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BINDING CHARACTERISTICS OF LECANEMAB, DONANEMAB AND OTHER AMYLOID-BETA ANTIBODIES TO DIFFERENT FORMS OF AMYLOID-BETA IN ALZHEIMER’S DISEASE BRAINS
Abstract
Aims
Lecanemab and donanemab have both shown positive data in phase 3 clinical trials. Lecanemab mainly targets soluble aggregated amyloid-beta species, while donanemab targets pyroglutamate modified amyloid-beta-pE3 in plaques. Immunotherapy with antibodies targeting amyloid-beta is associated with amyloid-related imaging abnormalities with edema (ARIA-E). The incidence of ARIA-E might correlate with antibody binding to amyloid-beta fibrils in cerebral amyloid angiopathy (CAA) in vessels. An ARIA-E rate of 12.6% was reported for lecanemab, and a rate of 24% was observed for donanemab. Here we have studied binding characteristics of different amyloid-beta targeting antibodies to amyloid-beta isolated from human brain.
Methods
Binding strength of lecanemab, donanemab, aducanumab, gantenerumab, bapineuzumab, crenezumab and solanezumab was evaluated by immunoprecipitation, surface plasmon resonance and mass spectrometry. Levels of amyloid-beta were measured in human postmortem brain (n=67). CAA was isolated from human meningeal tissue. Lecanemab was supplied by Eisai and the other antibodies were produced from published sequences.
Results
Levels of amyloid-beta-pE3 in brain were significantly elevated at later Braak stages as compared to lower Braak stages. Lecanemab showed strong binding to amyloid-beta protofibrils independent of amyloid-beta-pE3 levels and Braak stages. Amyloid-beta-40 was identified as the major amyloid-beta species in CAA and presence of amyloid-beta-pE3 was confirmed. Antibodies with higher CAA binding than lecanemab had higher ARIA-E frequency, supporting the hypothesis that CAA binding correlates to ARIA-E.
Conclusions
There was a good correlation between binding to CAA and frequency of ARIA-E for amyloid-beta antibodies. Amyloid-beta-pE3 was observed in brains with higher Braak stages, indicating that amyloid-beta-pE3 is a late phenomenon in the pathogenesis. These results indicate differences in clinical efficacy and safety between amyloid-beta antibodies targeting different amyloid species, especially when treating early in the disease.
ADUCANUMAB TREATMENT MODULATES MICROGLIAL ACTIVATION IN A SEX DEPENDENT MANNER
Abstract
Aims
Antibody therapy has been developed as a treatment for Alzheimer’s disease (AD) to exploit the body’s own immune system to remove amyloid-beta (Aβ) plaques. This approach has proven successful in phase 3 clinical trials of several monoclonal anti-Aβ antibodies, which show robust target engagement and a benefit on cognition, which correlates with the degree of plaque removal in a dose-dependent manner. Treatment is however associated with adverse side-effects, such as oedema and haemorrhages (ARIA-E and -H). The mechanisms of these side-effects are currently poorly understood, but are potentially linked to the induced immune response. To improve therapeutic safety, it is therefore imperative to understand the effects of anti-Aβ antibody treatment on immune cell function.
Methods
Here we investigate the effects of Aducanumab treatment on Aβ-pathology and microglial response in the APP-SAA triple knock-in mouse model. Aβ-pathology was investigated using longitudinal FBB PET, immunofluorescent staining and ELISA of brain extracts. Microglial activation was investigated longitudinally using TSPO and FDG-PET, as well as immunofluorescent staining and ELISA of brain extracts and cerebrospinal fluid (CSF). Isolated microglia from treated mice were subjected to bulk RNAseq and lipidomics.
Results
A dose-dependent reduction of Aβ by Aducanumab was accompanied by a parallel reduction of TREM2 and soluble TREM2 (sTREM2) in the brain, suggesting a reduction of microglial activation due to the removal of the pathological challenge. The reduction of sTREM2 was mirrored in CSF, however only in male mice.
Conclusions
Antibody mediated removal of Aβ, leads to a dose dependent reduction in microglial activation as measured by TREM2. In line with clinical trials, which show stronger effects in males, sex differences in effect size were observed, which are currently under investigation using bulk RNAseq and lipidomics.
LECANEMAB FOR THE TREATMENT OF EARLY ALZHEIMER’S DISEASE: THE EXTENSION OF EFFICACY RESULTS FROM CLARITY AD
Abstract
Aims
Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid-beta (Ab) protofibrils. In phase 3 development, lecanemab reduced markers of amyloid in early symptomatic Alzheimer’s disease (AD) and slowed decline of cognition and function at 18 months. Herein, we report the initial findings from the ongoing open-label extension (OLE) study, in which we evaluated whether the treatment benefits were maintained up to 24 months.
Methods
Clarity AD is an 18-month, randomized study (core) in patients with early AD, with an OLE phase where eligible participants received open-label lecanemab. Clinical (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) and biomarker (PET, Ab42/40 ratio, and ptau181) outcomes were evaluated overall as well as by examining ‘delayed start’ (core:placebo followed by OLE:lecanemab) and ‘early start’ (core:lecanemab followed by OLE:lecanemab) cohorts. Analyses by core baseline tau PET levels were conducted from the tau PET sub-study.
Results
Overall, 1385 participants enrolled in the OLE. Across clinical endpoints, lecanemab-treated participants continued to benefit through 24 months. Separation between early and delayed start was maintained between 18 and 24 months (p<0.05), with a similar disease trajectory when all participants received lecanemab. Biomarker changes continued to improve and were seen in as early as 3 months in newly-treated lecanemab participants. Across assessments, consistent rates of clinical stability or improvements were observed regardless of baseline tau levels, with the highest rates of improvements observed for the low tau group at 24 months (no decline:79%; improvement:50%).
Conclusions
In initial Clarity OLE data, maintenance of treatment difference with ongoing lecanemab treatment through 24 months, relative to the newly treated lecanemab participants, is consistent with a disease-modifying effect. Delayed start and lower pathology group results support early initiation of treatment with lecanemab.
STRUCTURAL DYNAMICS OF AMYLOID-Β PROTOFIBRILS AND ACTION OF LECANEMAB AS OBSERVED BY HIGH-SPEED ATOMIC FORCE MICROSCOPY
Abstract
Aims
Amyloid-β (Aβ) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in the pathogenesis of Alzheimer's disease. Lecanemab, an anti-Aβ PF antibody that showed positive results in Phase 3 Clarity AD, was approved in the US and Japan this year. However, due to the complexity of the Aβ aggregation pathway, the structural dynamics of aggregation intermediates, and how drugs such as lecanemab act on them, have not been clarified. The purpose of this study was to clarify the properties of intermediate Aβ aggregates and part of the mechanism of action of lecanemab.
Methods
Here, we investigated the structure of Aβ42 PF at the single-molecule level using high-speed atomic force microscopy, which is capable of acquiring both structural and kinetic information with a microcantilever that can capture moving images in 0.001 second increments. We observed the kinetics of PF, and interaction of lecanemab with PF and oligomers of Aβ. We also investigated the protective effect of lecanemab against these Aβ aggregates-induced neurotoxicity using SH-SY5Y cells.
Results
PF was found to be a curved nodal structure with stable binding angles between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PF and globular oligomers of Aβ, inhibiting the formation of large aggregates as well as reducing their cytotoxicity by alleviating membrane damage.
Conclusions
Our results provide direct evidence for the mechanism by which lecanemab directly interferes with Aβ aggregation process to reduce cytotoxicity.
DONANEMAB EXPOSURE- EFFICACY AND EXPOSURE-SAFETY (ARIA-E) RELATIONSHIPS IN PARTICIPANTS WITH ALZHEIMER’S DISEASE USING TRAILBLAZER-ALZ DATA
Abstract
Aims
Donanemab significantly slowed clinical progression in early symptomatic Alzheimer’s disease (Sims et al, 2023) . The objectives of these analyses were to characterise exposure-efficacy (amyloid plaque reduction, iADRS, CDR-SB) and exposure-safety (amyloid-related imaging abnormalities with edema or effusions ARIA-E).Methods
Analyses included participants with early symptomatic AD (mild cognitive impairment or mild-dementia due to AD) in the combined population from a phase 1 study (N=61; NCT02624778), phase 2 study (TRAILBLAZER-ALZ; N=256; NCT03367403) and phase 3 study (TRAILBLAZER-ALZ2; N=1954; NCT). Dose- and exposure-response relationships were characterized relative to i) amyloid plaque lowering using indirect response PK/PD models, ii) iADRS, CDR-SB, using disease progression model and iii) first occurrence of ARIA-E event, using time-to-event (TTE) analyses to quantify risk for each of identified significant covariates. Individual participant serum concentrations over time, where impact of body weight, immunogenicity and dosing were included, were used in exposure-efficacy and exposure-safety evaluations.Results
Amyloid reduction was associated with maintaining median serum donanemab concentrations over 15 µg/mL (95% confidence interval 8.54─18.0). No covariate effects, including APOE e4 and baseline tau burden, influencing amyloid removal were identified. The impact of completing active treatment on plaque reaccumulation was investigated by simulations and reaccumulation rate (median, 95% confidence interval) is estimated at 2.80 (2.16, 3.11) Centiloids/year.Donanemab disease progression model, using exposure-amyloid plaque-scores, showed clear treatment effect in both low-medium tau and combined populations. Treatment benefit favouring donanemab was observed in all baseline disease states (MCI/mild AD) and in all baseline tau participant groups, though greater efficacy was observed in participants with low-medium tau and in MCI, suggesting that treating patients earlier provides more benefit.
Using time-to-event analysis, ARIA-E risk is driven by donanemab treatment, APOE ε4 genotype, number of baseline microhemorrhages, average concentration at steady state, mean arterial blood pressure and time components, allowing for ARIA-E risk to be estimated for different months on treatment.
Conclusions
Although donanemab serum clearance increased with increasing ADA titer, the vast majority of participants (over 80%) maintained concentrations above the efficacy threshold. There is separation between amyloid baseline quartiles, showing that time to achieve amyloid plaque clearance depends on baseline. Age, weight, baseline tau, ADA titer and APOE ε4 genotype did not impact amyloid plaque removal. Lack of additional ADA titer effect may result from the appropriately selected dosing regimen, where even with faster serum clearance, the majority of participants had serum concentration above the threshold concentration associated with amyloid plaque removal. Donanemab disease progression model suggests that disease slowing increases over time compared with placebo. Simulations beyond 76 weeks, assuming linear progression rate, suggest that once amyloid is cleared, there is little impact of continuing active treatment on clinical efficacy further justifying limited duration dosing of donanemab. This is due to the very slow reappearance of amyloid once it has been removed by donanemab treatment. Limitations of disease progression analysis were that the model was built only on data that explored a single dosing regimen with a relatively narrow range of exposures. Although immunogenicity had an impact on serum exposure, there was no statistically significant impact of immunogenicity on risk of ARIA-E.ANTI-AMYLOID-BETA TREATMENT EFFECTS ON DOMINANTLY INHERITED ALZHEIMER DISEASE NEUROPATHOLOGY: PRELIMINARY AUTOPSY FINDINGS FROM THE DIAN-TU-001 TRIAL OF GANTENERUMAB OR SOLANEZUMAB
Abstract
Aims
Amyloid-beta plaques are a neuropathological hallmark of Alzheimer disease (AD) and a drug target for anti-amyloid-beta monoclonal antibodies. Clinical trials of these antibodies often monitor changes in amyloid-beta positron emission tomography (PET) signal to evaluate target engagement. Nonetheless, assessment of postmortem tissue is needed to investigate treatment effects on amyloid-beta aggregates and downstream AD neuropathologies at a microscopic level.
Methods
We compared ten cases from a clinical trial in dominantly inherited AD (DIAD) to ten cases from a DIAD observational study. Area fractions were calculated for ten neuroanatomical regions of interest, using postmortem samples stained by immunohistochemistry using antibodies for amyloid-beta (10D5), tau aggregates (PHF1), microglia (IBA1), and astrocytes (GFAP). Centiloids derived from antemortem amyloid-beta PET using the Pittsburgh compound B (PiB) radiotracer were calculated for the same regions.
Results
Gantenerumab-treated participants (n=4) had statistically significantly lower amyloid-beta area fractions than the (observational/placebo) control group (n=12), with evidence for a dose-dependent effect. Amyloid-beta PET at last visit detected no statistical differences in Centiloid between the gantenerumab-treated group (n=4) and control group (n=7; five participants did not undergo PET imaging); however, total drug received before the final PET visit was lower than by trial’s end. Immunohistochemical assessments of tauopathy, microgliosis, and astrocytosis did not find statistical differences between treatment arms and control group.
Conclusions
Our results demonstrate that gantenerumab treatment, as administered to these DIAD participants, likely: reduced, but did not completely eliminate, amyloid-beta deposits; effected clearance in a dose-dependent manner; and did not significantly alter area fractions of tau pathology, microglia, or astrocytes. We anticipate that higher doses, more effective antibodies/therapeutics, and/or earlier intervention with combined anti-amyloid-beta and anti-tau treatment will be the next steps for AD clinical trials.
RAPID DOSE-DEPENDENT AMYLOID PLAQUE DEPLETION WITH TRONTINEMAB, A NOVEL BRAINSHUTTLETM ANTIBODY IN DEVELOPMENT FOR THE TREATMENT OF ALZHEIMER’S DISEASE
Abstract
Aims
ObjectivesTo share the latest interim data from the ongoing Phase Ib/IIa “BrainshuttleTM AD” study of trontinemab in participants with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild-to-moderate AD (NCT04639050). Trontinemab is a novel BrainshuttleTM antibody targeting beta-amyloid that is currently in development for the treatment of AD.