E2012 / Eisai - LARVOL DELTA

Preserved Ratio Impaired Spirometry (PRISm) and Restrictive Spirometric Pattern (RSP): Associations With Mortality in 26,000 Men (ATS 2024) - "Education and mortality data (all-cause and cause-specific, EU 2012 classification, E-2012) were obtained through linkage to registries...RSP and PRISm+RSP were strongly associated with all-cause, cancer and cardiovascular mortality, with higher HRs compared to the obstructive pattern. These results suggest that PRISm and RSP have different mortality profiles."

Cardiovascular • Oncology

Understanding the Modulatory Role of E2012 on the γ-Secretase-Substrate Interaction. (PubMed, J Chem Inf Model) - "In addition, we explore a potential substrate-modulator binding before the formation of the enzyme-substrate complex. The insights gained from our study emphasize the importance of these interactions in the development of potential therapeutic interventions that target the functionality of the GS enzyme in AD."

Journal • Alzheimer's Disease • CNS Disorders

How Modulator Binding at the Amyloidβ-γ-Secretase Interface Enhances Substrate Binding and Attenuates Membrane Distortion. (PubMed, J Med Chem) - "Predicted effects of γ-secretase mutations on E2012 modulation were confirmed experimentally. We anticipate that the study will facilitate the future development of effective GSMs."

Journal • Alzheimer's Disease • CNS Disorders

Reduced lung function and cause-specific mortality: A population-based study of Norwegian men followed for 26 years. (PubMed, Respir Med) - "Spirometric obstruction was mainly related to pulmonary mortality. Spirometric restriction was mainly related to extra-pulmonary mortality."

Journal • Cardiovascular • Coronary Artery Disease • Diabetes • Genito-urinary Cancer • Heart Failure • Hematological Disorders • Hematological Malignancies • Lung Cancer • Metabolic Disorders • Oncology • Respiratory Diseases • Solid Tumor

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

Unraveling APP processing by γ-secretase (ACS-Fall 2023) - "Increased ratios of Aβ42 to Aβ40 in human brains have been associated with the development of Alzheimer's disease.In this study, we intend to use computational methods to unravel the main events that lead to the formation of the different Aβ peptides in order to suggest which factors could determine the enzymatic pathway and how to promote healthier and shorter Aβ peptides production. To this end, we study the substrate entry, the modulating effect of drug E2012 on sequential C99 cleavage, and Aβ peptides production and release; characterizing the conformational space of GS at each stage."

Alzheimer's Disease • CNS Disorders • Aβ42

Notch-dependent and independent functions of gamma secretase alter keratinocyte-mediated inflammation and adhesion (ISID 2023) - "We used commercially available inhibitors (SCP0004, Nirogacestat, and E2012) that differentiate between Notch-dependent and Notch-independent functions of gamma secretase. While keratinocyte-mediated inflammation was linked to loss of Notch cleavage, we observed disrupted keratinocyte adhesion by dispase dissociation assay (4-fold increase in fragmentation, p= 0.05) with the application of a Notch-sparing gamma secretase inhibitor. While Notch was important for controlling keratinocyte-mediated inflammation, Notch-independent effects on keratinocyte adhesion argue for the study of additional substrates of this complex that may be involved in gamma secretase linked familial HS cases."

Dermatology • Hidradenitis Suppurativa • Immunology • Inflammation • APP • CCL2 • CDH1 • CXCL8 • IL6

Exploring the modulation mechanism of Aβ peptides release | Poster Board #2334 (ACS-Fall 2022) - "In this work, we used the recent cryo-EM structure of GS complexed with the modulator E2012 to theoretically study its most probable binding mode and mechanism of action for the particular case when the APP substrate is present at the active site. Additionally, we studied the progressive release of Aβ peptides in the presence and absence of the E2012 molecule using computational chemistry methodologies."

Alzheimer's Disease • CNS Disorders

Structural basis of γ-secretase inhibition and modulation by small molecule drugs. (PubMed, Cell) - "Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors."

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

A systematic review of pharmacist-led medicines review services in New Zealand - is there equity for Māori older adults? (PubMed, Res Social Adm Pharm) - "Further investigation is needed to understand whether the development of culturally safe pharmacist-led medicines review services, responsive to community identified needs, can help to achieve equity in health outcomes for Māori older adults."

Clinical • Journal • Review

Eisai to resume clinical study to evaluate E2012 as a potential next generation Alzheimer's disease treatment (FierceBiotech) - Eisai received a notification from FDA that it may proceed with P1 clinical study for E2012 which was suspended in United States in Feb 2007 and has been requesting for resuming the study with data required by FDA

Anticipated trial initiation date • Alzheimer's Disease

Mechanism of gamma-secretase modulators (Neuroscience 2019) - "Together these results will allow us to pull down the photolabeled targets and analyze them with LC-MS/MS to map the binding sites on γ-secretase. Identification of these sites will define the molecular mechanism of GSMs, leading to a better understanding of their modulation for AD drug development."