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"Walker, Mike"
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Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model
Misfolded proteins in Alzheimer’s disease and Parkinson’s disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6–8% in CSF, 4–6% and 1–2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.
Journal Article
Quantitative systems pharmacology‐based exploration of relevant anti‐amyloid therapy challenges in clinical practice
INTRODUCTION Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real‐world evidence is not practical, nor feasible. METHODS Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid‐related imaging abnormality–edema (ARIA‐E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges. RESULTS Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aβ42 and the plasma Aβ42/ Aβ40 ratio—fluid biomarkers to detect central amyloid negativity—is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24‐month, 48‐month and 64‐month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA‐E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA‐E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA‐E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period. DISCUSSION This QSP platform could support clinical practice challenges to optimize real‐world treatment paradigms for new and existing amyloid drugs.
Journal Article
A combined physiologically‐based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease
Antibody‐mediated removal of aggregated β‐amyloid (Aβ) is the current, most clinically advanced potential disease‐modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aβ monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aβ40 and Aβ42 aggregation and clearance of aggregated Aβ by activated microglia cells, which is enhanced by the interaction of antibody‐bound Aβ. The model allows for the prediction of Aβ positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology‐based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aβ42 and plasma Aβ42/Aβ40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody‐bound, plaque‐mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid‐related imaging abnormalities with edema (ARIA‐E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aβ42/Aβ40 ratio while slightly overestimating the change in CSF Aβ42. ARIA‐E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid‐modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.
Journal Article
Black Petrels (Procellaria parkinsoni) Patrol the Ocean Shelf-Break: GPS Tracking of a Vulnerable Procellariiform Seabird
Reports on the first successful precision tracking of a c. 700 g seabird, the vulnerable Black Petrel, Procellaria parkinsoni, foraging at sea during the breeding season, using miniature GPS-logging technology. Presents data from nine individual foraging excursions tracked during the chick-rearing period in February 2006. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Journal Article
Lateglacial environmental change in Scotland
This paper reviews the evidence for environmental change during the Lateglacial period (c.14.7–11.7 ka), perhaps the most intensively studied episode in the Quaternary history of Scotland. It considers first the stratigraphic subdivision and nomenclature of the Lateglacial, before proceeding to a discussion of the various lines of proxy evidence that have been used to reconstruct the spatial and temporal patterns of environmental change during this time period. These include pollen and plant macrofossil data; coleopteran and chironomid records; diatom data; stable isotope and geochemical records; and evidence for human activity. The paper then considers the principal methods that have been employed to date and correlate Lateglacial events: radiocarbon dating; surface exposure dating; varve chronology; and tephrochronology. This is followed by an examination of the constraints imposed on environmental reconstructions, an account of the ways in which the evidence can be employed in the development of an event stratigraphy for the Lateglacial in Scotland, and a proposal for a provisional Lateglacial type sequence (stratotype) at Whitrig Bog in SE Scotland. Emphasis is placed throughout on the potential linkages between the Scottish records and the isotopic signal in the Greenland ice cores, which forms the stratigraphic template for the N Atlantic region. The paper concludes with a discussion of the strategies and approaches that should underpin future research programmes on Lateglacial environmental change in Scotland.
Journal Article
Grain Floatation During Equiaxed Solidification of an Al-Cu Alloy in a Side-Cooled Cavity: Part II—Numerical Studies
In this article, a single-phase, one-domain macroscopic model is developed for studying binary alloy solidification with moving equiaxed solid phase, along with the associated transport phenomena. In this model, issues such as thermosolutal convection, motion of solid phase relative to liquid and viscosity variations of the solid–liquid mixture with solid fraction in the mobile zone are taken into account. Using the model, the associated transport phenomena during solidification of Al-Cu alloys in a rectangular cavity are predicted. The results for temperature variation, segregation patterns, and eutectic fraction distribution are compared with data from in-house experiments. The model predictions compare well with the experimental results. To highlight the influence of solid phase movement on convection and final macrosegregation, the results of the current model are also compared with those obtained from the conventional solidification model with stationary solid phase. By including the independent movement of the solid phase into the fluid transport model, better predictions of macrosegregation, microstructure, and even shrinkage locations were obtained. Mechanical property prediction models based on microstructure will benefit from the improved accuracy of this model.
Journal Article
Grain Floatation During Equiaxed Solidification of an Al-Cu Alloy in a Side-Cooled Cavity: Part I—Experimental Studies
Experimental studies were performed to investigate the role and influence of grain movement on macrosegregation and microstructure evolution during equiaxed solidification. Casting experiments were performed with a grain-refined Al-Cu alloy in a rectangular sand mold. For the aluminum alloy studied, the equiaxed grains are lighter than the bulk melt and thus float up. Experiments were designed to investigate floatation phenomena of equiaxed grains in the presence of thermosolutal convection. Cooling curves were recorded at key locations in both the casting and the chill. Quantitative image analysis and spatial chemical analysis were performed on the solidified casting to observe the chemical and microstructural inhomogeneity created by the melt convection and solid floatation. Several notable features that can be attributed to grain movement were observed in temperature histories, macrosegregation patterns, and microstructures. In our experiments, the floatation of grains influences the thermal conditions and the overall flow direction in the casting cavity. In some cases, the induced flow resulting from the grain movement caused a flow reversal. This in turn influences the solidification direction, microstructure evolution, and the overall macrosegregation behavior.
Journal Article
Extraction of Nickel from Ultramafic Nickel Sulfide Concentrate by Metallic Iron Addition
Abundant low-grade nickel sulfide ore reserves hold potential as nickel resources but are hindered by high magnesium silicate content, limiting efficient utilization. The authors investigated the possibility of extracting nickel from a low-grade ultramafic nickel sulfide concentrate into ferronickel alloy. The nickel extraction study involved thermal upgrading and physical separation. Thermal upgrading efficiently concentrated nickel values from ultramafic concentrate into ferronickel alloy, achieving over 90 pct extraction with more than 40 pct nickel grade and a characteristic particle size of d80=100 µm. The presence of magnesium silicate gangues in the concentrate adversely impacted the thermal extraction of nickel. Multiple thermal treatment variables have been studied to improve nickel extraction efficiency, including metallic iron addition rate, heating duration, temperature, additives, and atmosphere. The proposed solid-state thermal upgrading method avoided smelting of materials and generation of sulfur dioxide. Magnetic separation recovered approximately 85 pct of nickel in the thermal treatment products into a ferronickel concentrate at 20 pct nickel grade.
Journal Article