atabecestat (JNJ-54861911) / J&J - LARVOL DELTA

Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Atabecestat Leads to Protein Adduct Formation on Glutathione S-Transferase Pi. (PubMed, Chem Res Toxicol) - "As irreversible protein modification is suspected to drive immunogenicity, this study aimed to characterize potential atabecestat protein adducts using HSA, GSTA1, and GSTP as model proteins. We have shown that atabecestat only formed a cysteine adduct on GSTP in the presence of metabolic systems, highlighting the important role of bioactivation in adduct formation and selectivity for the binding interaction."

Journal • Hepatology • Liver Failure • APP • GSTP1

Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimer's disease therapy. (PubMed, Sci Rep) - "This study investigates the inhibitory potential of phytochemicals derived from Bacopa monnieri, a plant renowned for its cognitive-enhancing properties, in comparison to established synthetic inhibitors such as Atabecestat, Lanabecestat, and Verubecestat. Furthermore, the development of the SIMANA ( https://simana.streamlit.app/ ) platform enhances the visualization and analysis of protein-ligand interactions, facilitating a deeper understanding of the dynamics involved. This research not only underscores the therapeutic promise of natural compounds in AD treatment but also advocates for a paradigm shift towards integrating traditional medicinal knowledge into contemporary drug discovery efforts."

Journal • Alzheimer's Disease • CNS Disorders

A Safety and Tolerability Study of JNJ-54861911 in Participants With Early Alzheimer's Disease (clinicaltrials.gov) - P2 | N=114 | Completed | Sponsor: Janssen Research & Development, LLC | Phase classification: P2a ➔ P2

Phase classification • Alzheimer's Disease • CNS Disorders • Plasma Aβ40

Rational design, docking, simulation, synthesis, and in vitro studies of small benzothiazole molecules as selective BACE1 inhibitors. (PubMed, J Biomol Struct Dyn) - "Herein, a set of 96 benzothiazoles were designed based on the structural features of Atabecestat and Riluzole to find a promising selective BACE-1 inhibitor. The selectivity and inhibitory potential (IC50) of compound 72 was estimated by in vitro BACE-1 and BACE-2 FRET assay. Compound 72 was found to inhibit BACE-1 with IC50 121.65 nM, while it was found to be less potent on BACE-2 (IC50 480.92 nM), as compared to Atabecestat (BACE-1, IC50 13.25 nM and BACE-2, IC50 7.15 nM)."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold. (PubMed, Bioorg Med Chem) - "Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors."

Journal • Alzheimer's Disease • CNS Disorders

Safety concerns associated with BACE1 inhibitors - past, present and future. (PubMed, Expert Opin Drug Saf) - "However, clinical trials of inhibitors like atabecestat, verubecestat, and lanabecestat have faced challenges, including limited efficacy and significant adverse effects. The trial results underscore the need for CNS-specific BACE1 inhibitors to reduce adverse effects. Future research should focus on optimizing drug design and identifying additional therapeutic avenues, such as prostate cancer and insulin resistance."

Journal • Review • Alzheimer's Disease • CNS Disorders • Genito-urinary Cancer • Hepatology • Mood Disorders • Oncology • Prostate Cancer • Psychiatry • Solid Tumor • APP

An Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer's Dementia (clinicaltrials.gov) - P2/3 | N=557 | Terminated | Sponsor: Janssen Research & Development, LLC | Phase classification: P2b ➔ P2/3

Phase classification • Alzheimer's Disease • CNS Disorders • Dementia • APOE

CYP3A4-Mediated Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor JNJ-54861911 Results in Redox-Neutral Addition of Glutathione via Catalysis by Glutathione S-Transferase α1, Identified as the Major Target Protein in Human Hepatocytes. (PubMed, Chem Res Toxicol) - "The latter could occur through a haptenization phenomenon and/or by inducing stress in hepatocytes. Such stress may activate an innate immune response, which, in turn, promotes the adaptive immune response."

Journal • Alzheimer's Disease • CNS Disorders • Hepatology • Liver Failure • APP • CYP3A4

Views and Perceptions of Amyloid Imaging in a Preclinical Alzheimer's Disease Trial. (PubMed, J Prev Alzheimers Dis) - "Investigators might consider adjusting recruitment strategies for future trials to align with the motivations to undergo biomarker testing and disclosure most strongly endorsed by participants with elevated amyloid."

Biomarker • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia

Selective HLA Class II Allele-Restricted Activation of Atabecestat Metabolite-Specific Human T-Cells. (PubMed, Chem Res Toxicol) - "DIAT-specific T-cell responses displayed HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 restriction. These data demonstrate that DIAT displays a degree of selectivity toward HLA protein and associated peptides, with expression of certain alleles increasing and that of others decreasing, the likelihood that a drug-specific T-cell response develops."

Journal • Alzheimer's Disease • CNS Disorders • Hepatology • Liver Failure • CD4 • HLA-DRB1

Pharmacological interventions (EAN 2024) - "Same was with ramipril study or study with discontinuation of antihypertensive drugs. In the A4 study, solanezumab, which targets monomeric amyloid, did not manage to slow cognitive decline. Studies with BACE- 1 inhibitor drug atabecestat was prematurely finished due to hepatic- related side effects while studies with umibecestat were stopped following an interim analysis showing worsening cognitive function with umibecestat treatment. SKYLINE study with gantenerumab was terminated following results of a pre- planned analysis of the safety and efficacy. Nonsteroid anti- inflammatory drugs (naproxen and aspirin) did not show improvement of cognition with severe side effects like major hemorrhage and all- cause mortality...Hypoglicemic drugs pioglitazone and linagliptin fail to delay the onset of mild cognitive impairment or to influence on an incident accelerated cognitive decline. There was also no effect of a casein- derived angiotensinconverting enzyme inhibitory..."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gene Therapies • Hematological Disorders

Molecular docking analysis of marine phytochemicals with BACE-1. (PubMed, Bioinformation) - "2583 compounds, retrieved from Comprehensive Marine Natural Product Database (CMNPD), were primarily screened for drug-likeliness and blood-brain barrier permeability using admetSAR 2.0 and in-house BBBper tool and resulted in a total of 635 phytochemicals, selected for further docking studies using BACE-1 as target receptor and Atabecestat as standard BACE-1 inhibitor...These compounds are worth investigating further to assess their neuroprotective efficacy and pharmacokinetic properties. The study also provides a rational framework to uncover novel pharmacophores from marine sources for AD therapy acting through BACE-1 inhibition."

Journal • Alzheimer's Disease • CNS Disorders • APP

Environmental Toxins and Alzheimer's Disease: a Comprehensive Analysis of Pathogenic Mechanisms and Therapeutic Modulation. (PubMed, Mol Neurobiol) - "Drugs like epigallocatechin-gallate, neflamapimod, salsalate, dexmedetomidine, and atabecestat are in different phases of clinical trials targeting the pathways for possible treatment of AD. This review aims to culminate the correlation between environmental toxicants and AD development. We emphasized upon the signaling pathways involved in the progression of the disease and the therapeutics under clinical trial targeting the altered pathways for possible treatment of AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation • Metabolic Disorders • BACE1 • PARP1 • TNFA

Genome-wide association study of abnormal elevation of ALT in patients exposed to atabecestat. (PubMed, BMC Genomics) - "The suggestive GWAS signals in the case-control GWAS analysis suggest the potential role of inflammation in atabecestat-induced liver enzyme elevation."

Journal • Alzheimer's Disease • CNS Disorders • Hepatology • Inflammation • NLRP1

Human CSF pharmacoproteomics establishes in vivo-relevant BACE1 substrates as pharmacodynamic biomarkers for chronic BACE inhibition in clinical trials (AAIC 2023) - "To identify such substrates, we carried out a quantitative proteomic analysis of cerebrospinal fluid (CSF) from a subset of participants of phase 2 clinical trials with umibecestat or atabecestat or of a phase 3 clinical trial with verubecestat. BACE inhibitors in clinical trials block cleavage of multiple BACE1 substrates in a dose-dependent manner. A reduction of the inhibitor dose to less than 50% BACE1 inhibition may be an appropriate strategy to avoid side effects in future clinical trials with BACE inhibitors. Our analysis also demonstrates that proteomics enables pharmacodynamic studies of multiple CSF proteins in single measurements, which are suitable for precision medicine approaches in future clinical trials with BACE inhibitors."

PK/PD data • Preclinical • Alzheimer's Disease • CNS Disorders • CHD1

Sensitivity of the Preclinical Alzheimer’s Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial (CTAD 2021) - "Cross sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/− group effect was statistically larger for PACC and marginally larger for PACC5 as compared with the RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time."

Late-breaking abstract • P2/3 data • P2b data • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia

ASSESSING CLINICALLY MEANINGFUL FUNCT IONAL OUTCOMES IN PRECLINICAL ALZHEIMER’S DISEASE. (CTAD 2022) - "Janssen Research & Development LLC and Shionogi and Co Ltd were developing atabecestat, a nonselective oral BACE-1 and BACE2 inhibitor... In this cross-sectional assessment, self and study partner rated versions of the CFI and CFIa were sensitive to amyloid status, and the CFI and ADCS-ADL-PI-self demonstrated generally moderate relationships (|r| ≥ 0.30) to the PACC. While CFI and CFIa were well-correlated, the level of correlation did not indicate a redundancy between measures indicating these tools may measure different aspects of function. Results of this analysis provide important information All abstracts are embargoed until the day and time of presentation at the CTAD Conference S187 on the sensitivity of these functional assessments to amyloid pathology and to neurocognitive assessment."

Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Depression • Geriatric Disorders • Mood Disorders • Psychiatry • APOE

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial. (PubMed, J Prev Alzheimers Dis) - "Cross-sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time."

Clinical • Journal • P2/3 data • P2b data • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia

BACE1: a key regulator in Alzheimer's disease progression and current development of its inhibitors. (PubMed, Curr Neuropharmacol) - "BACE1 is involved in the progression of AD. The current ongoing or failed clinical trials may help understand the role of BACE1 inhibition in regulating the Aβ load and cognitive status of AD patients."

Journal • Alzheimer's Disease • CNS Disorders

"(3/6) These are: Semagacestat, Avagacestat, Solanezumab, CAD106, Crenezumab, Gantenerumab, Avagacestat, Verubecestat, Atabecestat, Lanabecestat, Crenezumab, Elenbecestat, Umibecestat, Donanemab." (@AlbertoEspay)

Selective Secretase Targeting for Alzheimer's Disease Therapy. (PubMed, J Alzheimers Dis) - "In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities."

Journal • Review • Alzheimer's Disease • CNS Disorders

"Interesante reflexión sobre #atabecestat del @AlbertoEspay" (@pisanchezal)

Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial. (PubMed, J Med Chem) - "The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening."

Clinical • Journal • P2/3 data • P2b data • Alzheimer's Disease • CNS Disorders • APP

Atabecestat Associated With Cognitive Worsening in Alzheimer Disease (NeurologyLive) - P2/3, N=557; EARLY (NCT02569398); Sponsor: Janssen Research & Development, LLC; "The EARLY trial enrolled 557 amyloid positive and cognitively normal patients from 143 centers across 14 countries. Women made up 61.2% (n = 341) of patients and the mean age was 70.4 years (standard deviation [SD], 5.56). Patients were randomized to 10 mg or 25 mg of atabecestat, or placebo. The 10 mg dose was reduced to 5 mg, however, owing to TEAE concerns. Patient follow-up was performed after the trial's early halt....There is abundant genetic evidence that overproduction of Aβ42 leads to AD and interference with production of Aβ42 may be protective. Decreasing Aβ production remains attractive as a potential disease-modifying strategy for AD. However, for BACE [inhibitors] to be pursued safely researchers will need to explore lower doses with more modest enzyme inhibition, with careful safety/cognitive monitoring,' Sperling and colleagues concluded."

Media quote • P2/3 data • Alzheimer's Disease

Cognitive effects seen as transient for Alzheimer’s drug atabecestat (MDedge Neurology) - P=NA, N=557; "Most of the worsening seen in the study was associated with episodic memory tasks, including 'list learning, story memory, list recognition, story recall, and figure recall,' Dr. Sperling and colleagues found. Atabecestat was also associated with 'dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,' the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment....'This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause' of Alzheimer's disease, Dr. Aisen said in an interview. 'Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.'"

Clinical data • Media quote • Alzheimer's Disease