cycle of 5-AZA were evaluable for response. Hematological toxicity was mild and consisted of thrombocytopenia and leukopenia. Extramedullary toxicity was uncommon and consisted of pneumonia, arthralgia, diarrhea, and injection site irritation. Eighteen of the 46 transfusion dependent patients became transfusion independent (39%). Median duration of response was 7 months with three patients continuing beyond 2 years. French Anglo British (FAB) classification and the International Scoring System (ISS) did not predict response to 5-AZA. However, a decrease in the white blood cells (WBC) during the initial cycle of 5-AZA correlated with a higher response rate.

Outcome assessment of an antipsychotic drug algorithm: effects of the Mississippi State Hospital algorithm project.

OBJECTIVE: This study evaluated a state psychiatric hospital's algorithm for prescribing antipsychotic drugs for inpatients with schizophrenia to determine whether its emphasis on cost efficiency is compatible with quality of care. METHODS: Outcomes were compared for patients who received medication that was algorithm adherent or nonadherent. Risperidone and ziprasidone were first-step oral antipsychotics. Documentation of clinical rationale was acceptable for nonpreferred drug use. Outcomes of interest were length of hospitalization and "much improved" or "very much improved" status on the Clinical Global Impression severity scale (CGI-S). RESULTS: Of 401 patients, 70% were male. The CGI-S modal rating of severity was "markedly ill." Duration of illness was longer for patients given algorithm-nonadherent (17.6±9.7 years) versus -adherent (14.9±11.6 years, p=.013) medication. No statistically significant between-group differences were observed for mean length of stay (51.4±35.5 days versus 43.8±27.4 days, adjusted difference p=.18) or median improvement time (adherent, 41 days; nonadherent, 42 days; CI=34-48 days for both group medians). CONCLUSIONS: Prescription algorithm adherence was not associated with significantly increased length of inpatient stay or delayed time to improvement.

The antimicrobial defense mechanism of the female urethra: a reassessment.

PURPOSE: This review of the literature and study of the cytology of the urethra were done to define the potential role of the female urethra as a staging site for urinary tract infection and examine the evidence for a urethral defense mechanism. MATERIALS AND METHODS: We re-analyzed data on the quantitative microbiology of the female urethra published 3 decades ago, reviewed the literature on the initiation of ascending urinary tract infections, the cytology and anatomy of the urethra, and performed studies of the morphology of urethral cells in boys and girls, men, menstruating and menopausal women, and women with acute cystitis. We also considered clues about the urethral microenvironment provided by gonococcal cervicitis and urethritis. RESULTS: We found strong statistical evidence that the female urethra has a powerful antimicrobial defense mechanism, which appears to differ in women with and without recurrent urinary tract infections. We corroborated the findings of previous investigators that the female urethra is lined by cells identical to those of the vagina that respond similarly to estrogens. We found immature basal and parabasal cells in children, and a modest inflammatory response to urinary tract infection. CONCLUSIONS: The female urethra may provide a favorable environment for colonization by uropathogens but it is protected by a powerful defense mechanism. This mechanism may be explained by the shedding of uropathogens bound to exfoliating urethral cells, trapping of bacteria by mucus secreted by the paraurethral glands, intermittent washout by urine, local production of Ig, cytokines and defensins and mobilization of leukocytes.