bapineuzumab (AAB-001) / Pfizer, J&J, Perrigo Company - LARVOL DELTA

Deciphering the role of complement C3 in anti-amyloid antibody-induced ARIA (Neuroscience 2024) - "After 3 weeks, all mice received weekly i.p. injections of 25 mg/kg 3D6-L anti-Aβ mAb, a murine analog of bapineuzumab known to cause microhemorrhages, for 7 weeks...Our results suggest that C3 lowering might protect against anti-amyloid-induced microhemorrhages. Additional analyses are underway to identify mechanisms underlying this process and the potential of C3 as a therapeutical target for AD."

Alzheimer's Disease • CNS Disorders

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders. (PubMed, Int J Mol Sci) - "This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively."

Journal • Review • Alzheimer's Disease • CNS Disorders

Anti-Amyloid Immunotherapy for AD: A Potential Link between ARIA and Complement (AAIC 2024) - "Here, we compared recombinant 3D6-L, a murine version of bapineuzumab, and an isotype control IgG2a monoclonal antibody (mAb) to investigate potential mechanisms, including complement activation, involved in these side effects (ARIA-H or microhemorrhages) following passive immunization... Passive immunization against Aβ using 3D6-L amplified CAA-associated complement activation and altered expression of genes related to extracellular matrix degradation and vascular inflammation. The observed microhemorrhages appear to result from complement-mediated vascular inflammation induced by the binding of 3D6-L to vascular amyloid. These findings suggest potential biomarkers or targets for therapeutic interventions in the context of anti-Aβ immunization."

IO biomarker • Alzheimer's Disease • Hematological Disorders • Inflammation • Metabolic Disorders • ABCA1 • APOE • C1QA • C1QB • CD31 • CXCL12 • FCGR2A • FCGR3A • GFAP • IL1R1 • LGALS3 • MMP9 • PECAM1

(In)Equity in Alzheimer's Clinical Trials: A Long Road Ahead? (AAIC 2024) - " A total of 16055 individuals over 12 trials were evaluated in this work (ENGAGE, EMERGE, GRADUATE I and II, CLARITY-AD, A4, EXPEDITION3, ELN115727, CREAD and CREAD 2, TRAILBLAZER-ALZ 1 and 2)... Clinical trials using anti-amyloid drugs have failed to represent the majority of individuals living with AD-related cognitive impairment on a global scale. It ultimately increases the disparities presented in the diagnosis and treatment of individuals with dementia. Ideally, anti-amyloid trials should incorporate the epidemiology of individuals with dementia worldwide."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

A Review of Recent Advances in the Management of Alzheimer's Disease. (PubMed, Cureus) - "The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab...Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers...The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Diabetes • Inflammation • Insomnia • Metabolic Disorders • Sleep Disorder

Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities. (PubMed, Sci Rep) - "Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aβ present. The findings of this study support the proposal that Aβ antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aβ-based immunotherapies."

Journal • Alzheimer's Disease • CNS Disorders

Passive immunotherapy for Alzheimer's disease: challenges & future directions. (PubMed, J Transl Med) - "(N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aβ peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aβ antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects...However, other anti-Aβ antibodies, such as lecanemab (a humanized mAb binds to soluble Aβ protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aβ peptides) and aducanumab (a human mAb binds to the aggregated form of Aβ), have been shown to slow the decline of cognitive functions in early stage AD patients...There are several challenges and limitations of passive immunotherapy using anti-Aβ antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both..."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer's disease. (PubMed, Expert Opin Drug Discov) - "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. 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."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Inflammation

Abeta-Responsive Cells as a Therapy in Alzheimer's Disease (ASGCT 2024) - " As measured by luciferase expression, Aβ receptors constructed from bapineuzumab, gantenerumab, and donanemab recognize synthetic Aβ42 and Aβ40. Aβ synNotch receptors represent a promising new therapeutic approach to treating AD. Capitalizing on their native surveillance functions in the brain, astrocytes expressing these receptors can specifically recognize Aβ as a marker of disease and respond via direct upregulation of a programmed therapeutic transgene. Due to the versatility of the synNotch platform, it is possible to produce many different transgenes under control of Aβ receptors (Fig."

Alzheimer's Disease • CNS Disorders • Gene Therapies • Inflammation • Aβ42 • IL6 • TNFA

Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody. (PubMed, MAbs) - "Here, two antibodies were designed based on the Aβ antibody bapineuzumab (Bapi) - one monospecific IgG (Bapi) and one bispecific antibody with an antigen binding fragment (Fab) of the transferrin receptor (TfR) antibody 8D3 fused to one of the heavy chains (Bapi-Fab8D3) for active, TfR-mediated transport into the brain...Ex vivo autoradiography showed specific antibody retention in areas with abundant Aβ pathology. Taken together, these results suggest that reducing FcRn binding of a full-sized bispecific antibody increases the systemic elimination and could thereby drastically reduce the time from injection to in vivo imaging."

IO biomarker • Journal • Alzheimer's Disease • CNS Disorders

BINDING CHARACTERISTICS OF LECANEMAB, DONANEMAB AND OTHER AMYLOID-BETA ANTIBODIES TO DIFFERENT FORMS OF AMYLOID-BETA IN ALZHEIMER'S DISEASE BRAINS (ADPD 2024) - "Here we have studied binding characteristics of different amyloid-beta targeting antibodies to amyloid-beta isolated from human brain. Binding strength of lecanemab, donanemab, aducanumab, gantenerumab, bapineuzumab, crenezumab and solanezumab was evaluated by immunoprecipitation, surface plasmon resonance and mass spectrometry. 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."

Alzheimer's Disease • CNS Disorders • Solid Tumor

3D6-L, A RECOMBINANT MURINE VERSION OF BAPINEUZUMAB, BUT NOT A CDC-MUTANT ANTI-PGLU3-ABETA MAB, INDUCES COMPLEMENT ACTIVATION IN AMYLOID-LADEN BLOOD VESSELS (ADPD 2024) - "Our data suggest that the CDC mutation in 07/2a-k lowered C1q binding, reduced complement activation and microglia-associated C1q immunoreactivity, and resulted in fewer microhemorrhages; however, lower pGlu3-Aβ relative to general Ab in the vasculature in these mice may partially explain the lack of microhemorrhages compared to 3D6-L. It appears that vascular inflammation induced by 3D6-L, which binds vascular amyloid, may be mediated by complement."

Preclinical • Hematological Disorders • Inflammation • CD68 • CLEC7A

POTENTIAL MECHANISMS AND MITIGATION STRATEGIES FOR ANTI-AMYLOID ANTIBODY-INDUCED ARIA (ADPD 2024) - "Abstract Body: Background: Recent FDA approvals of two anti-amyloid antibodies, aducanumab and lecanemab, and positive Phase 3 results for a third anti-amyloid antibody, donanemab, for the treatment of early-stage Alzheimer's disease (AD) provide the first disease-modifying-treatments...Cerebral amyloid angiopathy (CAA) may be a key factor: ApoE4 carriers are predisposed to CAA, have impaired Aβ clearance across the BBB, and are at higher risk for ARIA. First, 17.5-mo-old APP/PS1; hApoE4 mice were chronically immunized by i.p. injection weekly with 500 µg 3D6-L, a murine version of bapineuzumab, or anti-mouse IgG2a for 13 weeks... We hypothesize that anti-amyloid antibodies bind vascular amyloid and trigger a local immune response, including complement activation. The rationale and supporting evidence for co-treatment with anti-inflammatories such as a GLP-1R agonist, an anti-C1s antibody, or an anti-APOE antibody (HAE-4) will be presented."

Alzheimer's Disease • CNS Disorders • Hematological Disorders • APOE • MMP9

Risk factors in developing amyloid related imaging abnormalities (ARIA) and clinical implications. (PubMed, Front Neurosci) - "By analyzing lecanemab, aducanumab, gantenerumab, donanemab, and bapineuzumab clinical trials; risk factors for developing ARIA can be identified to mitigate some of the ARIA risk. This review aims to discuss risk factors of ARIA and highlight important areas for further research. With more anti-amyloid monoclonal antibodies approved by the Food and Drug Administration, considering patient risk factors for developing ARIA is important to identify to minimize patient's risk while receiving these new therapies."

Journal • Review • Alzheimer's Disease • Cerebral Hemorrhage • CNS Disorders • Epilepsy • Hematological Disorders • Pain

Characterizing Treatment Non-responders vs. Responders in Completed Alzheimer's Disease Clinical Trials. (PubMed, medRxiv) - "We aim to extensively investigate pre-treatment features that moderate treatment effect of Galantamine, Bapineuzumab, and Semagacestat from completed trial data. 4 "negative" treatment trials had subsets of patients who had, in fact, responded. This study suggests that analyzing heterogeneity in treatment effects in "positive" or "negative" trials may be a very powerful tool for identifying distinct subgroups that are responsive to treatments, which may significantly benefit future clinical trial design and interpretation."

Clinical • Alzheimer's Disease • CNS Disorders • Dementia

Study Partner Effect on Retention in Alzheimer's Disease Trials (CTAD 2023) - " We used data from two trials of bapineuzumab for patients with mild-to-moderate AD, one for APOE e4 carriers and one for non-carriers... We found that a higher proportion of spousal dyads completed the trials compared to other dyad types. Differences in the completion rates, however, were lower in the carrier study compared to the non-APOE4 carrier study. The reasons for these differences are unclear."

Alzheimer's Disease • CNS Disorders • Dementia • APOE

Biomarker and clinical correlations for amyloid targeting monoclonal antibody (mAb) treatment responses (CTAD 2023) - "Clinical trials have demonstrated positive clinical outcomes for lecanemab, donanemab and aducanumab, specifically linking Amyloid PET lowering to clinical benefit. While not achieving clinical benefit bapineuzumab, gantenerumab and solanezumab added to and are in line with this correlation... There is a strong statistically significant correlation between clinical benefit and corresponding Amyloid PET as well as CSF pTau181 effect sizes. Amyloid PET effect sizes were strongly correlated with corresponding plasma pTau181, CSF Abeta 1-42 and CSF pTau181 effect sizes. This confirms the strong utility of biomarkers in AD drug development and in this case specifically the conversation from a target related pharmacodynamic marker (Amyloid PET) to a downstream marker (specifically pTau 181) demonstrating impact on disease modification in addition to clinical response."

Biomarker • Clinical • Alzheimer's Disease • CNS Disorders • CSF P-tau • CSF T-tau • p-tau181

Impact of study partner type on primary endpoint variability in two phase 3 registration trials in mild-to-moderate Alzheimer's disease (CTAD 2023) - P3 | " We analyzed data from the Bapineuzumab 301 (APOE e4 non-carriers) and 302 (APOE e4 carriers) phase 3 trials in mild-to-moderate AD, provided by the trial sponsor, Janssen Research & Development, LLC for use in these analyses... SP type was associated with differential change in variation across study time in SP-reported endpoints in the non-carrier study. Overall, though, no significant difference in variance of change-from-baseline scores in either trial indicates SP type has limited impact on trial primary analyses. . gov numbers: NCT00575055 and NCT00574132; EudraCT number: 2009-012748-17."

P3 data • Alzheimer's Disease • CNS Disorders • Dementia • APOE

Systematic in silico analysis of clinically tested drugs for reducing amyloid beta plaque accumulation in Alzheimer's disease (CTAD 2023) - "To that end, we developed a quantitative systems pharmacology (QSP) model using eight different Aβ targeting approaches (aducanumab, lecanemab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat). A QSP model calibrated to clinical data for multiple drugs with different target species and modalities enables meaningful comparisons between therapeutic strategies. The model simulations provide novel insights into clinical results and guidance for future therapeutic development."

Clinical • Alzheimer's Disease • CNS Disorders

News & views: anti-amyloid antibodies and novel emerging approaches to Alzheimer's disease in 2023. (PubMed, Mol Neurodegener) - No abstract available

Journal • Alzheimer's Disease • CNS Disorders

With new therapies that promise to slow Alzheimer’s disease, researchers race to reform how patients are diagnosed (CNN) - "'Getting the diagnosis right is absolutely critical to be able to provide these new therapies to the right patients,' said Dr. Gil Rabinovici...'And this was in specialty memory clinics,' Rabinovici said."

Media quote

Efficacy and Safety of Anti-Amyloid-β Monoclonal Antibodies in Current Alzheimer's Disease Phase III Clinical Trials: A Systematic Review and Interactive Web App-based Meta-Analysis. (PubMed, Ageing Res Rev) - "The meta-analysis included 14,980 patients in 14 studies and four mAbs: Bapineuzumab, Aducanumab, Solanezumab and Lecanemab. Meta-regression revealed that higher (better) baseline MMSE score was associated with improved ADAS Cog and CDR-SB. In order to improve reproducibility and update the analysis in the future, we developed AlzMeta.app, web-based application freely available at https://alzmetaapp.shinyapps.io/alzmeta/."

Clinical • Journal • P3 data • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Dementia • APOE

Safety Analysis of Bapineuzumab in the Treatment of Mild to Moderate Alzheimer's disease: A Systematic Review and Meta-Analysis. (PubMed, Comb Chem High Throughput Screen) - "Based on available evidence, bapineuzumab is found to be safe in the treatment of AD patients. However, vasogenic edema should be considered."

Clinical • Retrospective data • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Epilepsy • Hypertension • Oncology • Pain

Effectiveness and safety of monoclonal antibodies against amyloid-beta vis-à-vis placebo in mild or moderate Alzheimer's disease. (PubMed, Front Neurol) - "Our findings indicate that monoclonal antibodies against Aβ can effectively improve instrumental activities of daily life in mild or moderate AD. In particular, bapineuzumab can improve cognition and function, as well as activities of daily life, and meanwhile, it triggers serious adverse events."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Learnings about Aβ from human brain recommend the use of a live-neuron bioassay for the discovery of next generation Alzheimer's disease immunotherapeutics. (PubMed, Acta Neuropathol Commun) - "To test this principle, we directly compared 5 clinical antibodies (aducanumab, bapineuzumab,  BAN2401, gantenerumab, and SAR228810) together with an in-house aggregate-preferring antibody (1C22) and established relative ECs in protecting human neurons from human Aβ. Their relative efficacies in this morphological assay were paralleled by their functional ability to rescue oAβ-induced inhibition of hippocampal synaptic plasticity. This novel paradigm provides an unbiased, all-human system for selecting candidate antibodies for advancement to human immunotherapy."

Journal • Alzheimer's Disease • CNS Disorders