semagacestat (LY450139) / Eli Lilly - LARVOL DELTA

Interactions between daily sleep-wake rhythms, γ-secretase, and amyloid-β peptide pathology point to complex underlying relationships. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "To examine the relationship of Aβ production and its interaction with sleep and sleep dysfunction, we treated mice from an APP × PS1 mutant knock-in line (APPΔNLh/ΔNLh × PS1P264L/P264L) with an inhibitor of γ-secretase (LY-450,139; Semagacestat®) during a protocol of mild sleep fragmentation (SF)...These findings indicate that the relationship between disruption of the daily sleep-wake rhythm and the development of AD-related pathology is complex, and may involve unappreciated interactions with biological sex. Consideration of these factors is necessary for a better understanding of AD risk, especially the elevated risk in women."

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

Drug Development. (PubMed, Alzheimers Dement) - "IR is associated with increased variability in ADCS-ADL measurements between successive visits and should be considered when planning AD clinical trials."

Journal • Alzheimer's Disease • CNS Disorders

Impacts of Informant Replacement in Industry-Sponsored Alzheimer's Disease Clinical Trials (AAIC 2024) - " We conducted a retrospective analysis of two industry-sponsored AD clinical trials testing semagacestat in mild-to-moderate AD... IR is associated with increased variability in ADCS-ADL measurements between successive visits and should be considered when planning AD clinical trials."

Clinical • Alzheimer's Disease • CNS Disorders

Bioinformatics analysis of the potential receptor and therapeutic drugs for Alzheimer's disease with comorbid Parkinson's disease. (PubMed, Front Aging Neurosci) - "There was a high binding affinity between semagacestat and EGFRNTD, with seven hydrogen bonds and one hydrophobic bond. Semagacestat may improve the health of patients with AD complicated with PD through the regulation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways by EGFR, providing evidence supporting the structural modification of semagacestat to develop a more effective drug for treating AD complicated with PD."

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

SUBSTRATE ECTODOMAIN DEFINES GAMMA-SECRETASE SEQUENTIAL PROTEOLYSIS, AND THEREBY ABETA PRODUCT PROFILES, BY MODULATING PRODUCT RELEASE (ADPD 2024) - "Finally, our study reveals that the paradoxical production of longer Aßs caused by some GSIs (e.g. DAPT and semagacestat) arises from a competitive mechanism, wherein GSI binding to the substrate-binding site either blocks substrate entry or results in the release of partially digested Aß peptides. These findings assign a pivotal role to the substrate ECD in the sequential proteolysis by GSEC, and suggest it as a sweet spot for the potential design of APP targeting compounds, selectively promoting its processing by GSECs."

Alzheimer's Disease • CNS Disorders • Targeted Protein Degradation • APP

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

Treatment of app x ps1 mutant knock-in mice with the gamma-secretase inhibitor Semagacestat alters sex-related sleep differences (Neuroscience 2023) - "These results also suggest that pharmacological inhibition of gamma-secretase may result in complex, sex-dependent changes in daily sleep. Funding provided by NIH (AG068215)."

Preclinical • Alzheimer's Disease • CNS Disorders

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

Gamma Secretase as an Important Drug Target for Management of Alzheimer's Disease: A Comprehensive Review. (PubMed, Curr Top Med Chem) - "Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted."

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

Efficacy of Anti-Alzheimer’S (AD) Drugs in Cognitive Improvement: A Network Meta-Analysis (NMA) of Randomized Controlled Trials (RCTS) (ISPOR-EU 2023) - "The highest change in ADAS-Cog score (vs placebo) was obtained with Sodium oligomannate (GV-971) (150mg), followed by Masitinib (4.5mg/kg/day), and Donepezil (5mg/day); SMD [95% CI]: -2.15 [-3.37; -0.93], -2.15 [-3.61; -0.69], -2.12 [-3.77; -0.47]. Sodium oligomannate (GV-971) (150mg) showed highest improvement in ADAS-Cog score vs placebo, only Semagacestat (140mg/day) showed statistically significant SMD in MMSE score vs placebo, and none of the treatments showed improvement in CSD-SOB score. Although, lecanemab has recently been approved by USFDA for MCI and mild AD, the effect sizes were not significantly different from placebo."

Retrospective data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Pooling trial data to identify heterogeneity and characteristics of patients most likely to respond to treatment: a causal forest approach (AAIC 2023) - " We requested data from fifteen completed phase I–III trials investigating several compounds in AD individuals and were granted access to six trial datasets using compounds LY450139 (semagacestat), GSK933776, and BI409306 (with donepezil) with 2,397 participants (73.3±7.8 years old, 55% female, Table 1), through the Vivli platform. We took an innovative approach and provided a methodological basis to examine heterogeneity in treatment effects by pooling existing trial datasets. Our results imply that responsiveness to treatment may not be well-explained by the patient characteristics to our disposal, or that different compounds should be investigated. More research into other factors possibly related to treatment response is needed, e.g., fluid biomarkers and genetics."

Clinical • Heterogeneity • Alzheimer's Disease • CNS Disorders

Exosomes derived from TGF-β1-pretreated mesenchymal stem cells alleviate biliary ischemia-reperfusion injury through Jagged1/Notch1/SOX9 pathway. (PubMed, Int Immunopharmacol) - "Our results provided a vital insight that TGF-β1 pretreatment endowed MSCs-EXO with stronger protective effects to improve biliary IRI via Jagged1/Notch1/SOX9 pathway."

Journal • Cardiovascular • Inflammation • Reperfusion Injury • NOTCH1 • SOX9 • TGFB1

Notch signaling inactivation by small molecule gamma-secretase inhibitors restores the multiciliated cell population in the airway epithelium. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In sum, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases."

Journal • Asthma • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL13

Using Predictive Models to Reduce Heterogeneity in Alzheimer’s Disease Clinical Trials (AAN 2023) - "Design/Methods We used data from the placebo arm of five Phase III trials: two trials of semagacestat (LFAN and LZAN) and three trials of solanezumab (EXPEDITON1, EXPEDTION2, EXPEDITION3). Conclusions Despite enrollment in a clinical trial, 42-58% of participants in the placebo arm of five AD trials did not show MCD. Using predictive models can potentially increase sensitivity to treatment effects and reduce sample size requirements by increasing the proportion of participants with MCD enrolled in both arms of clinical trials."

Clinical • Heterogeneity • Alzheimer's Disease • CNS Disorders

TREATMENT OF APP X PS1 MUTANT KNOCK-IN MICE WITH THE GAMMA-SECRETASE INHIBITOR SEMAGACESTAT ALTERS SEX-RELATED SLEEP DIFFERENCES (ADPD 2023) - "These results suggest that pharmacological inhibition of gamma -secretase may result in sex -dependent changes in daily sleep."

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

THE Γ-SECRETASE SUBSTRATE PROTEOME REVEALS THE ROLE OF REGULATED INTRAMEMBRANE PROTEOLYSIS IN MAINTAINING MICROGLIA CELL STATES (ADPD 2023) - "Inhibition of γ-secretases using Semagacestat affects the microglia cell states in vitro and in vivo. Conclusions We conclude that γ-secretases maintain a tonic signaling level in microglia and that these proteases have cell-state-regulatory functions in microglia."

Alzheimer's Disease • CNS Disorders • Targeted Protein Degradation

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC Values in Aging and Alzheimer's Disease, Using the Physiologically Based LeiCNS-PK3.0 Model. (PubMed, Pharm Res) - "LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain) and intracellular (brain) fluids and cerebrospinal fluid of the subarachnoid space (CSF) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer's patients. CSF PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer's, this study shows that the impact of aging and Alzheimer's pathology on CNS distribution of the five drugs is insignificant."

Journal • Alzheimer's Disease • CNS Disorders