Welcome to the AD/PD™ 2022 Interactive Program
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SCIENCE OF THE AMYLOID CASCADE AND DISTINCT MECHANISM OF ACTION OF LECANEMAB
Abstract
Aims
Alzheimer disease (AD) is characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of tau protein. Genetic and biochemical studies point to Aβ as the starting point in the disease. There is a spectrum of aggregated Aβ species, ranging from dimers, oligomers, protofibrils and insoluble fibrillar Aβ, which exist in a complex equilibrium in the AD brain. The most toxic forms of Aβ are not the fibrils found in plaques, but rather the lower molecular weight species known as Aβ oligomers and protofibrils. The bulk of Aβ in the AD cortex is thus far less pathogenic than the smaller soluble oligomers and protofibrils. Immunotherapy against Aβ has emerged as a promising treatment for AD. mAb158, the mouse precursor antibody to lecanemab, was generated based on the Arctic mutation which causes AD due to an enhanced propensity to form protofibrils.
Methods
We review current understanding of the amyloid pathway and where lecanemab, an emerging Aβ therapy, fits into the pathway. We have examined the binding characteristics to Aβ of three antibodies, lecanemab, aducanumab and gantenerumab, by three different methods: inhibition ELISA, immunodepletion and Surface Plasmon Resonance.
Results
Data will be presented comparing the different antibodies and their affinities to different Aβ species.
Conclusions
Several clinical trials in AD with monoclonal antibodies against Aβ have failed due to lack of efficacy and/or adverse events. One explanation for these failures might be that these antibodies have been targeting non harmful forms of Aβ.
KEY TRIAL DESIGN ASPECTS AND CLINICAL OUTCOMES OF THE LECANEMAB PHASE 2 TRIAL AND OPEN-LABEL EXTENSION IN EARLY ALZHEIMER’S DISEASE
Abstract
Aims
Lecanemab is a humanized IgG1 monoclonal antibody that selectively targets soluble aggregated Aβ species. Key design features and latest results will be presented from a large, double-blind, placebo-controlled, randomized 18-month phase 2 proof-of-concept Core study (Study 201) with a Bayesian design and an open-label extension (OLE) recently conducted in early Alzheimer’s disease (AD).
Methods
In this presentation, the design and latest results from the lecanemab Study 201 Core, in which patients were randomized to five dose regimens or placebo will be reviewed. The latest data from the open-label extension (OLE) of Study 201, which was initiated to allow patients to receive open-label lecanemab 10mg/kg-biweekly for up to 24 months will also be reviewed.
Results
Lecanemab treatment can be initiated without titration and results in rapid and thorough amyloid reduction correlating with clinical benefit. Amyloid reduction achieved within 3 months and clinical efficacy within 6 months of treatment. Benefit in early AD patients is maintained after treatment discontinuation, suggesting potential disease modifying effects. ARIA-E and symptomatic ARIA rates were low in the Core and OLE. These data are supportive of important therapeutic effects and are supported by changes in key biomarkers as discussed by the next speaker. These findings will be further evaluated in the phase 3 Clarity AD trial which is ongoing.
Conclusions
The findings from Study 201 Core and OLE suggest that lecanemab 10mg/kg biweekly can be initiated to elicit rapid reduction of brain amyloid at the onset of treatment with relatively low incidence and severity of ARIA-E.
PHASE 2 LECANEMAB EARLY ALZHEIMER’S DISEASE STUDY BIOMARKER RESULTS AND CORRELATIONS WITH CLINICAL OUTCOMES
Abstract
Aims
Key fluid biomarker findings and their correlations with clinical outcome from the phase 2 lecanemab 201 trial (Core and open-label extension [OLE]) will be discussed. PET, CSF and plasma was used to assess longitudinal biomarker changes during the double-blind Core portion of the trial while patients were receiving placebo or treatment, after discontinuing treatment, and on resuming treatment. The Tau NexGen trial (part of the Dominantly Inherited Alzheimer Network Trials Unit [DIAN-TU]) evaluating lecanemab combined with E2814 (anti-MTBR tau) will also be highlighted.
Methods
Multimodal data accumulated for biomarkers, eg. amyloid, p-tau181, neurogranin, and neurofilament light (NfL) from the lecanemab Study 201 (Core and OLE) was analyzed and correlated with clinical outcomes. Samples of plasma and CSF, amyloid PET scans, and clinical outcomes across a duration of up to 5 years were utilized in the analysis.
Results
Correlation can be seen between clinical outcomes, amyloid PET SUVr & plasma Aβ42/40 ratio / pTau181 across 18 months of treatment. When treatment was discontinued for average of 2 years, these correlations were low. When treatment was re-initiated, there was return to earlier treatment effect on clinical outcomes as well as all the biomarkers.
Conclusions
Treatment with lecanemab in early AD was associated with change in CSF, plasma biomarkers, and amyloid PET, which were differentially correlated with clinical outcomes and response to therapy. Changes in multiple biomarkers following lecanemab treatment suggest a potential disease modifying effect. The DIAN-TU trial will utilize lecanemab as the background anti-amyloid therapy.
UPDATE ON LECANEMAB CLINICAL DEVELOPMENT, INCLUDING SUBCUTANEOUS FORMULATION
Abstract
Aims
This update on lecanemab (BAN2401) will review the study design, discuss the current status of the phase 3 study and the development of a new subcutaneous formulation.
Methods
Clarity AD is a multicenter, double-blind, placebo-controlled, parallel-group study of 18-month treatment duration with open-label extension (OLE) in patients with early AD with confirmed amyloid pathology. Eligible patients are randomized to placebo or 10 mg/kg biweekly (top dose identified in Phase 2 POC study 201) initiated with full therapeutic dosing. The primary endpoint is change from baseline in Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) compared to placebo at 18 months. Key secondary endpoints include change from baseline at 18 months in amyloid PET standardized uptake value ratio (sub-study), AD COMposite Score (ADCOMS) and AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14). A subcutaneous dose is under development based on PK/PD modeling and bioavailability data.
Results
A total of 1795 patients were randomized in CLARITY AD. ApoE4 carriers make up 69% of the population and 62% are mild cognitive impairment. The median age of patients was 72 years (range: 50-90 years). Clinical baseline characteristics are well balanced when comparing Clarity AD to the Phase 2 study 201. A subcutaneous dose will be introduced into the Clarity AD OLE to evaluate PK/PD of the formulation.
Conclusions
The phase 3 Clarity AD study is designed to confirm the clinical efficacy and safety of lecanemab versus placebo in patients with early AD. Development of a subcutaneous lecanemab formulation is progressing with the goal of more treatment options for patients.
HEAD-TO-HEAD COMPARISON OF PLASMA BIOMARKERS OF AMYLOID, TAU, AND INFLAMMATION FOR THE IDENTIFICATION OF AD PATHOPHYSIOLOGY
Abstract
Aims
To perform a head-to-head comparison of plasma phosphorylated tau (p-Tau) 181 and p-Tau231, neurofilament light chain (NfL), glial fibrillary protein (GFAP), and amyloid (Aβ)42/Aβ40 against Aβ PET and Tau PET across the Alzheimer Disease (AD) spectrum.
Methods
Plasma p-Tau231, p-Tau181, NfL, GFAP, Aβ42/Aβ40 were measured by Simoa, [18F]AZD4694 Aβ-PET, [18F]MK6240 Tau-PET, MRI and cognitive assessment from 230 individuals [142 Cognitive unimpaired (CU), 88 cognitive impaired (CI)] were obtained from the McGill TRIAD cohort. Linear regressions test the associations between biomarkers. Demographics (sex, age, and APOE ε4 status) were added to the models when appropriated. The discriminative performance of biomarkers was assessed with the area under the curve (AUC).
Results
In the CU group, p-tau231 adjusted for demographics showed the strongest association with both Aβ PET (R-squared = 35.73% and AUC = 0.877) and tau PET (R-squared = 35.73% and AUC = 0.877) (Figure 1). In the CI group, GFAP adjusted for demographics showed the strongest association with both Aβ PET (R-squared = 29.04% and AUC = 0.935) and Tau PET (R-squared = 43.94% and AUC = 0.906) (Figure 1).
Conclusions
We showed that plasma p-Tau231, a novel biomarker of early AD, best depicts AD pathophysiology in CU. Interestingly, GFAP, an astrocyte reactivity marker, is better associated with Aβ and Tau PET than plasma p-tau and Aβ markers in CI individuals. Our results highlight - for the first time - that the performance of the novel plasma biomarkers of amyloid, tau, and inflammation to detect brain AD pathophysiology is driven by disease stages.
DISTINCT REGIONAL AMYLOID PATTERNS FACILITATE TAU SPREADING IN AGING AND ALZHEIMER’S DISEASE
Abstract
Aims
To assess the contribution of regional amyloid load to tau spreading in a cohort of amyloid-positive (Aß+) subjects using PET data.
Methods
Data of 41 cognitively unimpaired (CU) and 31 MCI patients was retrieved from ADNI, who had undergone two 18F-AV1451 (tau) and a baseline 18F-AV45 (amyloid) PET scan. Pre-processed PET scans were z-transformed using Aß- and age-matched CU subjects (n=38) as reference group. Subsequently, tau PET z-maps were thresholded at z > 1.96 and annual tau z-score change maps were computed. To identify linked regional combinations of baseline amyloid distribution and tau spreading, baseline amyloid z-maps and annual tau change maps were submitted to a data-driven parallel ICA which yields maximally correlated component pairs of these two measures. Next, regional overlap between resulting component pairs was quantified using the dice similarity coefficient (DSC). Finally, group-specific spearman correlations were performed to test the association between baseline amyloid load and annual tau change extracted from the component pairs.
Results
The p-ICA resulted in three significant component pairs (Figure 1) with relative spatial overlap suggesting a spatial disconnect between antecedent amyloid burden and subsequent tau spreading. Greater amyloid burden was positively associated with higher annual tau change in component pairs 1 and 3 in the CU group, and in component pair 2 for the MCI group pointing towards a stage-dependent role of regional amyloid on tau spreading.
Conclusions
Baseline amyloid distribution patterns may inform on subsequent regional increases of tau pathology, and thus the neuropathological course of Alzheimer’s disease.