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Abstract: Plasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid-positive (Aß+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aß+ MCI clinical trial placebo subjects. Performance was evaluated in two validation cohorts. An 18-month ≥1 increase in the Clinical Dementia Rating Sum of Boxes was the clinical decline criterion. Baseline plasma pTau181 concentration matched clinical assessments' prediction performance. Adding pTau181 to clinical assessments significantly improved the prediction of an 18-month clinical decline and the 36-month progression from Aß+ MCI to AD. The area under the receiver operating characteristic curve for the latter increased from 71.8% to 79%, and the hazard ratio for time-to-progression improved from 2.26 to 3.11 (p < 0.0001). Baseline plasma pTau181 has the potential for identifying Aß+ MCI subjects with faster clinical decline over time. Highlights: This study assessed pTau181 as a prognostic predictor of 18-month clinical decline and extended progression to Alzheimer's disease (AD) in amyloid-positive patients with mild cognitive impairment (Aß+ MCI).The research findings underscore the promise of baseline plasma pTau181 as a screening tool for identifying Aß+ MCI individuals with accelerated clinical decline within a standard 18-month clinical trial period. The predictive accuracy is notably enhanced when combined with clinical assessments.Similar positive outcomes were noted in forecasting the extended progression of Aß+ MCI subjects to AD.
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INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.
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BACKGROUND: This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aß) 42/Aß40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. METHODS: Quantification of plasma pTau217R and Aß42/Aß40 employed immunoprecipitation-mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts. RESULTS: Models integrating pTau217R outperformed Aß42/Aß40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R-based models for low amyloid levels reduced PET scans by 70.5% to 78.6%. DISCUSSION: pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aß42/Aß40's range. Combining it with plasma Aß42/Aß40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility. GOV IDENTIFIERS: NCT02956486 (MissionAD1), NCT03036280 (MissionAD2), NCT04468659 (AHEAD3-45), NCT03887455 (ClarityAD) HIGHLIGHTS: Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid-PET Centiloid (CL) across a broad spectrum. Integrating pTau217R with Aß42/Aß40 extends the CL prediction upper limit to 89.1 CL. Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals. This model identifies subjects above or below various CL thresholds with high accuracy. pTau217R-based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Brain , Positron-Emission Tomography , tau Proteins , Humans , Alzheimer Disease/blood , Alzheimer Disease/diagnostic imaging , tau Proteins/blood , tau Proteins/cerebrospinal fluid , Amyloid beta-Peptides/blood , Male , Female , Aged , Brain/diagnostic imaging , Brain/metabolism , Biomarkers/blood , Middle Aged , Phosphorylation , Peptide Fragments/blood , Peptide Fragments/cerebrospinal fluid , Cohort StudiesABSTRACT
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).
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/drug therapy , Male , Double-Blind Method , Female , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Middle Aged , Amyloid beta-Peptides/metabolism , Magnetic Resonance Imaging , Treatment OutcomeABSTRACT
INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P < 0.001). Among plasma eligible participants, PET eligibility did not differ by group. DISCUSSION: These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members. HIGHLIGHTS: Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Biomarkers , Positron-Emission Tomography , Aged , Female , Humans , Male , Alzheimer Disease/blood , Alzheimer Disease/ethnology , Alzheimer Disease/diagnostic imaging , Amyloid beta-Peptides/blood , Biomarkers/blood , Brain/diagnostic imaging , Brain/pathology , Ethnicity , Racial GroupsABSTRACT
BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.
Subject(s)
Algorithms , Alzheimer Disease , Amyloid beta-Peptides , Biomarkers , Brain , Mass Spectrometry , Peptide Fragments , Positron-Emission Tomography , tau Proteins , Humans , Amyloid beta-Peptides/blood , Female , Male , tau Proteins/blood , Alzheimer Disease/blood , Alzheimer Disease/diagnosis , Alzheimer Disease/diagnostic imaging , Aged , Peptide Fragments/blood , Brain/diagnostic imaging , Brain/metabolism , Biomarkers/blood , Middle Aged , Aged, 80 and over , ROC CurveABSTRACT
Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.
Subject(s)
Lewy Body Disease , Humans , Lewy Body Disease/diagnosis , Lewy Body Disease/therapyABSTRACT
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.
Subject(s)
Alzheimer Disease , Antibodies, Monoclonal, Humanized , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/drug therapy , Randomized Controlled Trials as Topic , Ethnicity , BiomarkersABSTRACT
INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aß) into screening algorithms may improve screening efficiency. METHODS: Plasma Aß, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aß42/Aß40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aß42/Aß40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aß42/Aß40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Peptide Fragments , Amyloid , tau Proteins , Positron-Emission Tomography , BiomarkersABSTRACT
BACKGROUND: Models for forecasting individual clinical progression trajectories in early Alzheimer's disease (AD) are needed for optimizing clinical studies and patient monitoring. METHODS: Prediction models were constructed using a clinical trial training cohort (TC; n = 934) via a gradient boosting algorithm and then evaluated in two validation cohorts (VC 1, n = 235; VC 2, n = 421). Model inputs included baseline clinical features (cognitive function assessments, APOE ε4 status, and demographics) and brain magnetic resonance imaging (MRI) measures. RESULTS: The model using clinical features achieved R2 of 0.21 and 0.31 for predicting 2-year cognitive decline in VC 1 and VC 2, respectively. Adding MRI features improved the R2 to 0.29 in VC 1, which employed the same preprocessing pipeline as the TC. Utilizing these model-based predictions for clinical trial enrichment reduced the required sample size by 20% to 49%. DISCUSSION: Our validated prediction models enable baseline prediction of clinical progression trajectories in early AD, benefiting clinical trial enrichment and various applications.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/pathology , Magnetic Resonance Imaging/methods , Cognitive Dysfunction/pathology , Brain/pathology , Disease ProgressionABSTRACT
Alzheimer's disease (AD) is the major cause of dementia that is now threatening the lives of billions of elderly people on the globe, and recent progress in the elucidation of the pathomechanism of AD is now opening venue to tackle the disease by developing and implementing "disease-modifying therapies" that directly act on the pathophysiology and slow down the progression of neurodegeneration. A recent example is the success of clinical trials of anti-amyloid b antibody drugs, whereas other therapeutic targets, e.g., inflammation and tau, are being actively investigated. In this dual perspective session, we plan to have speakers from leading pharmas in the field representing distinct investments in the AD space, which will be followed by the comment from scientific leadership of the Alzheimer's Association who will speak on behalf of all stakeholders. Neuroscientists participating in the Society for Neuroscience may be able to gain insights into the cutting edge of the therapeutic approaches to AD and neurodegenerative disorders, and discuss future contribution of neuroscience to this field.
Subject(s)
Alzheimer Disease , Humans , Aged , Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Inflammation/drug therapy , tau ProteinsABSTRACT
INTRODUCTION: We speculated that social media data from Alzheimer's disease (AD) stakeholders (patients, caregivers, and clinicians) could identify barriers along the patient journey in AD, and that insights gained may help devise strategies to remove barriers, and ultimately improve the patient journey. METHODS: Our sample was drawn from a repository of social media posts extracted from 112 public sources between January 1998 and December 2021 using natural language processing text-mining algorithms. The patient journey was classified into three phases: (1) early signs/experiences (Early Signs); (2) screening/assessment/diagnosis (Screening); and (3) treatment/management (Treatment). In the Early Signs phase, issues/challenges derived from a conceptual AD identification framework (ADIF) were examined. In subsequent phases, behavioral/psychiatric challenges, access/barriers to health care, screening/diagnostic methods, and symptomatic treatments for AD were identified. Posts were classified by AD stakeholder type or disease stage, if possible. RESULTS: We identified 225,977 AD patient journey-related social media posts. Anxiety was a predominant issue/challenge in all patient journey phases. In the Screening and Treatment phases combined, access/barriers to care were described in 16% of posts; unwillingness/resistance to seeking care was a major barrier (≥ 75% of access-related posts across all stakeholders). Commonly identified structural barriers (e.g., affordability/cost, geography/transportation/distance) were more common in patient/caregiver posts than clinician posts. Among Screening-related posts, imaging/scans were commonly mentioned by all stakeholders; biomarkers were more commonly mentioned by patients than clinicians. Treatment-related concerns were identified in 17% of stakeholder-specified posts that named pharmacological agents/classes for the symptomatic management of AD. CONCLUSION: This descriptive analysis of out-of-clinic experiences reflected in AD social media posts found that unwillingness/resistance to seeking care was a key barrier, followed by structural barriers to health care, such as affordability/cost. Insights from the lived experiences of AD stakeholders are valuable and highlight the need to improve the patient journey in AD and ease patient and caregiver burden.
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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.
Subject(s)
Alzheimer Disease , Humans , Female , Aged , Bayes TheoremABSTRACT
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.
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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.).
Subject(s)
Alzheimer Disease , Antibodies, Monoclonal, Humanized , Nootropic Agents , Humans , Activities of Daily Living , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/cerebrospinal fluid , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Cognition/drug effects , Double-Blind Method , Nootropic Agents/adverse effects , Nootropic Agents/pharmacology , Nootropic Agents/therapeutic useABSTRACT
Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/drug therapy , Patient SelectionABSTRACT
INTRODUCTION: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aß) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aß 42/40 ratio (Aß 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. RESULT: The focus of this article is on the innovative design of the study. DISCUSSION: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Tauopathies , Humans , Middle Aged , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Amyloid beta-Peptides/metabolism , Australia , Tauopathies/metabolism , Brain/diagnostic imaging , Brain/metabolism , Positron-Emission Tomography , Cognitive Dysfunction/metabolism , Biomarkers/metabolism , tau Proteins/metabolismABSTRACT
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.
Subject(s)
Alzheimer Disease , Humans , Bayes Theorem , Alzheimer Disease/drug therapy , Proof of Concept Study , Research DesignABSTRACT
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 .