Welcome to the AD/PD™ 2021 Interactive Program
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- Live Session | 
- On Demand Session | 
- On Demand with Live Q&A
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FOLLOWING THE LIVE DISCUSSION, THE RECORDING WILL BE AVAILABLE IN THE ON-DEMAND SECTION OF THE AUDITORIUM.
ADVANCES IN ALZHEIMER’S DISEASE PREVENTION TRIALS: DIAN-TU UPDATES AND TRANSITION TO BLOOD TEST
Abstract
Abstract Body
Objective:In 2012, the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Adaptive Prevention Trial platform launched a double-blind, randomized, placebo-controlled, parallel group trial of two anti-amyloid-beta monoclonal antibodies, gantenerumab and solanezumab (NCT01760005) in participants at-risk for or with mild symptoms of dominantly inherited AD (DIAD).
Methods:
DIAN-TU enrolled 194 participants in this phase 2/3 trial testing effects on cognitive, clinical, and biological measures of AD with a common close at 4 years (average 5.2 years) in November 2019. Amendments increased the dose of each drug and extended the study from 2 year biomarker to 4 year cognitive endpoint.
Results:
The findings of drug effects on clinical and cognitive measures, MRI, CSF, blood and amyloid PET scans will be presented for each drug comparing active to placebo and control participants from the DIAN Observational study. The primary cognitive endpoints were not met, however, key secondary outcomes of decreasing amyloid plaques, phospho-tau and neurodegeneration markers were met for gantenerumab. These results inform about AD hypotheses of causation, timing of treatment and the prospect of slowing or preventing AD in DIAD and sporadic AD.
Conclusions:
A remaining challenge in sporadic AD is identifying those who will get dementia and predicting the age of onset. Recent developments of blood-based biomarkers now offer potential accuracy and precision similar to PET or CSF measures of amyloid plaques and tau tangles. These advancements enable the possibility of using simple blood tests to implement treatment and prevention trials faster and with larger numbers of participants, increasing the power to identify effective treatments.
REGIONAL EFFECTS OF GANTENERUMAB ON NEUROIMAGING MARKERS IN THE DOMINANTLY INHERITED ALZHEIMER NETWORK TRIALS UNIT (DIAN-TU)
Abstract
Aims
To evaluate treatment effects of anti-amyloid antibody Gantenerumab on neuroimaging outcomes in individuals carrying autosomal dominant mutations in PSEN1, PSEN2, APP genes enrolled in the DIAN-TU
Methods
Participants were randomized into drug (n=52) or placebo arms (n=40) and received up to 48 months of drug treatment. Longitudinal structural MRI, [11C]-Pittsburgh Compound B (PiB) PET, and [18F]-fluorodeoxyglucose (FDG) PET imaging data were processed using FreeSurfer and the PET Unified Pipeline (PUP) and analyzed using linear mixed effects models. Models estimated the longitudinal effects of Gantenerumab treatment on imaging outcomes of the DIAN-TU trial.
Results
Treatment significantly reduced the longitudinal increase of mean cortical PiB PET signal (β = -.06, SE = .01, t = -5.83, p < .0001), but did not affect the additional imaging endpoints of precuneus FDG (β = -.01, SE = .005, t = -1.579, p = .118) or precuneus thickness (β = .003, SE = .007, t = 0.388, p = .69). Estimated effects on PiB PET varied regionally in a pattern distinct from baseline PiB PET levels (Figure 1).
Conclusions
Gantenerumab successfully lowered levels of beta-amyloid as indexed by PiB PET imaging. The regional pattern of drug effects suggest clearance is not solely driven by baseline levels of pathology. The observed pattern may be influenced by Gantenerumab having a differential impact on diffuse versus dense-core beta-amyloid plaques or variability in blood brain barrier permeability that may lead to differential local concentration of the drug.
DONANEMAB SLOWS PROGRESSION OF EARLY SYMPTOMATIC ALZHEIMER’S DISEASE IN PHASE 2 PROOF OF CONCEPT TRIAL
Abstract
Aims
Donanemab is an antibody targeting a modified form of Aβ called N3pG. This study aimed to assess the potential treatment effects of donanemab on disease progression in individuals with early symptomatic Alzheimer’s Disease (AD).
Methods
TRAILBLAZER-ALZ (NCT03367403) was a randomized, placebo-controlled, double-blind, multi-center Phase 2 study assessing the safety, tolerability and efficacy of donanemab in patients with early symptomatic AD. The trial enrolled 272 patients, selected based on cognitive assessments in conjunction with amyloid and tau positron emission tomography (PET). The primary efficacy endpoint was change from baseline to 76 weeks in the Integrated AD Rating Scale (iADRS), a composite tool combining the AD Assessment Scale-Cognitive subscale (ADAS-Cog13) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL) for function. Secondary endpoints included changes in CDR-SB, ADAS-Cog13, ADCS-iADL, MMSE, amyloid PET, tau PET, and volumetric MRI.
Results
Donanemab significantly slowed the clinical decline compared to placebo on the primary outcome, iADRS, by 32%. On average, patients who received donanemab showed an 84 centiloid reduction of amyloid plaque at 76 weeks. In the donanemab treatment group, amyloid-related imaging abnormalities – edema (ARIA-E) occurred in 27% of treated participants. Secondary and exploratory outcome measures will be presented.
Conclusions
In this Phase 2 study, donanemab showed a safety profile consistent with the Phase 1 data. Donanemab also showed significant slowing of clinical decline in a composite measure of cognition and daily function and reduced amyloid plaque compared to placebo in patients with early symptomatic AD.EVALUATION OF ADUCANUMAB EFFICACY IN EARLY ALZHEIMER’S DISEASE
Abstract
Aims
To evaluate the efficacy of aducanumab treatment in EMERGE and ENGAGE, Phase 3 studies of aducanumab in early Alzheimer’s disease.Methods
EMERGE and ENGAGE were identically designed, randomized, double-blind, placebo-controlled, global Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients aged 50-85 years with early Alzheimer’s disease (MCI due to AD or mild AD dementia, and confirmed amyloid pathology). Participants received high-dose aducanumab, low-dose aducanumab, or placebo, randomized 1:1:1, via intravenous injection monthly for 18 months. The primary endpoint was change from baseline on the CDR-SB at Week 78. Secondary endpoints included change from baseline on MMSE, ADAS-Cog13, and ADCS-ADL-MCI at Week 78. NPI-10 was a tertiary efficacy measure.Results
In EMERGE, treatment with high-dose aducanumab resulted in a consistent and statistically significant reduction of clinical decline across both the primary and secondary endpoints. ENGAGE did not meet its primary endpoint; dose exposure, amongst other factors, contributed to the discordant results observed between the two studies in the high-dose aducanumab arm. In each study, aducanumab showed statistically significant and dose-dependent reduction in brain amyloid beta (Aβ) pathology. Effects on downstream biomarkers specific to Alzheimer disease (tau PET and CSF p-tau) and neurodegeneration (CSF t-tau) further support the clinical findings.Conclusions
The results of the EMERGE trial indicate a beneficial effect of high-dose aducanumab in patients with early Alzheimer’s disease. The discordant results of the ENGAGE trial may be explained, at least in part, by lower exposure to the drug.EVALUATION OF ADUCANUMAB SAFETY IN EARLY ALZHEIMER’S DISEASE
Abstract
Aims
To characterize the aducanumab Phase 3 safety profile.Methods
EMERGE and ENGAGE were identically-designed, randomized, double-blind, placebo-controlled Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients with early Alzheimer’s disease (AD; mild cognitive impairment due to AD or mild AD dementia). Participants received (via intravenous injection) high-dose aducanumab, low-dose aducanumab, or placebo, monthly, randomized 1:1:1, for 18 months. Amyloid Related Imaging Abnormalities (ARIA) risk minimization included dose titration, routine brain magnetic resonance imaging (MRI) monitoring and dose suspension. An independent data monitoring committee routinely reviewed safety data. To minimize the potential of functional unblinding due to ARIA, clinical efficacy raters were different from the raters who assessed and monitored safety and efficacy raters remained blinded to all safety assessments.Results
The integrated dataset from EMERGE and ENGAGE consisted of a total of 3,285 participants (n=2,198 aducanumab-treated; n=1087 placebo-treated) who received at least 1 dose during the placebo-controlled period. ARIA-Edema (ARIA-E) were the most common adverse events (35.2%) in the 10 mg/kg group, with a higher incidence in apolipoprotein ε4 (ApoE ε4) carriers compared to noncarriers (43.0% versus 20.3%, respectively). ARIA-E were transient and typically asymptomatic (74.0%). Brain microhemorrhages and localized superficial siderosis were typically asymptomatic and were more common in aducanumab-treated participants who had ARIA-E (40.3% and 38.7%, respectively), compared to participants without ARIA-E (7.6% and 1.6%, respectively). There were no fatal events due to ARIA.Conclusions
ARIA are predominantly transient and asymptomatic and can be mitigated with dose titration and routine brain MRI monitoringPRELIMINARY AMYLOID PET ANALYSIS IN BAN2401 PHASE 2 OPEN-LABEL EXTENSION IN SUBJECTS WHO PARTICIPATED IN THE CORE IMAGING SUBGROUP
Abstract
Aims
To evaluate preliminary findings for BAN2401, a humanized IgG1 monoclonal antibody that selectively binds Aβ protofibrils, to evaluate the longitudinal amyloid positron emission tomography (PET) findings in subjects who participated in the Core amyloid imaging subgroup.
Methods
A total of 39 subjects who participated in the Core imaging subgroup are evaluated in the Open Label Extension (OLE) imaging subgroup (Core allocation: placebo:10; 10 mg/kg monthly:19; 10 mg/kg biweekly:10). All subjects received 10 mg/kg biweekly for up to 12 months in the OLE. All subjects were amyloid positive at baseline in the core study based on PET visual read. Piecewise regression analyses were conducted on amyloid PET standard uptake value ratio (SUVr) over the 18-month core period, at baseline of the OLE, and over 12 months during the OLE.
Results
Reductions were dependent on Core treatment assignment and PET SUVr at OLE baseline, with model-estimated slope for change from baseline SUVr of -0.026 in Core placebo-treated subjects, compared to -0.004 in Core 10 mg/kg biweekly-treated subjects over the 12-month OLE. Change from core baseline point estimate SUVr values for Core placebo-treated subjects were 0.05022, -0.027, -0.104, and -257 at OLE baseline, 3, 6, and 12 months, respectively, in the OLE. Point estimate SUVr values for Core BAN2401-treated subjects changed less relative to OLE baseline over the 12-month OLE.
Conclusions
Results from this preliminary analysis suggest that 10 mg/kg biweekly BAN2401 elicits rapid reduction of brain amyloid that is apparent as early as 3 months of treatment.