elenbecestat (E2609) / Eisai, Biogen - LARVOL DELTA

GENOME-WIDE ASSOCIATION STUDY IN MISSION AD CLINICAL TRIALS IDENTIFIES NOVEL GENETIC VARIANTS ASSOCIATED WITH COGNITIVE DECLINE IN ALZHEIMER'S DISEASE (ADPD 2026) - "This study aims to identify genetic loci associated with the rate of cognitive decline in AD, which may further our understanding of AD biology and inform the development of new therapies. The Mission AD studies are phase 3 trials to investigate the efficacy and safety of elenbecestat, an oral BACE1 inhibitor, for treatment of mild cognitive impairment (MCI) and early AD... We identify loci with candidate genes potentially affecting cognitive decline and AD pathogenesis by using data from AD clinical trials. These findings may improve the mechanistic insight and lead to novel drug targets and therapeutic approaches in AD."

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

Discordance in amyloid positivity between visual reads and Centiloids: Impact of white matter uptake. (PubMed, J Prev Alzheimers Dis) - "Variations in WM uptake significantly contribute to discordances by introducing positive or negative bias in CL values and altering the GM to WM contrast, which forms the basis of the VR. Nevertheless, the rates of discordant cases are low and VR represents a robust and validated method to determine the presence of amyloid deposition. VR enables enrolling patients with amyloid beta pathology, as seen on amyloid PET scans, whereas CL scaling was developed to provide standardized units that more consistently characterize longitudinal amyloid‑β change. These findings reflect the complementary roles of VR and CL in amyloid PET evaluation, with implications for refining diagnostic accuracy and disease monitoring in AD clinical trials and practice."

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

Discontinued BACE1 Inhibitors in Phase II/III Clinical Trials and AM-6494 (Preclinical) Towards Alzheimer's Disease Therapy: Repurposing Through Network Pharmacology and Molecular Docking Approach. (PubMed, Pharmaceuticals (Basel)) - "This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer's disease (AD). This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand-hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer's disease, warranting further in silico refinement and experimental validation."

Journal • P2/3 data • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • AKT1 • BCL2 • BCL2L1 • CASP3 • CASP8 • CDC37 • HSP90AA1 • HSP90AB1 • STAT3

Biomarkers. (PubMed, Alzheimers Dement) - "Targeted multiplexed panels such as NULISASeq quantifies multiple analytes in a single run thereby reducing the amount of precious input material and the time required for analysis. This offers advantage over fluid and neuroimaging-based measurements tailored to singular targets. We have demonstrated the utility of a multiplexed panel for reliable detection of amyloid status as well as highlighted the potential of discovering novel biomarkers associated with AD."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • GFAP • MAPT • NEFH • p-tau181

Biomarkers. (PubMed, Alzheimers Dement) - P3 | "LB, a common copathology of AD, may be a source of heterogeneity. Incorporation of SAA, a specific biomarker of LB-pathology, can help account for disease heterogeneity and potentially improve assessment of treatment response in amyloid and synuclein status confirmed AD target population."

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

Drug Development. (PubMed, Alzheimers Dement) - P3 | "The replication of the five AD molecular subtypes in an independent clinical trial cohort further supports the robustness of these subtypes and paves the way for personalized medicine and novel combination therapy approaches in AD. Reference 1. Tijms, B. M. et al. Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles. Nat. Aging 33-47 (2024) doi:10.1038/s43587-023-00550-7."

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

Clinical Manifestations. (PubMed, Alzheimers Dement) - "The sensitivity of the ISLT to memory dysfunction in MCI due to AD is improved by addition of information about sex and 5-year age strata to normative data."

Journal • Alzheimer's Disease • CNS Disorders

Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates. (PubMed, Proteomics) - "The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF."

Journal • Alzheimer's Disease • CNS Disorders • VCAM1

BACE1 Inhibition Protects Against Type 2 Diabetes Mellitus by Restoring Insulin Receptor in Mice. (PubMed, Int J Mol Sci) - "Remarkably, the administration of Elenbecestat restored InsR levels and improved their downstream signaling pathways, leading to increased insulin sensitivity and enhanced glucose tolerance. In summary, our findings suggest that inhibiting BACE1 can restore InsR expression and improve insulin-signaling sensitivity, ultimately resulting in enhanced diabetic phenotypes."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • BACE1 • IR

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

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

Eligibility rates among racially and ethnically diverse US participants in Phase 2 and Phase 3 placebo-controlled, double-blind, randomized trials of lecanemab and elenbecestat in early Alzheimer's disease. (PubMed, Ann Neurol) - "Differential eligibility may contribute to underrepresentation of some minoritized racial and ethnic groups in early AD trials. Amyloid biomarker eligibility is a requirement to confirm the diagnosis of AD and for treatment with amyloid lowering drugs and differed among racial and ethnic groups."

Clinical • Journal • P2 data • P3 data • Alzheimer's Disease • CNS Disorders

Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics. (PubMed, Molecules) - "In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

New Highly Selective BACE1 Inhibitors and Their Effects on Dendritic Spine Density In Vivo. (PubMed, Int J Mol Sci) - "Treatment with those inhibitors showed a reduction in soluble Sez6 (sSez6) levels to 27% (elenbecestat, Biogen, Eisai Co., Ltd., Tokyo, Japan), 17% (Shionogi compound 1) and 39% (Shionogi compound 2), compared to animals fed with vehicle pellets...In conclusion, highly selective BACE1 inhibitors do alter dendritic spine density similar to non-selective inhibitors if soluble (sSez6) levels drop too much. Low-dose BACE1 inhibition might be reasonable if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first week of treatment."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Epilepsy • SEZ6

Novel Bace 1 selective inhibitor does not affect dendritic spine plasticity (AAIC 2023) - " By using longitudinal in vivo two-photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with 2 novel highly selective BACE1 inhibitors developed at Shionogi in comparison to Elenbecestat which reduce soluble Sez6 to 27% (Elenbecastat), 17% (Shionogi Compound 1) and 39% (Shionogi Compound2) of baseline levels in untreated animals... Selective BACE1 inhibitors do not alter dendritic spine plasticity in mice if dosing reduces synaptic BACE1 cleavage of Sez6 not below 27% of baseline soluble Sez6 levels. BACE1 selective inhibitors may be potential novel candidates for clinical trials treating AD if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first weeks of treatment."

Alzheimer's Disease • CNS Disorders • Epilepsy

Discordance in amyloid positivity defined by Visual Reads VR and Centiloids CL (AAIC 2023) - "The objective of this analysis was to assess the rate and cause of discordance in defining amyloid pathology using VR and CL in Eisai’s Elenbecestat MissionAD Phase 3 program... VR+/CL- discordant cases show fewer amyloid positive cortical regions, computing CLs results in below cut-off values due to a dilution effect. These cases are considered VR+ as per manufacturer’s guidelines as they show at least one area of amyloid accumulation. On the other hand, VR-/CL+ discordant cases result from an increased WM uptake, reducing GM/WM contrast required to determine visual read positivity."

Discordant • Alzheimer's Disease • CNS Disorders • Dementia

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

Pharmacological Inventions for Alzheimer Treatment in the United States of America: A Revision Patent from 2010 - 2020. (PubMed, J Prev Alzheimers Dis) - "The molecules Elenbecestat and LY3202626 decreased the burden of Aβ plaques without significant cognitive improvement, Donanemab is in Phase 3 clinical trial, and the FDA has designated it Breakthrough Therapy. CPC-201 and PXT864 demonstrated, in Phase 2, good tolerability and improvement of AD symptoms...The most advanced treatments in their research are those focused on treating Aβ accumulation. More studies are needed to prove the efficacy of the patented molecules."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Immunology • Inflammation

THREE GROUP CLASSIFICATION OF PARTICIPANTS BASED ON FULLY AUTOMATED PLASMA Β-AMYLOID MEASUREMENTS TO ACHIEVE HIGH POSITIVE AND NEGATIVE PREDICTIVE VALUES. (CTAD 2022) - " Plasma Aβ40 and Aβ42 were measured using a fully automated immunoassay platform in a set of plasma samples sourced from participants in the screening phase of the elenbecestat Phase 3 program... Our Aβ assay achieved PPV and NPV ≥ 90% by classifying participants into the three groups. Majority of participants were classified as positive or negative Aβ groups by plasma Aβ42/Aβ40 ratio, indicating that our assay may contribute to reduce amyloid PET scan or CSF Aβ testing, which could be helpful in applications such as the recruitment step of clinical trials. CLINICAL TRIALS: COGNITIVE AND FUNCTIONAL ENDPOINTS"

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Plasma Aβ40 • Plasma Aβ42

Diversity in Phase 2 and Phase 3 Placebo-Controlled, Double-Blind, Lecanemab and Elenbecestat Early Alzheimer’s Disease Studies (AAIC 2022) - No abstract available

Clinical • P2 data • P3 data • Alzheimer's Disease • CNS Disorders

Evaluation of tau deposition using F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study. (PubMed, Alzheimers Res Ther) - P3 | "The findings support the hypothesis that F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Immunology • CSF P-tau

Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy. (PubMed, Alzheimers Res Ther) - "The plasma Aβ42/Aβ40 ratio measured using the HISCL series achieved high accuracy in predicting amyloid PET status. Since our blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it may contribute to the diagnosis of AD in routine clinical practice."

Amyloid PET • Journal • Alzheimer's Disease • CNS Disorders • Plasma Aβ40 • Plasma Aβ42

Increasing the Cognitive Screening Efficiency of Global Phase III Trials in Early Alzheimer Disease: The Cognitive Task Force. (PubMed, Alzheimer Dis Assoc Disord) - "The establishment of a CTF to support efficient cognitive screening is highly recommended for future Alzheimer disease studies. Additional benefits included improved site relationships, increased engagement in MissionAD and access to a group of cognitive experts for consulting, with a focus on achieving more efficient trial recruitment."

Journal • P3 data • Alzheimer's Disease • CNS Disorders

EVALUATION OF TAU DEPOSITION IN AMYLOID-POSITIVE MCI AND MILD-AD DEMENTIA SUBJECTS FROM THE MISSIONAD PROGRAM USING 18F-PI-2620 (ADPD 2022) - " Placebo-treated, amyloid-positive patients with a diagnosis of MCI due to AD or mild AD dementia from the elenbecestat MissionAD Phase 3 program (n=74, 76 ± 7 yrs, 38 females) underwent a baseline 18F-PI-2620 PET, T1-weighted MRI, and several cognitive tests... This study supports the utility of 18F-PI-2620 PET to assess tau deposits in an early AD population showing significant correlations with established structural and CSF biomarkers and inverse correlations with cognitive scores in domain-specific patterns."

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

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