AN1792 / J&J, Pfizer - LARVOL DELTA

SPATIAL TRANSCRIPTOMICS REVEALS MICROGLIAL MECHANISMS OF AMYLOID-BETA CLEARANCE IN IMMUNIZED ALZHEIMER'S DISEASE PATIENTS (ADPD 2025) - "Post-mortem brain analyses from the first active Aβ immunotherapy clinical trial (AN1792) indicate clearance of Aβ in some AD patients...Additionally, we used spatial proteogenomics and single-cell RNA sequencing to investigate mechanisms of Aβ clearance and microglial activation following lecanemab treatment, a passive anti-Aβ therapeutic...Conclusions Altogether, these data uncover the molecular mechanisms through which microglia facilitate Aβ clearance in the human AD brain following immunization against Aβ. Understanding these mechanisms may aid in the development of more targeted and effective therapeutic strategies for AD."

Clinical • Alzheimer's Disease • CNS Disorders • Metabolic Disorders • A2M • RAB13

Virus-like Particles-Based Vaccine to Combat Neurodegenerative Diseases. (PubMed, Curr Pharm Biotechnol) - "Researchers have turned their attention to VLPs as an active immunotherapy candidate for AD due to the lessons learned from the AN1792 trial...This review compiles the findings of preclinical animal model studies and clinical investigations on VLP-based vaccines for neurogenerative diseases thus far. The technical limitations and potential difficulties associated with the future application of VLP-based vaccines in patients with neurodegenerative diseases have also been covered."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

Distinct Methylomic Signatures Emerge in the Prefrontal Cortex Following Amyloid-Beta Immunisation, with Altered Expression Patterns in Astrocytes (AAIC 2024) - "Background: Post-mortem neuropathological examinations following the first active immunotherapy strategy (AN-1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid-β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals... Indicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing genotyping data to identify potential methylation quantitative trait loci and further our understanding of the relationship between single nucleotide polymorphisms and methylation changes."

IO biomarker • Alzheimer's Disease • CNS Disorders • Preventive care • CELF2

Immunotherapeutic approaches for Alzheimer's disease: Exploring active and passive vaccine progress. (PubMed, Brain Res) - "ACC001 or PF05236806 vaccine has the same Aβ fragment and QS21 as an adjuvant. CAD106 stimulates response against Aβ1-6...AN1792, the first-generation vaccine was formulated in proinflammatory QS21 adjuvant...Immunotherapies have been at the forefront of these initiatives in recent years. The review covers the recent updates on active and passive immunotherapy for AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dermatology • Infectious Disease

PARADOXICAL CEREBRAL VOLUME CHANGES ON MRI IN ANTI-AMYLOID IMMUNOTHERAPY TRIALS: POSSIBLE EXPLANATIONS AND PLAUSIBILITY (ADPD 2024) - "Originally described in the first vaccination trial (AN1792) excess volume loss has also been seen with a number of monoclonal antibodies including most recently donanemab and lecanemab. This "paradoxical" volume loss or "pseudo-atrophy" is an area of great interest and controversy, with potential explanations ranging from it being a marker of effective amyloid removal, through to it being an indication of treatment-related toxicity. I will review these different hypotheses and consider their plausibility and their compatibility with recent data."

IO biomarker

Therapeutic dendritic cell Vaccine Targeting Oligomeric amyloid-β in mouse model of Alzheimer’s disease (Neuroscience 2023) - "The suppression of these T cell epitopes can help prevent the autoimmune response observed in some patients receiving the AN-1792 vaccine... The PDM vaccine may be safer for patients with impaired immune systems. Given the mounting evidence suggesting that the oligomeric form of Aβ is detrimental to neurons, the specificity of PDM antibodies for these "oligomeric" Aβ species may offer clinical benefits to patients with AD."

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

Long-term neuropathological effects of amyloid-β immunization revealed by spatial transcriptomics (AAIC 2023) - "We show that active Aβ immunotherapy induces long-term adaptive immune effects in the AD cortex."

IO biomarker • Alzheimer's Disease • CNS Disorders • Dementia • B2M • CD74 • GZMA • VCAM1

Amyloid-beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain (AAIC 2023) - "Background: Post-mortem neuropathological examinations following the first active immunotherapy strategy (AN-1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid-β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals... Indicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data."

IO biomarker • Alzheimer's Disease • CNS Disorders • Preventive care • CRISP2

Attempts to Develop Vaccines Against Alzheimer's Disease: A Systematic Review of Ongoing and Completed Vaccination Trials in Humans. (PubMed, Cureus) - "Apart from the development of meningoencephalitis in 6% of patients receiving AN1792 in an interrupted phase II trial, the rest of the trial reported promising results on the safety and immunogenicity of vaccines...The serological response rate ranged from 100% (4/16 trials) to 19.7% in an interrupted trial. Although current trials show promising results, adequately powered phase III studies are needed to conclusively establish the safety, immunogenicity and therapeutic efficacy of vaccines."

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

PRE-CLINICAL AND INTERIM CLINICAL PHASE 1 ANTIBODY TITRE ANALYSIS OF ANTI-AMYLOID BETA OLIGOMER VACCINE ALZ-101 (ADPD 2023) - P1 | "Aims: The first immune therapy candidate targeting amyloid beta (Abeta) to treat Alzheimer's dise ase (AD), the vaccine AN1792, appeared to provide plaque removal without clinical improvement (Holmes et al., 2008). Four late -stage clinical trials on monoclonal antibodies have recently provided similar aducanumab, lecanemab, gantenerumab, and donanemab; all reducing plaque load, but with questionable safety and very modest clinical efficacy... The current evidence supports the continued clinical development of ALZ -101 as a specific, long -acting, and safe immunotherapy for targeting toxic Abeta oligomers in AD."

P1 data • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Aβ42

ABVAC40 ELICITS A PREDOMINANTLY TH2 IMMUNE RESPONSE THAT SUPPORTS ITS EXCELLENT SAFETY PROFILE. (CTAD 2022) - "AN1792, the first Alzheimer´s disease (AD) vaccine entered clinical trials, was terminated due to meningoencephalitis attributed to a cellmediated immflamatory response (1, 2). ABvac40 drug substance induces a Th2 polarized T-helper immune response that promotes a humoral response and minimizes a proinflammatory effect, which is consistent with the excellent safety profile shown by ABvac40 in phase I and phase II studies."

Clinical • Alzheimer's Disease • CNS Disorders • Inflammation • Targeted Protein Degradation • APP • IFNG • IL4

Advantages of next generation SupraAntigen® platform liposomal vaccines to immunize against pathological targets of Alzheimer’s disease (CTAD 2022) - " For Abeta, several vaccines were generated as follows: a liposome-based SupraAntigen® vaccine (i.e., optimized ACI-24) containing the antigenic peptide Abeta 1-15, an adjuvant and a universal T-helper cell peptide; and CRM-conjugated vaccines containing various antigenic Abeta peptides (e.g., ACC-001) or full-length Abeta (i.e., AN1792) mixed with adjuvant...This was in line with the epitope mapping data, which demonstrated strong binding to the phosphorylated residues for the ACI-35.030-induced antibodies... For both Abeta and Tau targeting vaccines, the liposome-based SupraAntigen® vaccines demonstrated a superior quality of the IgG repertoire generated post-immunization. The responses in NHPs were well tolerated, homogenous, robust and boostable over time, while broadly engaging relevant pathological epitopes. For Abeta, the liposome-based SupraAntigen® vaccine generated the highest titers of antibodies specifically targeting pyroGlu-Abeta."

Alzheimer's Disease • CNS Disorders

"AN1792 data available for >20 years." (@ProfRobHoward)

"To some maybe even to Mdme Roland the guillotine was both liberating and innovative in its time. Ever wonder why an early ABeta vaccine was called AN-1792 and not 1793?" (@LonSchneiderMD)

Clinical

Histopathological correlates of haemorrhagic lesions on ex vivo magnetic resonance imaging in immunized Alzheimer's disease cases. (PubMed, Brain Commun) - "Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active amyloid β immunization with AN1792 for Alzheimer's disease...This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of haemorrhagic lesions observed in the context of amyloid β immunotherapy. These findings suggest a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against amyloid β with available in vivo MRI during life."

Journal • MRI • Preclinical • Alzheimer's Disease • CNS Disorders

Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer's Disease. (PubMed, Biology (Basel)) - "In this narrative review, we illustrate the working hypothesis behind immunization against β-amyloid as a vaccination strategy for Alzheimer's disease, and the outcome of the active immunization strategies that have been tested in humans. On the basis of the lessons learned from preclinical and clinical research, we discuss roadblocks and current perspectives in this challenging enterprise in translational immunology."

Journal • Review • Alzheimer's Disease • CNS Disorders • Immunology • Infectious Disease • Oncology

[VIRTUAL] Past and current vaccine and immunotherapy development in Alzheimer’s disease (CTAD 2020) - "Vaccine candidates such as CAD106 and UB-311 use selective epitopes and were developed to avoid the undesirable inflammatory effects that were seen with AN1792...Positive ADAS-cog effect sizes were seen for AN1792, Solanezumab EXPEDITION 3, BAN2401 and Aducanumab ENGAGE...Active vaccination achieving a predictable and high antibody response in amyloid positive, early AD participants increases the likelihood of technical success. The longer duration of immune response with active immunization combined with safety advantages make the modality well suited to AD"

IO Biomarker • Allergy • Alzheimer's Disease • CNS Disorders

An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β. (PubMed, J Alzheimers Dis) - "The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody's specificity for these "oligomeric" Aβ species could provide the opportunity to produce some clinical benefits in AD subjects."

IO Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Immune Modulation • Immunology • Inflammation

[VIRTUAL] MRI-histopathology correlations of Amyloid-Related Imaging Abnormalities (ARIA) in post mortem human brain samples (AAIC 2020) - " Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active A immunization for AD (AN1792; Elan Pharmaceuticals Inc) (iAD cases; mean age at death 81 years, mean survival time from first immunization 107 months)... These findings suggest that ARIA in the context of anti-A immunotherapy may result in lasting neuropathological alterations (perhaps even in the absence of clinical symptoms) and that advanced CAA likely plays a role in the pathophysiology of ARIA."

Alzheimer's Disease • CNS Disorders • MRI

[VIRTUAL] Understanding the Pathophysiology of Amyloid-Related Imaging Abnormalities (ARIA) following A immunotherapy (AAIC 2020) - " Neuropathological examination of cases from the first trial of immunotherapy with active A42 immunisation (AN1792) and comparison with later imaging studies... ARIA is due to dynamic changes in the localisation of A and associated inflammation. Passive immunotherapy protocols have the advantage of permitting monitoring by imaging and reduction or temporary or permanent withdrawal of dosing if ARIA is sufficient to cause concern. If evidence were to support employment of A active immunotherapy as a preventative measure for AD, before the brain contains a significant amount of amyloid, it seems likely that ARIA would not occur."

Alzheimer's Disease • CNS Disorders • Hematological Disorders • Immunology • Vasculitis • APOE

Aβ43 in human Alzheimer's disease: effects of active Aβ42 immunization. (PubMed, Acta Neuropathol Commun) - "Neuropathological follow-up of patients with Alzheimer's disease (AD) who participated in the first clinical trial of Amyloid-β 42 (Aβ42) immunization (AN1792, Elan Pharmaceuticals) has shown that immunization can induce removal of Aβ42 and Aβ40 from plaques, whereas analysis of the cerebral vessels has shown increased levels of these Aβ peptides in cerebral amyloid angiopathy (CAA)...Furthermore, we have shown that Aβ43 is cleared from plaques after Aβ immunotherapy, similar to Aβ42 and Aβ40. Cerebrovascular Aβ43 levels did not change after immunotherapy."

Journal • Alzheimer's Disease • CNS Disorders

Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease. (PubMed, Brain) - "Twenty-two participants of a clinical trial of active amyloid-β42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied...Despite modification of Alzheimer's pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Lewy Body Disease • Movement Disorders • Progressive Supranuclear Palsy • Tauopathies And Synucleinopathies • Vascular Neurology

Safety and efficacy of active and passive immunotherapy in mild-to-moderate Alzheimer's disease: A systematic review and network meta-analysis. (PubMed, Clin Invest Med) - "In terms of efficacy, the review showed a statistically, but not clinically significant, improvement in favor of immunotherapy versus placebo. Further clinical trials are required to demonstrate any cognitive benefits of immunotherapies in mild-to-moderate AD."

Journal • Retrospective data • Review