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In the last decade, the efforts conducted for discovering Alzheimer's Disease (AD) treatments targeting the best-known pathogenic factors [amyloid–β (Aβ), tau protein, and neuroinflammation] were mostly unsuccessful. Given that a systemic failure of Aβ clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aβ monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results. The present Drug Discovery Case History analyzes the failures of RCTs of solanezumab on AD. Furthermore, the authors review the pharmacokinetics, pharmacodynamics, and tolerability effect of solanezumab from preclinical studies with its analogous m266 in mice. Finally, they describe the RCTs with cognitive, cerebrospinal fluid and neuroimaging findings in mild-to-moderate AD (EXPEDITION studies) and in secondary prevention studies (A4 and DIAN-TU). Solanezumab was one of the first anti-Aβ monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aβ level by acting on soluble monomeric form of Aβ peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aβ cascade hypothesis of AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double‐blind phase 3 DIAN‐TU‐001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid‐no‐change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid‐reduction class exhibited reductions in the annual decline rates compared to the amyloid‐growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. Highlights: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker.Despite similar baseline characteristics, the amyloid‐reduction class exhibited remarkably better outcomes compared to the amyloid‐growth class across multiple measures.LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects. [ABSTRACT FROM AUTHOR]

Introduction: Solanezumab is a monoclonal antibody that binds to the mid‐domain of soluble amyloid β peptide. This meta‐analysis evaluated the effect of low‐dose solanezumab on clinical progression in three phase 3 studies. Methods: The population comprised patients aged ≥55 years with Alzheimer's disease (AD) with mild dementia, randomized to 400 mg solanezumab or placebo every 4 weeks for 80 weeks. Frequentist mixed‐model repeated‐measures (MMRM) and Bayesian disease progression model (DPM) longitudinal analyses were conducted. Results: Pooled MMRM analyses showed a statistically significant effect of solanezumab across cognitive and functional outcome measures. DPM results were generally consistent with MMRM results, ranging from 15% to 30% slowing of clinical progression. Discussion: These analyses suggest low‐dose solanezumab slows clinical progression of AD with mild dementia. The ongoing A4 solanezumab study in participants with preclinical AD will ascertain the effect of a higher dose of solanezumab in an earlier disease stage. Highlights: Individual EXPEDITION studies were negative but suggest low‐dose solanezumab had an effect in slowing the clinical progression of Alzheimer's disease (AD) with mild dementia.At 80 weeks, mixed‐model repeated‐measures analyses showed numeric reductions in measures of clinical decline in solanezumab‐treated arms compared with placebo across almost every outcome measure, and statistical significance in multiple outcome measures in each study.Pooled analyses suggest a high probability that low‐dose solanezumab has at least some effect on slowing the clinical progression of AD with mild dementia.Across cognitive and functional outcome measures, estimates from disease progression model analyses range from 15% to 30% slowing of decline with low‐dose solanezumab in AD with mild dementia. [ABSTRACT FROM AUTHOR]

AimTo analyze the late-stage failures of monoclonal antibody drugs. The later a drug fails in development, the more time and expense is incurred by the sponsor.MethodsWe review the late stage, Phase III, failures of 21 monoclonal antibody drugs between 2014 and 2019 using published and publicly available information to characterize the reasons for these failures.ResultsIn some cases, the failures are unavoidable due to the lack of adequate science, but in others, we characterize the causes of such failures and recommend how such failures may have been avoided.ConclusionBy learning from previous mistakes and adhering to the principles and recommendations provided, it is possible to avoid these common pitfalls, increasing the likelihood of success in phase III clinical trials, and thus securing regulatory approval.

Abstract Introduction Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low‐dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Methods Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor‐based morphometry (EXPEDITION3). Results The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) ε4+ carriers (N = 1835), and patients with mild (N = 2497) or moderate AD dementia (N = 428). No significant effect (all P‐values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 carriers, in either WBV or VV change. Discussion Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low‐dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken.

Introduction: Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low-dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Methods: Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor-based morphometry (EXPEDITION3). Results: The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) e4+ carriers (N = 1835), and patients with mild (N=2497) or moderateADdementia (N=428). No significant effect (all P-values =.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE e4 carriers, in eitherWBV or VV change. Discussion: Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low-dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken. [ABSTRACT FROM AUTHOR]

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5‐fold, and solanezumab was increased 4‐fold. We evaluated to what extent mid‐trial dose increases produced a dose‐dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low‐ and high‐dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose‐dependent treatment effects (significant for gantenerumab, non‐significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose‐dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid‐trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose‐dependent treatment effect of two different amyloid‐specific immunotherapies.Dose‐dependent treatment effects were observed in some biomarkers.No dose‐dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations. [ABSTRACT FROM AUTHOR]

Introduction: Despite strong evidence linking amyloid beta (Aβ) to Alzheimer's disease, most clinical trials have shown no clinical efficacy for reasons that remain unclear. To understand why, we developed a quantitative systems pharmacology (QSP) model for seven therapeutics: aducanumab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat. Methods: Ordinary differential equations were used to model the production, transport, and aggregation of Aβ; pharmacology of the drugs; and their impact on plaque. Results: The calibrated model predicts that endogenous plaque turnover is slow, with an estimated half‐life of 2.75 years. This is likely why beta‐secretase inhibitors have a smaller effect on plaque reduction. Of the mechanisms tested, the model predicts binding to plaque and inducing antibody‐dependent cellular phagocytosis is the best approach for plaque reduction. Discussion: A QSP model can provide novel insights to clinical results. Our model explains the results of clinical trials and provides guidance for future therapeutic development. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is a chronic neurodegenerative disorder with complex pathophysiology that affects over 50 million people worldwide. Most drug therapies, to date, have focused on targeting the amyloid-beta (Aβ) pathway, but clinical outcomes of anti-Aβ antibodies have been unsuccessful and unable to meet their primary endpoints. Similar trends have also been observed in treatments that target the tau pathway. Summary: This paper reviews recent anti-Aβ passive monotherapies, since Bapineuzumab, that have progressed to phase 3 clinical trials. Specifically, we discuss the 4 clinical trial programs of Solanezumab (targets Aβ monomers), Aducanumab (targets Aβ oligomers and plaques), Crenezumab (targets Aβ oligomers), and Gantenerumab (targets Aβ fibrils) which are all exogenous monoclonal antibodies. We conclude with potential reasons for why they have not met their primary endpoints and discuss lessons learnt from these trials. Key Message: Future disease-modifying trials (DMTs) for AD should be conducted in asymptomatic, Aβ-positive individuals. Moreover, potential additive and/or synergistic benefits focusing on anti-Aβ and anti-tau drug combinations merit further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab., Methods: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker., Results: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes., Discussion: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials., Highlights: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease is the most common form of dementia, that affects millions of people worldwide. According to the widely accepted amyloid cascade hypothesis, misfolding and aggregation of Aβ peptides is the principal cause of Alzheimer's disease. In the present mini-review, we have discussed the different structures of Aβ protein from monomer to fibrils and their arrangement in different symmetries. We have highlighted the critical amino acid residue that plays a crucial role in the early stage misfolding of Aβ monomers, Aβ fibrils arrangement in different symmetries, the elongation process and Aβ protein interaction with the membrane. We have further discussed the antibodies that are currently in clinical trial phase III for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD). Multiple clinical drugs and antibodies such as AZD3293 and Solanezumab are being tested to investigate their therapeutical potential against AD. The current study explores the binding pattern of AZD3293 and Solanezumab against their target proteins such as β-secretase (BACE1) and mid-region amyloid-beta (Aβ) (PDBIDs: 2ZHV & 4XXD), respectively using molecular docking and dynamic simulation (MD) approaches. The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively. However, the heavy chain of Solanezumab interacts with Lys16 and Asp23 of amyloid beta having bond length 2.82, 2.78, and 3.00 Å, respectively. The dynamic cross correlations and normal mode analyses show that BACE1 depicted good residual correlated motions and fluctuations, as compared to Solanezumab. Using MD, the Root Mean Square Deviation and Fluctuation (RMSD/F) graphs show that AZD3293 residual fluctuations and RMSD value (0.2 nm) was much better compared to Solanezumab (0.7 nm). Moreover, the radius of gyration (Rg) results also depicts the significance of AZD3293 docked complex compared to Solanezumab through residual compactness. Our comparative results show that AZD3293 is a better therapeutic agent for treating AD than Solanezumab.

Introduction: There is no cure for Alzheimer's disease, which is the sixth leading cause of death in the USA. Lecanemab is anti-Aβ monoclonal antibody approved for the treatment of early Alzheimer's disease but is only marginally effective. Other antibodies are being developed including solanezumab., Areas Covered: A phase 3 clinical trial of solanezumab in preclinical Alzheimer's disease. In the A4 study, solanezumab did not reduce the decline in cognition or function and had no effect on brain amyloid burden., Expert Opinion: After the poor results in the EXPEDITION series of trials, the development of solanezumab should have been terminated. The rationale for undertaking the A4 trial was questionable, and the lack of benefit was probable. The controversial approval of two anti-Aβ monoclonal antibodies (aducanumab and lecanemab) for the treatment of Alzheimer's disease by the US Food and Drug Administration (FDA), despite a high incidence of amyloid-related imagining abnormalities (ARIA), may be fueling this continuation of clinical development of agents such as solanezumab. The lesson from the A4 trial is that more careful/realistic consideration needs to be given before embarking on further phase 3 trials with anti-Aβ monoclonal antibodies.

Introduction We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results Longitudinal percent change between placebo and solanezumab using CBL was not significant ( P = .536) but was significant for SSWMnr ( P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. Discussion Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change. [ABSTRACT FROM AUTHOR]

Background Solanezumab, an anti-amyloid monoclonal antibody that binds soluble forms of amyloid, might have disease-modifying properties that slow the progression of Alzheimer's disease. Delayed-start design was proposed as a method to show a disease-modifying effect. In the global study, delayed-start analysis suggested that treatment advantages obtained during the placebo-controlled period in the mild subgroup of solanezumab-treated patients were preserved at the primary time-point (108 weeks). Aim We applied the delayed-start analysis to the Japanese subpopulation with mild Alzheimer's disease who participated in the global studies to see whether a disease-modifying effect was also shown in the Japanese subpopulation. Methods A possible disease-modifying effect of solanezumab was assessed using a new statistical method including non-inferiority testing. Treatment differences were compared during the placebo-controlled period with those after the placebo patients crossed over to solanezumab in the delayed-start period. Results A total of 126 Japanese patients with mild Alzheimer's disease were included in the present study. Least squares mean difference for the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale at the end of the placebo-controlled period between patients with early- and delayed-start of solanezumab was 2.85 (95% confidence interval 0.01-5.69) and 5.86 (95% confidence interval 2.22-9.51) at 108 weeks. Treatment difference during the placebo-controlled period for the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale was preserved at 108 weeks in the delayed-start period. Conclusion Results from the Japanese subpopulation showed overall consistency with those from the global study, and are supportive for the possible disease-modifying effects of solanezumab. [ABSTRACT FROM AUTHOR]

Introduction: Solanezumab is a monoclonal antibody that binds to the mid-domain of soluble amyloid β peptide. This meta-analysis evaluated the effect of low-dose solanezumab on clinical progression in three phase 3 studies., Methods: The population comprised patients aged ≥55 years with Alzheimer's disease (AD) with mild dementia, randomized to 400 mg solanezumab or placebo every 4 weeks for 80 weeks. Frequentist mixed-model repeated-measures (MMRM) and Bayesian disease progression model (DPM) longitudinal analyses were conducted., Results: Pooled MMRM analyses showed a statistically significant effect of solanezumab across cognitive and functional outcome measures. DPM results were generally consistent with MMRM results, ranging from 15% to 30% slowing of clinical progression., Discussion: These analyses suggest low-dose solanezumab slows clinical progression of AD with mild dementia. The ongoing A4 solanezumab study in participants with preclinical AD will ascertain the effect of a higher dose of solanezumab in an earlier disease stage., Highlights: Individual EXPEDITION studies were negative but suggest low-dose solanezumab had an effect in slowing the clinical progression of Alzheimer's disease (AD) with mild dementia. At 80 weeks, mixed-model repeated-measures analyses showed numeric reductions in measures of clinical decline in solanezumab-treated arms compared with placebo across almost every outcome measure, and statistical significance in multiple outcome measures in each study. Pooled analyses suggest a high probability that low-dose solanezumab has at least some effect on slowing the clinical progression of AD with mild dementia. Across cognitive and functional outcome measures, estimates from disease progression model analyses range from 15% to 30% slowing of decline with low-dose solanezumab in AD with mild dementia., (© 2023 Eli Lilly and Company. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Amyloid Related Imaging Abnormalities (ARIA) represent the major severe side effect of amyloid-beta (Aβ) immunotherapy for Alzheimer’s disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-Aβ autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-A autoantibody as a promising candidate biomarker for ARIA in clinical trials.

Introduction: Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer’s disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer’s disease. Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert commentary: We suggest a new methodology for future treatment research in Alzheimer’s disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period. [ABSTRACT FROM PUBLISHER]

As the population of the world increases, there will be larger numbers of people with dementia and an emerging need for prompt diagnosis and treatment. Early dementia screening is the process by which a patient who might be in the prodromal phases of a dementing illness is determined as having, or not having, the hallmarks of a neurodegenerative condition. The concepts of mild cognitive impairment, or mild neurocognitive disorder, are useful in analyzing the patient in the prodromal phase of a dementing disease; however, the transformation to dementia may be as low as 10% per annum. The search for early dementia requires a comprehensive clinical evaluation, cognitive assessment, determination of functional status, corroborative history and imaging (including MRI, FDG-PET and maybe amyloid PET), cerebrospinal fluid (CSF) examination assaying Aβ1-42, T-τ and P-τ might also be helpful. Primary care physicians are fundamental in the screening process and are vital in initiating specialist investigation and treatment. Early dementia screening is especially important in an age where there is a search for disease modifying therapies, where there is mounting evidence that treatment, if given early, might influence the natural history-hence the need for cost-effective screening measures for early dementia. [ABSTRACT FROM AUTHOR]

Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population. [ABSTRACT FROM AUTHOR]

Background: The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression.Objective: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials.Methods: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time.Results: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa.Conclusions: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process. [ABSTRACT FROM AUTHOR]

Background: In patients with Alzheimer's disease (AD), the relationship between cognitive and functional progression is not fully understood; however, functional decline has been postulated to follow cognitive decline. Objective: To assess the relationship between cognitive and functional treatment effects in mild AD dementia patients. Methods: Data of patients with mild AD were pooled from two multicenter, double-blind, Phase 3 studies. Patients were randomized to infusions of 400-mg solanezumab (n = 654), or placebo (n = 660) every 4 weeks for 18 months. Cognitive and functional outcome measures were assessed using the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL), respectively. Analyses included comparisons among normalized scales, correlations between outcome measures, and path analyses to model the relationship of treatment effect on cognition and function. Results: Normalized ADAS-Cog and ADCS-ADL scales showed cognitive impairment was more evident than functional impairment in mild AD. The correlation between cognition and function increased over time. Path analyses demonstrated that 87% of the treatment effect on function was driven by the treatment effect on cognition, with the remaining 13% due to direct treatment effect. Conclusion: Findings from this study are consistent with the hypothesis that functional impairment is primarily driven by and follows cognitive decline in mild AD dementia. The cognitive treatment effect appeared to explain the majority of the functional treatment effect. It is possible that a cognitive treatment effect may be considered as a leading indicator for functional outcomes in an 18-month clinical trial for milder stages of AD. [ABSTRACT FROM AUTHOR]

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD. [ABSTRACT FROM AUTHOR]

Background High-profile Phase 3 clinical trials of bapineuzumab and solanezumab, antibodies targeted at amyloid-beta (Aβ) removal, have failed to meet their primary endpoints. Neither drug improves clinical outcomes in patients with late onset AD, joining a long list of unsuccessful attempts to treat AD with anti-amyloid therapies. Discussion These therapies are based on the assumption that Aβ accumulation is the primary pathogenic trigger of AD. Current evidence suggests that Aβ may actually accumulate as part of an adaptive response to long-term chronic brain stress stimuli that would make more suitable candidates for therapeutic intervention. Summary At this juncture it is no longer unreasonable to suggest that further iterations of anti-Aβ therapies should be halted. Clinicians and researchers should instead direct their attention toward greater understanding of the biological function of Aβ both in healthy and demented brains, as well as the involvement of long-term chronic exposure to stress in the etiology of AD. [ABSTRACT FROM AUTHOR]

Among active and passive anti-β-amyloid (Aβ) immunotherapies for Alzheimer's disease (AD), bapineuzumab and solanezumab, two humanized monoclonal antibodies, failed to show significant clinical benefits in mild-to-moderate AD patients in large Phase III clinical trials. Another ongoing Phase III trial of solanezumab aims to confirm positive findings in mild AD patients. Gantenerumab is the first fully human anti-Aβ monoclonal antibody directed to both N-terminal and central regions of Aβ. A 6-month PET study in 16 AD patients showed that gantenerumab treatment dose-dependently reduced brain Aβ deposition, possibly stimulating microglial-mediated phagocytosis. Two ongoing Phase III trials of gantenerumab in patients with prodromal or mild dementia due to AD will determine if any reduction in brain Aβ levels will translate into clinical benefits. An ongoing secondary prevention trial of gantenerumab in presymptomatic subjects with genetic mutations for autosomal-dominant AD will verify the utility of anti-Aβ monoclonal antibodies as prevention therapy. [ABSTRACT FROM AUTHOR]

Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD. [ABSTRACT FROM AUTHOR]

Both active and passive anti-β-amyloid (Aβ) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain Aβ deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of Aβ, were disappointing. Also solanezumab, directed at the mid-region of Aβ, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active Aβ vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-Aβ immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-Aβ immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the Aβ cascade hypothesis of AD. [ABSTRACT FROM AUTHOR]

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect., Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes., Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes., Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases., Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations., Competing Interests: Guoqiao Wang, PhD, is the biostatistics core co‐leader for the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and as a statistical consultant for Alector. Eric McDade, DO, is the Associate Director of the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and Alector; as a scientific consultant for Eisai and Eli Lilly and Company; receiving institutional grant support from Eli Lilly and Company, F. Hoffmann‐La Roche, Ltd., and Janssen. Anne M. Fagan, PhD, is the Biomarker Core Leader of the DIAN‐TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and DiademRes and also consults for DiamiR and Siemens Healthcare Diagnostics, Inc. Tammie L.S. Benzinger, MD, PhD, has investigator‐initiated research funding from the NIH, the Alzheimer's Association, the Barnes‐Jewish Hospital Foundation, and Avid Radiopharmaceuticals. Dr. Benzinger participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen, and F. Hoffmann‐La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker's Bureau for Biogen. David B. Clifford, MD, is Medical Director of the DIAN‐TU and serves as scientific consultant to Biogen, Takeda, Millennium, Genzyme, Amgen, F. Hoffmann‐La Roche, Ltd./Genentech, Glaxo Smith Kline, Serono, Inhibikase, Dr Reddy's Lab, Bristol Myers Squibb, Atara, Mitsubishi Tanabe, Excision BioTherapeutics, Up to Date, and Wolters Kluwer; on DSMB/Data Monitoring Committees for Genentech/ F. Hoffmann‐La Roche, Ltd., Wave, EMD Serono, Shire, Pfizer, Sanofi; does legal consulting: Cook County, State Farm, Wilke & Wilke PC, Shevlin Smith, Sal Indomenico PC. He receives research support from NIH NINDS, NIMH, NIAID, NCATS, and NIA. Andrew J. Aschenbrenner, PhD, has served as a consultant for Biogen Inc, and H. Lundbeck HS. Jason Hassenstab, PhD, is a paid consultant for F. Hoffmann‐La Roche, Ltd., Takeda, and Lundbeck, and is on the Data Safety and Monitoring Board for Eisai. Catherine Mummery, MD, is a consultant for Biogen. Mario Masellis, MD, is a consultant to Arkuda Therapeutics, Ionis, and Alector and receives research funding from F. Hoffmann‐La Roche, Ltd., Novartis, and Alector. Serge Gauthier, MD, FRCPC, is a member of the Scientific Advisory Board for Alzheon, Biogen, Eli Lilly and Company, and TauRx and a member of the Data Safety Monitoring Board for ADCS, ATRI, and Banner Health. Scott Andersen, MS; Karen C. Holdridge, MPH; Saptarshi Chatterjee, PhD; John R. Sims, MD; and Roy Yaari, MD are employees and shareholders of Eli Lilly and Company. Randall J. Bateman, MD, is the Director of the DIAN‐TU and Principal Investigator of the DIAN‐TU‐001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN‐TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman‐La Roche, Ltd., and Avid Radiopharmaceuticals), Alzheimer's Association, GHR Foundation, Anonymous Organization, DIAN‐TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann‐La Roche, Ltd./Genentech. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). He has been an invited speaker for Novartis and serves on the Advisory Board for F. Hoffman La Roche, Ltd. Barbara A. Wendelberger, PhD; Susan L. Mills BS; Anna M. Santacruz BS; Kelley A. Coalier, MS; Brian A. Gordon, PhD; Jorge J. Libre‐Guerra, MD; Austin McCullough; Nelly Joseph‐Mathurin, PhD; Charlie Chen; Yan Li, PhD; Chengji Xiong, PhD, have no conflicts of interest to disclose. Paul Delmar, Geoffrey A. Kerchner, Tobias Bittner, and Carsten Hofmann are full‐time employees of F. Hoffmann‐La Roche, Ltd. and own stock in F. Hoffmann‐La Roche, Ltd. David Holtzman, MD, the prior Department Head of Neurology where the research was conducted, is an inventor on patents for solanezumab, which was tested in the DIAN‐TU‐001 clinical trial. If solanezumab is approved as a treatment for AD or dominantly inherited AD, Washington University and Dr. Holtzman will receive part of the net sales of solanezumab from Eli Lilly and Company, which has licensed patents related to solanezumab from Washington University. All the other authors reported no conflicts of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)