lanabecestat (AZD3293) / AstraZeneca, Eli Lilly - LARVOL DELTA

Design, Synthesis, and biological evaluation of β-secretase inhibitors: An integrated study of molecular docking, dynamics, pharmacokinetics, quantum chemistry, and in-vitro analysis for Alzheimer’s disease. (PubMed, Bioorg Chem) - "In silico molecular docking and molecular dynamics simulations suggest that these compounds exhibit strong potential as β-secretase (BACE1) inhibitors, demonstrating high interaction and binding energies compared to reference inhibitors AZD3293 and E2602...Additionally, ADMET descriptors and density functional theory (DFT) calculations were employed to assess the pharmacokinetics, chemical stability, and binding affinity of the synthesized compounds. The findings from this study pave the way for future in vivo investigations to assess the reversal of Alzheimer's disease phenotypes, along with comprehensive safety and toxicity evaluations."

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

AI-guided patient stratification improves outcomes and efficiency in the AMARANTH Alzheimer's Disease clinical trial. (PubMed, Nat Commun) - "The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid...In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials."

Journal • Alzheimer's Disease • CNS Disorders

Studying the Role of Myenteric Amyloidosis in Gastrointestinal Dysmotility and Enteric Neural Dysfunction Using APP/PS1 Mice-Is It an Adequate Animal Model? (PubMed, Neurogastroenterol Motil) - "APP/PS1 mice do not recapitulate myenteric amyloidosis persistently and lack the phenotype of constipation observed in human AD patients; these mice should not be considered an adequate murine model for studying the role of myenteric amyloidosis in GI dysmotility. An adequate animal model with myenteric amyloidosis is required for further study."

Journal • Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Inflammation

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

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

Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity. (PubMed, Cytotherapy) - "These data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN."

CAR T-Cell Therapy • Journal • Gastrointestinal Cancer • Hepatology • Mesothelioma • Oncology • Pancreatic Cancer • Solid Tumor

Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance. (PubMed, iScience) - "Treatment with the γ-secretase inhibitor DAPT also shortened night sleep bouts, whereas the BACE-1 inhibitor lanabecestat lengthened sleep bouts. Intraventricular injection of P3 also shortened night sleep bouts, suggesting that the proper balance of Appb proteolytic processing is required for normal sleep maintenance in zebrafish."

Journal • Alzheimer's Disease • CNS Disorders • APP • Aβ42

Bace1 deletion in the adult reverses epileptiform activity and sleep-wake disturbances in AD mice. (PubMed, J Neurosci) - "Intriguingly, treating 5xFAD and APP (APP KI) mice of either sex with one BACE1 inhibitor Lanabecestat (AZD3293) dramatically increased epileptiform spiking, likely resulting from an off-target effect...We further showed that one of clinically tested BACE1 inhibitors does have off-target effects, and development of safer BACE1 inhibitors will be beneficial to AD patients. Results from this study will provide useful guidance for additional drug development."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Epilepsy • Sleep Disorder • APP

Incremental declines in independence associated with disease progression in early symptomatic Alzheimer's disease (AD) (AAIC 2023) - " Participants included amyloid-positive participants assigned to placebo in EXPEDITION-1/2/3 (solanezumab) and AMARANTH (lanabecestat) studies. Early symptomatic AD participants who progressed over 18 months had reduced independence and required more care partner time. Treatments that slow DP may preserve independence and reduce overall health care burden."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

BACE-1 Inhibitors Targeting Alzheimer's Disease. (PubMed, Curr Alzheimer Res) - "In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives."

Journal • Alzheimer's Disease • CNS Disorders • APP

Copper-Catalyzed Racemization-Recycle of a Quaternary Center and Optimization Using a Combined Kinetics-DoE/MLR Modeling Approach. (PubMed, J Org Chem) - "The copper-catalyzed racemization of a complex, quaternary center of a key intermediate on route to lanabecestat has been identified...The use of a definitive screening design with mechanistically relevant factors and a mixture of fitted kinetic descriptors and empirical measurements facilitated the generation of a model that accurately predicted complex reaction time course behavior. The synergistic model was used to minimize the formation of dimer byproducts, determine optimal conditions for batch operation, and highlight superheated conditions that could be accessed in flow, leading to a further increase in yield which was predicted by the original model."

Journal

BACE1 DELETION IN THE ADULT REVERSES EPILEPTIFORM ACTIVITY AND SLEEP-WAKE DISTURBANCES IN AD MICE MODELS (ADPD 2023) - "Meth ods: We performed video -EEG/EMG recordings in 12 -hour light/12 -hour dark cycle in nine -month -old 5xFAD and APP KI (APP NL-G-F/NL -G-F) mice treated with or without BACE1 inhibitor AZD3293 as well as adult BACE1fl/fl/thyCre, BACE1fl/fl/aldh1l1CreERT2, and BA CE1fl/fl/ubcCreERT2 mice... Our study provides insight into functional impairments of epileptiform activity and sleep disruption in two AD mouse models, BACE1 deletion and inhibition rescues deficits in 5xFAD mice but not APP KI mice."

Preclinical • Alzheimer's Disease • CNS Disorders • Epilepsy • Sleep Disorder • APP

Combination of regional flortaucipir quantification and event-based modeling in clinical trial analyses (CTAD 2022) - P2, P2/3, P3 | "Analyzed images were collected in 1) observational phase 2/3 18F-AV-1451-A05 study (NCT02016560); 2) EXPEDITION 3 phase 3 solanezumab trial (NCT01900665); 3) NAVIGATE-AD phase 2 trial with BACE inhibitor (NCT02791191); 4) AMARANTH phase 2/3 trial with lanabecestat (NCT02245737); and 5) DAYBREAK-ALZ phase 3 trial with lanabecestat (NCT02783573)...Overall, more slowing in tau was observed (p<0.001) across the EBM sequence in participants treated with donanemab relative to placebo... Our analyses suggest that EBM can provide useful information in multi-regional analyses of flortaucipir images by ordering brain regions according to the pathologic sequence of tau progression. The EBM approach may better illustrate the therapeutic effect of AD treatment on tau PET by providing evidence of tau spread (Schwarz, Neurotherapeutics, 2021) to complement global tau measures. Larger trial data can further confirm these observations."

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

Unbiased phenotypic screening of diverse sets of compounds through cell painting. | Poster Board #3374 (ACS-Fall 2022) - "Indeed, XK00001387 is structurally similar to lanabecestat, an oral beta-secretase inhibitor under clinical development.We developed a new method (“Aza-Yang cyclization”) for the synthesis of azetidinol ring through photochemistry...We will compare the differences and similarities of the generated fingerprints against a standard set of compounds with a known mechanism of action. Results of the cell painting experiment will be introduced."

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

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

Clinical Results with Novel Approaches that Reverse BFCN Dysfunction (CTAD 2021) - "In the case of BACE inhibition, clinical evidence supporting the approach to target BFCN dysfunction was provided in a combined retrospective analysis of phase 3 clinical trials conducted with verubecestat and lanabecestat, respectively, in which the effects of these BACE inhibitors on specific cognitive domains were evaluated...In the case of p38α inhibition, results of a phase 2, 91-patient, 16-week, placebo-controlled study (“AscenD-LB”) with the specific p38α kinase inhibitor neflamapimod (at 40mg TID) demonstrated statistically significant, clinically relevant effect size (0.5) improvement relative to placebo in a cognitive test battery assessing attention and executive function...Finally, dose-dependent improvement relative to placebo was seen in hallucination severity and frequency, another outcome considered related to cholinergic dysfunction. The results of the AscenD-LB study, the totality of which indicates a substantial positive effect on BFCN function, are..."

Clinical • CNS Disorders • Movement Disorders • Parkinson's Disease • RAB5A

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

BACE1 controls synaptic function through modulating release of synaptic vesicles. (PubMed, Mol Psychiatry) - "Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

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

Lanabecestat: Neuroimaging results in early symptomatic Alzheimer's disease. (PubMed, Alzheimers Dement (N Y)) - "Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • FDG PET • MRI

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. (PubMed, JAMA Neurol) - P2/3, P3 | "Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Dermatology • Psychiatry • Vitiligo

Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. (PubMed, Alzheimers Dement) - "In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement."

Journal • Alzheimer's Disease • CNS Disorders

[VIRTUAL] Reasons for Study Exclusion by Sex in Lanabecestat Studies AMARANTH and DAYBREAK-ALZ (AAIC 2020) - P2/3, P3 | "These results suggest females presenting for screening may have more advanced disease. Possible reasons include late referral of females due to advanced verbal memory skills delaying recognition of disease, social circumstances, faster disease progression of females identified from clinical trial site databases, or differences in educational attainment."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Amyloid PET

Data from Lilly at Alzheimer's Association International Conference 2020 (AAIC 2020) to Showcase Clinical Advances in Alzheimer's Research (PRNewswire) - "Eli Lilly and Company...today announced that new results from 17 research studies will be presented at the upcoming Alzheimer's Association International Conference® 2020 (AAIC® 2020) which will be held virtually July 27-31, 2020."

Biomarker • Diagnostic • P2/3 data • P3 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Parkinson's Disease