Updated safety results from phase 3 lecanemab study in early Alzheimer's disease.

BACKGROUND: Alzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aß)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aß protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo. METHODS: Clarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally. RESULTS: Overall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3-6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%). CONCLUSIONS: Lecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care. TRIAL REGISTRATION: ClinicalTrials.gov numbers: Clarity AD NCT03887455).

Eligibility Rates among Racially and Ethnically Diverse US Participants in Phase 2 and Phase 3 Placebo-Controlled, Double-Blind, Randomized Trials of Lecanemab and Elenbecestat in Early Alzheimer Disease.

OBJECTIVE: Many factors contribute to inadequate diversity in Alzheimer disease (AD) clinical trials. We evaluated eligibility rates among racial and ethnic groups at US sites in large global multisite trials in early AD. METHODS: Using screening data from 4 randomized, double-blind, placebo-controlled clinical trials in early AD, we assessed rates of eligibility among racial and ethnic groups controlling for other demographic covariates. Each trial incorporated positron emission tomography and/or cerebrospinal fluid to evaluate brain amyloid pathology, as well as typical eligibility criteria used in early AD trials. RESULTS: Across the trials, 10,804 US participants were screened: 193 (2%) were of Hispanic ethnicity and Black race, 2,624 (25%) were of Hispanic ethnicity and White race, 118 (1%) were of non-Hispanic ethnicity (NH) and Asian race, 696 (7%) were of NH ethnicity and Black race, and 7,017 (65%) were of NH ethnicity and White race. Data from 156 participants who did not fit into these categories were excluded. Accounting for age, sex, and trial and using NH White participants as a reference group, we observed higher probabilities of ineligibility for amyloid biomarker criteria among Hispanic Black (odds ratio [OR] = 3.20, 95% confidence interval [CI] = 2.11-4.88), Hispanic White (OR = 4.15, 95% CI = 3.58-4.83), NH Asian (OR = 2.35, 95% CI = 1.23-4.55), and NH Black (OR = 3.75, 95% CI = 2.80-5.06) participants. INTERPRETATION: Differential eligibility may contribute to underrepresentation of some minoritized racial and ethnic groups in early AD trials. Amyloid biomarker eligibility is a requirement to confirm the diagnosis of AD and for treatment with amyloid-lowering drugs and differed among racial and ethnic groups. ANN NEUROL 2024;95:288-298.

Lecanemab for Patients With Early Alzheimer Disease: Bayesian Analysis of a Phase 2b Dose-Finding Randomized Clinical Trial.

Importance: Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness. Objective: To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in the prospective design and also treatment-dependent types of missing data. Design, Setting, and Participants: This study was a bayesian analysis of a clinical trial comparing the efficacy of 5 lecanemab 201 dosages for treatment of early Alzheimer disease. The goal of the lecanemab 201 trial was to identify the effective dose 90 (ED90), the dose achieving at least 90% of the maximum effectiveness of doses considered in the trial. This study assessed the bayesian adaptive randomization used, in which patients were preferentially assigned to doses that would give more information about the ED90 and its efficacy. Interventions: Patients in the lecanemab 201 trial were adaptively randomized to 1 of 5 dose regimens or placebo. Main Outcomes and Measures: The primary end point of lecanemab 201 was the Alzheimer Disease Composite Clinical Score (ADCOMS) at 12 months with continued treatment and follow-up out to 18 months. Results: A total 854 patients were included in trial treatment: 238 were in the placebo group (median age, 72 years [range, 50-89 years]; 137 female [58%]) and 587 were assigned to a lecanemab 201 treatment group (median age, 72 years [range, 50-90 years]; 272 female [46%]). The bayesian approach improved the efficiency of a clinical trial by prospectively adapting to the trial's interim results. By the trial's end more patients had been assigned to the better-performing doses: 253 (30%) and 161 (19%) patients to 10 mg/kg monthly and 10 mg/kg biweekly vs 51 (6%), 52 (6%), and 92 (11%) patients to 5 mg/kg monthly, 2.5 mg/kg biweekly, and 5 mg/kg biweekly, respectively. The trial identified 10 mg/kg biweekly as the ED90. The change in ADCOMS of the ED90 vs placebo was -0.037 at 12 months and -0.047 at 18 months. The bayesian posterior probability that the ED90 was superior to placebo was 97.5% at 12 months and 97.7% at 18 months. The respective probabilities of super-superiority were 63.8% and 76.0%. The primary analysis of the randomized bayesian lecanemab 201 trial found in the context of missing data that the most effective dose of lecanemab nearly doubles its estimated efficacy at 18 months of follow-up in comparison with restricting analysis to patients who completed the full 18 months of the trial. Conclusions and Relevance: Innovations associated with the bayesian approach can improve the efficiency of drug development and the accuracy of clinical trials, even in the context of substantial data missingness. Trial Registration: ClinicalTrials.gov Identifier: NCT01767311.

ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer's disease.

INTRODUCTION: Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß species (protofibrils) with activity at amyloid plaques. Amyloid-related imaging abnormalities (ARIA) profiles appear to differ for various anti-amyloid antibodies. Here, we present ARIA data from a large phase 2 lecanemab trial (Study 201) in early Alzheimer's disease. METHODS: Study 201 trial was double-blind, placebo-controlled (core) with an open-label extension (OLE). Observed ARIA events were summarized and modeled via Kaplan-Meier graphs. An exposure response model was developed. RESULTS: In the phase 2 core and OLE, there was a low incidence of ARIA-E (<10%), with <3% symptomatic cases. ARIA-E was generally asymptomatic, mild-to-moderate in severity, and occurred early (<3 months). ARIA-E was correlated with maximum lecanemab serum concentration and incidence was higher in apolipoprotein E4 (ApoE4) homozygous carriers. ARIA-H and ARIA-E occurred with similar frequency in core and OLE. DISCUSSION: Lecanemab can be administered without titration with modest incidence of ARIA.

Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer's disease.

BACKGROUND: Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aß species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. METHODS: The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. RESULTS: The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. CONCLUSIONS: The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

Lecanemab in patients with early Alzheimer's disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study.

BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aß species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. METHODS: The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). RESULTS: At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aß42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aß42/40 ratio, and reductions in plasma p-tau181. CONCLUSIONS: Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01767311 .

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study.

BACKGROUND: The ability of 18F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer's disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using 18F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition. METHODS: Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive 18F-florbetaben PET scan (n=74, 76 ± 7 years, 38 females) underwent a baseline 18F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aß42/Aß40 ratio, p-tau, t-tau) (n=22) and several cognitive tests. A 1-year follow-up 18F-PI-2620 PET scans and cognitive assessments were done in 15 subjects. RESULTS: Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in 18F-florbetaben Centiloids (CL) (7.7% (<36 CL), 80% (>83 CL)). 18F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased 18F-florbetaben CL in several regions of interest. Elevated 18F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau (p=0.0006 and p=0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline (p=0.006 (mesial temporal); p=0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex (p=0.04, p=0.047, p=0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline. CONCLUSIONS: The findings support the hypothesis that 18F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in 18F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of 18F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents. TRIAL REGISTRATION: Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov ( NCT02956486 ;  NCT03036280 ).

Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment.

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-ß (Aß) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aß42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aß42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aß42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aß42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

PURPOSE: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS: Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.

Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma.

BACKGROUND: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus. METHODS: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0). RESULTS: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus). CONCLUSIONS: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT01136733.

Concordance of Lumipulse cerebrospinal fluid t-tau/Aß42 ratio with amyloid PET status.

INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer's disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut-points using high-throughput automated assays are necessary for general clinical use. METHODS: CSF amyloid ß42 peptide (Aß42), t-tau, and t-tau/Aß42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401-201/MISSION AD E2609-301/302, n = 138; C: Knight Alzheimer's Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut-points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best-performing cut-point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609-301/302, n = 240). RESULTS: Virtually identical t-tau/Aß42 cut-points (∼0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve [AUCs] [A/B: 0.95; C: 0.94]). The cut-point yielded an overall percent agreement with amyloid PET of 85.0% in validation cohort D. DISCUSSION: Lumipulse CSF biomarker measures with validated cut-points have clinical utility in identifying AD pathology.

Identification of prognostic factors to predict cognitive decline of patients with early Alzheimer's disease in the Japanese Alzheimer's Disease Neuroimaging Initiative study.

INTRODUCTION: The objective of this study was to determine the factors including neuropsychological test performances and cerebrospinal fluid (CSF) biomarkers which can predict disease progression of early Alzheimer's disease (AD) in a Japanese population. METHODS: The group classification on early AD population in both Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and North American ADNI (NA-ADNI) was performed using the inclusion criteria including brain amyloid positivity on positron emission tomography or CSF. Participants with early AD from each cohort were stratified into two groups based on a cutoff 1.0 of Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) change at month 24 (m24): participants in "progress group" have CDR-SB change ≥ 1.0 and participants in "stable group" have CDR-SB change < 1.0. Then, we performed identification of prognostic factors from baseline items including neuropsychological scores (Assessment Scale-Cognitive Subscale[ADAS-cog 13], Mini-Mental State Examination (MMSE), CDR, FAQ, and Geriatric Depression Scale ), CSF markers (t-tau, p-tau, and beta-amyloid 1-42), vital signs (body weight, pulse rate, etc.,), by using two statistical approaches, Welch's t-test and simple linear regression by ordinary least squares. Comparisons between participants with J-ADNI and participants with NA-ADNI were also performed. RESULTS: Trends of CDR-SB changes were very similar between J-ADNI and NA-ADNI early AD population enrolled in this study. Baseline levels of CSF t-tau, p-tau, Mini-Mental State Examination, FAQ, and ADAS-cog13 were identified as prognostic factors in both J-ADNI and NA-ADNI. Based on a detailed subscale analysis on ADAS-cog13, four subscales (Q1: word recall, Q3: construction, Q4: delayed word recall, and Q8: word recognition) were identified as prognostic factors in both J-ADNI and NA-ADNI. DISCUSSION: Characterizing population with early AD can provide benefits for promoting efficiency in conducting AD clinical trials for disease-modifying treatments. Thus, implementing these prognostic factors into clinical trials may be potentially a good method to enrich participants with early AD who are suitable for evaluating treatment effects.