Dataset Information

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.

ABSTRACT:

Importance

Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes.

Objective

To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease.

Design, setting, and participants

TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels.

Interventions

Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction.

Main outcomes and measures

Change in plasma biomarker levels after donanemab treatment.

Results

In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively).

Conclusions and relevance

Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation.

Trial registration

ClinicalTrials.gov Identifier: NCT03367403.

SUBMITTER: Pontecorvo MJ

PROVIDER: S-EPMC9577883 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.

Pontecorvo Michael J MJ Lu Ming M Burnham Samantha C SC Schade Andrew E AE Dage Jeffrey L JL Shcherbinin Sergey S Collins Emily C EC Sims John R JR Mintun Mark A MA

JAMA neurology 20221201 12

<h4>Importance</h4>Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes.<h4>Objective</h4>To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease.<h4>Design, setting, and participants</h4>TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory bioma ...[more]

PMID: 36251300

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Project description:ImportanceThere are limited efficacious treatments for Alzheimer disease.ObjectiveTo assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.Design, setting, and participantsMulticenter (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).InterventionsParticipants 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 measuresThe 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.ResultsAmong 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 relevanceAmong 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 registrationClinicalTrials.gov Identifier: NCT04437511.

Project description:ImportanceAmyloid-related imaging abnormalities (ARIA) are the major adverse event associated with amyloid-targeting immunotherapy. Identifying clinical features and individual risk factors for ARIA could facilitate effective prediction and prevention strategies.ObjectiveTo characterize ARIA in participants treated with donanemab.Design, setting, and participantsThese prespecified and post hoc exploratory analyses use data from the placebo-controlled portions of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials, conducted from December 2017 to December 2020 and from June 2020 to April 2023, respectively. Additional analyses are included from a stand-alone open-label addendum conducted from August 2021 through August 2023. Participants in the placebo-controlled trials and the open-label addendum aged 60 to 85 years with early symptomatic Alzheimer disease and elevated amyloid levels were included. The placebo-controlled trials, but not the addendum, had tau inclusion criteria.InterventionsPlacebo-controlled trial participants were randomized 1:1 to receive placebo or donanemab, and all open-label participants received donanemab. Donanemab was administered every 4 weeks for up to 72 weeks.Main outcomes and measuresThe primary outcomes were the frequency, radiographic severity, seriousness, symptoms, timing relative to donanemab treatment, and risk factors for ARIA.ResultsAcross 3030 total participants (placebo-controlled trials: 999 placebo participants, 984 donanemab participants; open-label addendum: 1047 donanemab participants), mean (SD) age was approximately 73.7 (6.0) years and 1684 participants (55.6%) were female. Frequencies of ARIA-edema/effusions (ARIA-E) and ARIA-microhemorrhages and hemosiderin deposition (ARIA-H) were higher with donanemab (24.4% and 31.3% in placebo-controlled trials, respectively; 19.8% and 27.2% in open-label addendum, respectively) than with placebo (1.9% and 13.0%, respectively). ARIA-E was mostly mild or moderate in severity. Serious ARIA-E was reported in 1.5% and symptomatic ARIA-E in 5.8% of donanemab-treated participants in the placebo-controlled trials. Symptoms most frequently reported with ARIA-E were headache and confusional state. In 58.3% of donanemab-treated participants with ARIA-E, the first event occurred by the third infusion (approximately month 3). Risk analysis demonstrated independent associations between ARIA-E and 6 baseline variables, including increased risk with APOE ε4 allele number, greater number of microhemorrhages, presence of cortical superficial siderosis, higher amyloid plaque, and elevated mean arterial pressure, and decreased risk with antihypertensive use.Conclusions and relevanceARIA is an adverse event associated with donanemab treatment that requires safety monitoring. Individual ARIA risk can be assessed by APOE ε4 status and baseline imaging findings.Trial registrationsClinicalTrials.gov Identifiers: NCT03367403 and NCT04437511.

Project description:Importanceβ-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease.ObjectiveTo perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures.Design, setting, and participantsThe 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.InterventionsDonanemab (an antibody specific for the N-terminal pyroglutamate β-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 measuresChange in amyloid, tau, and clinical decline after donanemab treatment.ResultsThe 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 relevanceResults 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 registrationClinicalTrials.gov Identifier: NCT03367403.

Project description:ImportanceSeveral anti-amyloid monoclonal antibodies have been developed for slowing the progression of Alzheimer disease (AD). Among the furthest developed are aducanumab, which received accelerated approval from the US Food and Drug Administration in 2021, and donanemab, which is currently undergoing phase 3 trials. The cost-effectiveness of these treatments has not been established.ObjectivesTo estimate the cost-effectiveness of aducanumab and donanemab relative to standard care for early AD in the US.Design, setting, and participantsA decision analytic model was used to estimate the lifetime health and economic outcomes of adults with early AD, from US healthcare sector and societal perspectives. Simulated patients had a mean (SD) age of 75.2 (5.5) years; 65% had mild cognitive impairment and 35% had mild dementia. Analyses were conducted from April 6, 2021, to January 20, 2022.InterventionsStandard care, aducanumab (selected inputs including disease progression hazard ratio [HR] of 0.89 [95% CI, 0.63-1.15], annual price of $28 000, and twice-yearly monitoring with magnetic resonance imaging [MRI] of the brain), or donanemab (selected inputs including disease progression HR of 0.68 [95% CI, 0.44-0.99], annual price of $28 000, and twice-yearly monitoring with MRI of the brain and amyloid positron emission tomography [PET] monitoring). Donanemab was switched to placebo after substantial amyloid reduction on PET imaging, which occurred in 27% of patients at 6 months and 55% of patients at 12 months.Main outcomes and measuresQuality-adjusted life-years (QALYs); costs, in 2020 US dollars; incremental cost-effectiveness ratios (ICERs); and value-based prices, defined as the maximum price at which a treatment would be cost-effective given a cost-effectiveness threshold of ICER of $150 000/QALY.ResultsLifetime QALYs increased by 0.133 with aducanumab and 0.408 with donanemab. Total health care sector and societal costs increased by $130 100 and $127 800, respectively, with aducanumab and by $78 700 and $71 600, respectively, with donanemab, driven largely by drug costs ($119 000 for aducanumab and $44 600 for donanemab). Health care sector and societal ICERs relative to standard care were $981 000/QALY and $964 000/QALY, respectively, for aducanumab and $193 000/QALY and $176 000/QALY, respectively, for donanemab. In sensitivity analysis, aducanumab's value-based price remained less than $50 000/y, even when assuming a 90% reduction in disease progression. Donanemab's value-based price surpassed $50 000/y once its efficacy exceeded 50%.Conclusions and relevanceThese findings suggest that at current expected prices, neither aducanumab nor donanemab would be cost-effective for early AD in the US. Donanemab's dosing scheme, in which patients suspend treatment on achieving substantial amyloid reductions, may provide a rubric by which sufficiently effective anti-amyloid antibody treatments could be cost-effective even when priced comparably to other biologics.

Project description:ImportancePhysical activity (PA) is a nonpharmacological intervention for dementia prevention. The association between PA and Alzheimer disease (AD) plasma biomarkers remains underexplored.ObjectiveTo investigate the associations among PA; plasma biomarkers, including β-amyloid 42/40 (Aβ42/40), phosphorylated-tau217 (ptau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL); and cognition.Design, setting, and participantsThis cross-sectional study included participants with and without cognitive impairment recruited from multiple memory clinics in South Korea between May 2019 and May 2022. Data were analyzed from June to December 2024.ExposuresPA was assessed as metabolic equivalent task minutes per week using the International Physical Activity Questionnaire and categorized into quartiles from the lowest (Q1) to the highest (Q4).Main outcomes and measuresPlasma Aβ42/40, ptau217, GFAP, and NfL were measured. Cognition was assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB).ResultsAmong 1144 participants (mean [SD] age 70.9 [8.7] years; 744 [65.0%] female), the highest PA quartile showed significantly lower ptau217 (estimate [SE], -0.14 [0.06]; P = .01) and NfL (estimate [SE], -0.12 [0.05]; P = .01) compared with the lowest quartile. Higher PA quartiles were associated with higher MMSE scores (estimate [SE]: Q2, 0.93 [0.31]; P = .003; Q3, 0.82 [0.32]; P = .009; Q4, 0.94 [0.32]; P = .004) and lower CDR-SB scores (estimate [SE]: Q2, -0.33 [0.16]; P = .04; Q3, -0.37 [0.16]; P = .02; Q4, -0.55 [0.16]; P = .001) after adjusting for age, sex, education years, and β-amyloid uptake. In subgroup analyses according to age and cognitive status, the associations of PA and plasma biomarkers with cognition were more pronounced in the older (age ≥65 years) and cognitively impaired groups compared with the younger and cognitively unimpaired groups.Conclusions and relevanceThese findings suggest that PA may help delay cognitive decline by modulating neurodegeneration and AD-specific tau pathologies. However, the cross-sectional design limits causal inference, and longitudinal studies are needed to confirm and clarify these associations.

Project description:BackgroundIdentifying risk factors for Alzheimer disease in women is important as women compose two-thirds of individuals with Alzheimer disease. Previous work links vasomotor symptoms, the cardinal menopausal symptom, with poor memory performance and alterations in brain structure, function, and connectivity. These associations are evident when vasomotor symptoms are monitored objectively with ambulatory skin conductance monitors.ObjectiveThis study aimed to determine whether vasomotor symptoms are associated with Alzheimer disease biomarkers.Study designBetween 2017 and 2020, the MsBrain study enrolled 274 community-dwelling women aged 45 to 67 years who had a uterus and at least 1 ovary and were late perimenopausal or postmenopausal status. The key exclusion criteria included neurologic disorder, surgical menopause, and recent use of hormonal or nonhormonal vasomotor symptom treatment. Women underwent 24 hours of ambulatory skin conductance monitoring to assess vasomotor symptoms. Plasma concentrations of Alzheimer disease biomarkers, including amyloid β 42-to-amyloid β 40 ratio, phosphorylated tau (181 and 231), glial fibrillary acidic protein, and neurofilament light, were measured using a single-molecule array (Simoa) technology. Associations between vasomotor symptoms and Alzheimer disease biomarkers were assessed via linear regression models adjusted for age, race and ethnicity, education, body mass index, and apolipoprotein E4 status. Additional models adjusted for estradiol and sleep.ResultsA total of 248 (mean age, 59.06 years; 81% White; 99% postmenopausal status) of enrolled MsBrain participants contributed data. Objectively assessed vasomotor symptoms occurring during sleep were associated with significantly lower amyloid β 42/amyloid β 40, (beta, -.0010 [standard error, .0004]; P=.018; multivariable), suggestive of greater brain amyloid β pathology. The findings remained significant after additional adjustments for estradiol and sleep.ConclusionNighttime vasomotor symptoms may be a marker of women at risk of Alzheimer disease. It is yet unknown if these associations are causal.

Project description:ImportanceAlzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression.ObjectiveTo assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia.Design, setting, and participantsAMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging-Alzheimer's Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study.InterventionsPatients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo.Main outcomes and measuresThe primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population.ResultsAmong 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo.Conclusions and relevanceTreatment with lanabecestat was well tolerated and did not slow cognitive or functional decline.Trial registrationClinicalTrials.gov identifiers: NCT02245737 and NCT02783573.

Dataset Information

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.

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