umibecestat (CNP520) / Novartis, Amgen, Banner Alzheimer’s Institute - LARVOL DELTA

Small molecule inhibits BACE1 activity by a dual mechanism confirmed by simulations-based study. (PubMed, J Biomol Struct Dyn) - "We have used Umibecestat (CNP-520) as a positive control...The two shortlisted molecules were then subjected to atomistic molecular dynamics simulations study. Overall, our study proposes a much better inhibitor and a rational molecule for lead development against AD."

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

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies. (PubMed, Alzheimers Dement) - "This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • APOE • APP

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

Targeting key players in Alzheimer's disease: bioactive compounds from Moringa oleifera, Desmodium gangeticum, and Centella asiatica as potential therapeutics. (PubMed, J Biomol Struct Dyn) - "Astilbin, Delphinidin 3-glucoside, and kaempferol 7-O-glucoside showed good binding affinity and structural stability when compared to other compounds and the control CNP520...Through microsecond simulation, it was found that Astilbin alters BACE1's behavior and induces conformational rearrangements. Thus, this study opens a gateway to inhibit the activity of BACE1 protein through Astilbin thereby disclosing the possibility of managing Alzheimer's Disease.Communicated by Ramaswamy H. Sarma."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • APP

Alzheimer's disease and clinical trials. (PubMed, J Basic Clin Physiol Pharmacol) - "Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources."

Journal • Review • Alzheimer's Disease • CNS Disorders

Revealing the binding mechanism of BACE1 inhibitors through molecular dynamics simulations. (PubMed, J Biomol Struct Dyn) - "This study employs molecular dynamics simulations and binding energy analysis to investigate the binding interactions between BACE1 and four selected small molecules: CNP520, D9W, NB641, and NB360. Hydrogen bond analysis reveals a limited number of bonds between BACE1 and each small molecule, highlighting the importance of structural modifications to enable more stable hydrogen bonds. This research provides valuable insights into the molecular mechanisms of potential Alzheimer's disease therapeutics, guiding the way for improved drug design and the development of effective treatments targeting BACE1.Communicated by Ramaswamy H. Sarma."

Journal • Alzheimer's Disease • CNS Disorders

Unravelling the Untapped Pharmacological Potential of Plant Molecules as Inhibitors of BACE1: In Silico Explorations for Alzheimer's Disease. (PubMed, Appl Biochem Biotechnol) - "In the absorption and distribution assessment, these phytochemicals showed significantly better values than the inhibitors CNP520...In both the molecular docking and ADMET assessments, these natural chemicals have shown optimism as potential drug candidates for Alzheimer's disease. However, in order to understand the detailed biological metabolism of these compounds in AD, they need to be evaluated in in vivo studies to validate its efficacy."

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

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes. (PubMed, Alzheimers Dement) - "This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials."

Journal • Alzheimer's Disease • CNS Disorders • APOE

Screening of Spirulina Components for Anti-Parkinson's and Anti-Alzheimer's Activity by in Silico Methods and Docking Studies. (PubMed, Adv Exp Med Biol) - "Four potential targets, two for each activity, that is, structure of parkinE3 ligase (PDB ID:4I1H) and structure of BACE bound to 5-(3-(5-chloropyridin-3-yl)phenyl)-5-cyclopropyl-2-imino-3-methylimidazolidin-4one (PDBI D:4DJx) for anti-Parkinson's activity and structure of human MAO B in complex with selective inhibitor safinamide (PDB ID:2V5Z) and crystal structure of human BACE-1 in complex with CNP520(PDB ID:6EQM) for anti-Alzheimer's activity, have been selected. The in silico results and scoring of virtual screening, that is, molecular docking, were compared with commonly used marketed drugs such as levodopa for Parkinson's disease (PD) and rivastigmine (Rösler et al., BMJ, 318(7184):633-40, 1999) for Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Oncology • Parkinson's Disease • Targeted Protein Degradation

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

Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program. (PubMed, J Prev Alzheimers Dis) - "It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • APOE

DEVELOPING BETA-SECRETASE INHIBITORS FOR TREATMENT OF ALZHEIMER’S DISEASE (ADPD 2022) - "In this paper, AD pathophysiology, beta-secretase structure, BACE1classification, and their correlated adverse and beneficial effects as well as BACE1 inhibitors that are being investigated in clinical trials like LY2811376, LY3314814 (AZD3293) ,CNP520 ,Elenbecestat (E2609) ,Mk8931 (Verubecestat) , LY2886721. The capability of BACE1 to apply such a therapeutic candidate for AD therapy has just been examined during the previous decade. There is proof indicate that the 1 inhibitor administrating time is critical and make big difference in how successful they are in curing AD."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease. (PubMed, J Med Chem) - "Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pK of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic."

Journal • Alzheimer's Disease • CNS Disorders

Generation S2: A Study of CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=1145; Terminated; Sponsor: Novartis Pharmaceuticals; Completed ➔ Terminated; The study was terminated due to safety issues.

Clinical • Trial termination • Alzheimer's Disease • CNS Disorders • APOE • MRI

Human CSF pharmacoproteomics establishes in vivo-relevant BACE1 substrates as pharmacodynamic biomarkers for chronic BACE inhibition with umibecestat (AAIC 2021) - "This analysis demonstrates that pharmacoproteomics enables to combine pharmacodynamic studies of multiple CSF proteins in single samples. Multiple in vivo-detectable BACE1 substrates were affected by umibecestat in a dose-dependent manner to different degrees. Correlation of changes in their CSF concentrations with the occurrence of adverse findings may help to define a therapeutic window for safe and efficient chronic Abeta lowering."

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

"(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

Unravelling the molecular basis of AM-6494 high potency at BACE1 in Alzheimer's disease: an integrated dynamic interaction investigation. (PubMed, J Biomol Struct Dyn) - "To elucidate the binding mechanism of AM-6494 relative to umibecestat (CNP-520) as well as the structural changes when bound to BACE1, advanced computational techniques such as accelerated MD simulation and principal component analysis have been utilised. Besides the catalytic Asp32/228 dyad, Tyr14, Leu30, Tyr71 and Gly230 represent critical residues in the potency of these inhibitors at BACE1 binding interface. The findings highlighted in this research provide a basis to explain AM-6494 high inhibitory potency and might assist in the design of new inhibitors with improved selectivity and potency for BACE1."

Journal • Alzheimer's Disease • CNS Disorders

Computational modelling of potent β-secretase (BACE1) inhibitors towards Alzheimer's disease treatment. (PubMed, Biophys Chem) - "Herein, we simulated two potent BACE1 inhibitors (AM-6494 and CNP-520) to understand their binding affinity at the atomistic level...However, both models could sufficiently describe ligand binding to BACE1 at the atomistic level. Understanding the detailed molecular interaction of these inhibitors could serve as a basis for pharmacophore exploration towards improved inhibitor design."

Journal • Alzheimer's Disease • CNS Disorders

[VIRTUAL] Umibecestat in the API Generation Program: Worsening in RBANS and/or CDR on treatment reverses after wash-out (AAIC 2020) - "The negative effect of umibecestat vs placebo on RBANS and CDR-SOB was detected as early as month 3 and was detectable throughout the treatment period, but was no longer present after wash-out of umibecestat. This effect seems to be independent of the presence of brain amyloid. Confirmation of the contemporary reversibility of worsening in measures of cognition is an important result to inform development of future prevention therapies for Alzheimers disease (AD)."

Alzheimer's Disease • CNS Disorders

[VIRTUAL] The API Generation Program: Umibecestat treatment and discontinuation effects on hippocampal and whole brain volumes in the overall population and amyloid-negative APOE4 homozygotes (AAIC 2020) - "BACE inhibitor-related brain shrinkage appears to be early, non-progressive, related to pre-existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials."

Clinical • MRI

[VIRTUAL] The Generation Program: Baseline characteristics of cognitively unimpaired APOE4 carriers recruited for Generation Study 1 and Generation Study 2 (AAIC 2020) - P2/3 | "Background: The Alzheimer Prevention Initiative (API) Generation Program evaluated the effectiveness of the BACE1 inhibitor, umibecestat, and the active immunotherapy, CAD106, in delaying the onset of AD symptoms in APOE4 carriers. The Generation program collected a broad set of parameters for the worlds largest cohort of cognitively unimpaired APOE4 carriers. Baseline characteristics of participants enrolled in the Generation Program were consistent with the target population at risk for AD. Findings in relation to genotype, age, sex and amyloid status will be discussed."

Alzheimer's Disease • CNS Disorders

[VIRTUAL] The API Generation Program: Biomarker phenotyping of cognitively unimpaired participants screened in Generation Study 1 and Generation Study 2 (AAIC 2020) - "Background: API Generation Program evaluated the effectiveness of the BACE1 inhibitor umibecestat and the active immunotherapy CAD106 in delaying the onset of AD symptoms in APOE4 carriers. These data describe the biomarker signature of the worlds largest cohort of cognitively unimpaired APOE4 carriers with and without elevated amyloid. The anonymized study data, biomarker samples as well as images collected will be shared with the scientific community after study completion and reporting. ELECSYS is a registered trademark of Roche."

Biomarker • IO Biomarker • Amyloid PET • CSF Aβ42 • CSF P-tau • FDG PET • MRI • Tau PET

[VIRTUAL] Success of referring participants to the Generation Program and lessons learned for future enrollment into Alzheimers disease prevention trials (AAIC 2020) - "Recruitment in the Generation Program and treatment with umibecestat was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function... The Generation Program was on track to complete enrollment in 2019 and GeneMatch was a successful program in helping to recruit APOE4 carriers. Lessons learned include the importance for GeneMatch to coordinate with study sites to ensure they are prepared to receive referrals Future analyses will examine success of GeneMatch (vs. other recruitment sources) for randomization."

Alzheimer's Disease • CNS Disorders • APOE

[VIRTUAL] The Alzheimers Prevention Initiative Generation Program: a global perspective on best practices for site support and engagement to accelerate participant recruitment (AAIC 2020) - " Recruitment was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function with umibecestat... Collaboration between study sponsor and site teams and the development of flexible recruitment plans and materials that can be adapted to meet sites needs played a crucial role in the successful recruitment, enrollment, and retention of participants for the API Generation Program."

Clinical • Alzheimer's Disease • CNS Disorders