LY2886721 / Eli Lilly - LARVOL DELTA

Ipsc-derived cerebral organoids to advance drug discovery for neuroinflammation and alzheimer's disease (Neuroscience 2025) - "The BACE1 inhibitor LY2886721 significantly attenuated Aβ42 secretion and restored Aβ42/Aβ40 ratios...Taken together, we demonstrated cytokine-driven neuroinflammation and Aftin-4-induced Alzheimer's-like pathology models in cerebral organoids, with pharmacological intervention effectively reversing disease phenotypes. This organoid-based platform shows translational potential for accelerating therapeutic development against neuroinflammation and Alzheimer's disease."

Alzheimer's Disease • CNS Disorders • APP • Aβ42 • CXCL8 • IFNG • IL13 • IL1B • IL6 • TNFA

Human platelets release amyloid peptides β and β in response to haemostatic, immune, and hypoxic stimuli. (PubMed, Res Pract Thromb Haemost) - "The selective β secretase (BACE) inhibitor LY2886721 showed no effect on the release of either Aβ or Aβ in our ELISA experiments...Although further studies are required to fully characterise this phenomenon, we suggest the possibility of a role for platelets in the deposition of Aβ peptides and the formation of amyloid plaques. Interestingly, the combination of hypoxia and inflammation that we simulated in vitro with reduced oxygen tension and LPS may increase the release of fibrillogenic Aβ and, consequently, exacerbate amyloid plaque deposition in the brain of AD patients."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation

BACE INHIBITION AND SYNAPTIC DYSFUNCTION: MECHANISTIC INSIGHTS FROM IPSC-DERIVED HUMAN NEURONS (ADPD 2023) - " Human cortical neurons derived from induced pluripotent stem cells (iPSC) were exposed to the BACE inhibitor LY2886721... BACE inhibitors are still a p recious resource to delay or prevent AD progression. Unraveling the mechanisms by which these drugs affect synaptic functionality is important for a reassessment of this treatment strategy."

Alzheimer's Disease • CNS Disorders • APP • NEFL

EXPRESSION AND INTRACELLULAR LOCALIZATION OF Α-, Β-, AND Γ-SECRETASES, AND THE EFFECT OF THEIR INHIBITORS IN THE PERI-INFARCT ZONE IN MICE (WSC 2022) - "α-secretase inhibitor Batimastat (BB-94) and β-secretase inhibitor LY2886721 had no effect on the apoptosis of peri-infarct cells... Probably, inhibition of γ-secretase reduces inflammation and activation of astrocytes, which contributes to a decrease in the level of apoptosis and, consequently, the amount of damage after ischemia. Thus, DAPT may be considered as a potential drug for stroke therapy. This work was supported by the Ministry of Science and Higher Education of the Russian Federation (grant No."

Preclinical • Cardiovascular • Immunology • Inflammation • Ischemic stroke • Targeted Protein Degradation • ADAM10 • APP

Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss. (PubMed, Int J Mol Sci) - "In this study, hippocampal slices were incubated with equipotent isoflurane (iso), sevoflurane (sevo), or xenon (Xe) with/without pretreatment of the BACE inhibitor LY2886721 (LY). Taken together, our study suggests that sevo partly elevates BACE activity and interferes with synaptic remodeling, whereas iso mildly modulates synaptic changes in the CA1 region of the hippocampus. On the other hand, Xe does not alternate dendritic spine remodeling."

Journal • Anesthesia • APP

BACE INHIBITION AND SYNAPTIC DYSFUNCTION: MECHANISTIC INSIGHTS FROM HUMAN IPSC- DERIVED NEURONS (ADPD 2022) - " We treated human induced pluripotent stem cells (iPSCs)-derived cortical neurons with high- dose BACE inhibitor LY2886721 (Eli Lilly)... Accumulation of APP in neurons as a result of missed β-cleavage could explain synaptic dysfunction phenotype caused by pharmacological inhibition of BACE. Unraveling this mechanism is important for a reassessment of such promising treatment strategy."

Alzheimer's Disease • CNS Disorders • APP

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

[VIRTUAL] REGULATION OF INTRACELLULAR INNATE IMMUNE AMYLOID BETA (Aβ) CLEARANCE (AAIC 2021) - " THP-1 cells were differentiated toward macrophages, and treated with various inhibitors including IDE inhibitor (6bK, Tocris),BACE1 inhibitor (LY2886721, Tocris), Nep inhibitor (Phosphoramidon, Tocris), Bafilomycin A1(Sigma)(1h) and Rapamycin (Sigma) (18h) before adding 100 ng/ml Aβ40 (2h), followed by 4h chase. We demonstrate a novel assay for Aβ degradation by Innate immune cells including THP-1 and iPSC derived microglia. Inhibition of Nep and BACE1 reduces 20-x peptide generation indicating this as a potential marker for Aβ. Modulation of autophagy affects 20-x peptide generation indicating the potential of targeting endo-lysosomal and autophagic pathway against AD."

IO biomarker • Alzheimer's Disease • CNS Disorders • GLI2

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor. (PubMed, J Med Chem) - "We have previously reported the clinical development of LY2811376 and LY2886721. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges."

Clinical • Journal • Alzheimer's Disease • CNS Disorders

The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Our data provide support for a role of BACE1 as a regulator of systemic glucose homeostasis and suggest BACE1 inhibitors for the treatment of T2DM-associated pathologies, especially in cases where diabetes is comorbid to AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • APP

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

[VIRTUAL] REGULATION OF INTRACELLULAR INNATE IMMUNE AMYLOID BETA (AΒ) CLEARANCE (ADPD 2021) - "We present assays for Aβ catalysis in myeloid cells (THP-1 cells and human iPSC microglia).  Methods THP-1 cells were differentiated toward macrophages, and treated with various inhibitors including IDE inhibitor (6bK, Tocris), BACE inhibitor (LY2886721, Tocris), NEP inhibitor (Phosphoramidon, Tocris) and Bafilomycin (1h) before adding 100 ng/ml Aβ40 (2h), followed by 4h chase...Autophagy inhibitor BafA1 increases both 1-40 and 20-x fragments indicating the role of the endo-lysosomal system in the degradation of full length and 20-x Aβ.  Conclusions We demonstrate a novel assay for Aβ degradation by Innate immune cells including THP-1 and iPSC derived microglia. Inhibition of Nep and BACE reduces 20-x peptide generation indicating this as a potential marker for Aβ clearance."

IO biomarker • Alzheimer's Disease • CNS Disorders • GLI2

Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission. (PubMed, Alzheimers Res Ther) - "Our results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function."

Journal • Alzheimer's Disease • CNS Disorders

Pharmacokinetic (PK) and pharmacodynamic (PD) effects of BACE inhibitor LY2886721 in healthy volunteers (HVs) at steady state (AAN 2013) - Presentation time: Monday, March 18, 2013 2:00 PM; P1, N=42; NCT01227252; "LY2886721 produced dose-dependent lowering...plasma Aβ1-40 compared to baseline. The 35 and 70 mg doses were associated with >80% plasma Aβ1-40 reduction at nadir and levels did not return to baseline at 168 hours after any investigated dose."

P1 data • Alzheimer's Disease

Study of LY2886721 in mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease (clinicaltrials.gov) - P1/2, N=129; Recruiting; Sponsor: Eli Lilly; Completion Date: Jan 2015 - Feb 2014

Trial completion date • Alzheimer's Disease

A study of two dosage forms of LY2886721 in healthy participants (clinicaltrials.gov) - P1, N=30; Sponsor: Eli Lilly; Not yet recruiting -> Recruiting.

Enrollment open • Alzheimer's Disease

Preclinical and phase I clinical characterization of LY2886721, A BACE1 inhibitor in phase II development for Alzheimer's disease (ADPD 2013) - Presentation time: 07.03.2013, 17:15-19:15; P1, N=0; NCT01133405 P1, N=42; NCT01227252; "In the SAD Phase I studies, LY2886721...lowered plasma and CSF Aβ and all doses were well tolerated. In the MAD Phase I studies, LY2886721...lowered plasma and CSF Aβs with steady state reduction of CSF Aβ 1-42 exceeding 70% in the 70 mg dose cohort."

P1 data • Preclinical • Alzheimer's Disease

A safety study of LY2886721 multiple doses in healthy subjects (clinicaltrials.gov) - P1, N=42; N=60 → 42; Active, not recruiting → Completed

Enrollment • Trial completion • Alzheimer's Disease

Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F). (PubMed, Cell Prolif) - "Taken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future."

Clinical • Journal

Quantitative Analysis of F-PF-06684511, a Novel PET Radioligand for Selective β-secretase 1 Imaging, in Non-human Primate Brain. (PubMed, J Nucl Med) - " Initial brain PET measurements were performed at baseline and after oral administration of 5 mg/kg of LY2886721, a BACE1 inhibitor, in 2 cynomolgus monkeys...The effective dose of F-PF-06684511 was 0.043 mSv/MBq for humans. F-PF-06684511 is the first successful PET radioligand for BACE1 brain imaging that demonstrates favorable in vivo binding and brain kinetics in NHPs."

Journal

Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints. (PubMed, Bioorg Med Chem) - "We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described."

Journal

Melanoma-secreted amyloid beta supresses neuroinflammation and promotes brain Metastasis (SMR 2019) - "Finally, we show that treatment of mice with a beta secretase inhibitor (LY2886721), which prevents amyloid beta production, decreases brain metastatic burden. Our results demonstrate a critical role for amyloid beta in melanoma brain metastasis, establish a novel connection between brain metastasis and neurodegenerative pathologies, and show that amyloid beta is a promising therapeutic target for brain metastasis treatment. Studies to further characterize how amyloid beta acts in the melanoma brain metastasis microenvironment are currently underway."

EFFECTS OF ALTERED AΒ PRODUCTION ON SYNAPTIC ACTIVITY (ADPD 2019) - "...Methods In this study, primary rat cortical cultures were treated with a range of β- and γ-secretase inhibitors (e.g. BACE inhibitor-IV, LY2886721, LY411575; all commercially available)...Some but not all inhibitors affected synaptic activity and there was no clear relationship between the reduction in Aβ levels and measures of synaptic transmission. Conclusions Inhibition of secretases at doses that are relevant to clinical trials (30% to 90% reduction in Aβ levels) may impair synaptic activity in an Aβ-independent manner."