elenbecestat (E2609) / Eisai, Biogen - LARVOL DELTA

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

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

A Stepwise Tier-Based Approach for Determining Patient Eligibility in CLARITY AD: A Phase 3 Placebo-Controlled, Double Blind Study to Confirm the Safety and Efficacy of Lecanemab (BAN2401) 10 mg/kg Biweekly in Patients with Early Alzheimer’s Disease (CTAD 2021) - P2, P3 | "These results are consistent with those observed in the phase 2 POC study as well as the elenbecestat phase 3 MissionAD studies. The stepwise tier-based approach utilized in the CLARITY AD study reduced trial burden on both clinical sites and patients by disqualifying approximately 70% of non-eligible patients early in the screening process. This approach eliminates unnecessary, time-consuming, and invasive procedures in these patients, allowing for sites to focus their resources and attention on potentially qualified patients for the trials. Such an approach substantially reduces overall recruitment time and costs."

Clinical • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Amyloid PET • MRI

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD – a MissionAD tau sub-study (CTAD 2021) - " The study population consisted of patients with a diagnosis of MCI due to AD (n=72) or mild AD dementia (n=2) from the elenbecestat Mission AD Phase 3 program (n=74, 76 ± 7 yrs, 38 females) who were invited to join a 18F-PI 2620 tau PET imaging sub-study... This study supports the utility of 18F-PI-2620 PET to assess tau deposits in an early AD population. 18F-PI-2620 SUVR values demonstrated significant correlations with established structural and CSF biomarkers and inverse correlations with cognitive scores in domain-specific patterns. The findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD."

Late-breaking abstract • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Immunology • CSF Aβ40 • CSF Aβ42 • MRI • Tau PET

COGNITIVE OUTCOMES IN THE VERY MILD SUBGROUP IN THE PHASE 3 STUDIES OF ELENBECESTAT IN EARLY AD (MISSION AD PROGRAM) (AAIC 2021) - "There was no evidence of a treatment effect on CDR-SB or ADCOMS for elenbecestat in the early terminated MissionAD program, even in the very mild subjects."

P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

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

Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer's disease. (PubMed, Alzheimers Dement) - "A QSP model can provide novel insights to clinical results. Our model explains the results of clinical trials and provides guidance for future therapeutic development."

Clinical • Journal • Alzheimer's Disease • CNS 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

Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Participants With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P2; N=70; Terminated; Sponsor: Eisai Inc.; Completed ➔ Terminated; This study was terminated early by the sponsor on the recommendation of an independent data safety monitoring board following review of unblinded data from the Phase 3 studies E2609-G000-301 (NCT02956486) and E2609-G000-302 (NCT03036280).

Clinical • Trial termination • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • MRI

[VIRTUAL] EFFICACY AND SAFETY OF ELENBECESTAT IN SUBJECTS WITH EARLY ALZHEIMER'S DISEASE: RESULTS FROM THE MISSIONAD PHASE 3 PROGRAM (ADPD 2021) - "Incidence of adverse events were similar between groups with lymphopenia, rash, dizziness, weight loss, and abnormal dreams occurring more frequently with elenbecestat. Conclusions There was no evidence of a treatment effect on CDR-SB or ADCOMS for elenbecestat in the early terminated MissionAD studies."

Clinical • P3 data • Alzheimer's Disease • CNS Disorders • Amyloid PET