ceperognastat (LY3372689) / Eli Lilly - LARVOL DELTA

EVIDENCE FOR OGA INHIBITION TO IMPACT NEURODEGENERATIVE PATHOLOGIES (ADPD 2025) - P1 | "Conclusions Nonclinical data indicated OGA inhibition has the potential to be an effective treatment for AD and suggested a manageable safety profile to move ceperognastat into clinical studies. However, lack of efficacy in a phase 2 study in early symptomatic AD suggests the potential for further clinical development needs to be considered carefully."

Alzheimer's Disease • Cardiovascular • CNS Disorders • OGA

UPDATED: Eli Lilly lops Alzheimer's and obesity assets from pipeline in Q4 update (FierceBiotech) - "Eli Lilly has thinned its pipeline in two critical therapeutic areas, axing clinical-phase Alzheimer’s disease and obesity candidates as part of its quarterly clear-out...The removal of ceperognastat, Lilly’s oral O-GlcNAcase anti-tau agent, from the pipeline comes months after the candidate failed...to slow clinical decline in early symptomatic Alzheimer’s disease patients in a phase 2 trial....Lilly removed the candidate, which it called DACRA QW II and LY3541105, from its pipeline Thursday."

Discontinued • Alzheimer's Disease • Obesity

Biomarkers. (PubMed, Alzheimers Dement) - P2 | "DTI was successfully implemented in phase 2 multi-center PROSPECT-ALZ study. Cross-sectional analysis suggests that DTI measures can differentiate individuals based on global tau burden and cognition, presumably capturing differences in cortical microstructure. Future work will focus on multimodal evaluation of longitudinal changes in DTI, tau, and cognition."

Biomarker • Clinical • Journal • Alzheimer's Disease • CNS Disorders • OGA

A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer's Disease (clinicaltrials.gov) - P2 | N=330 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Aug 2024 ➔ Feb 2025

Trial completion date • Alzheimer's Disease • CNS Disorders

Evaluation of Baseline Diffusion Tensor Imaging Biomarkers in phase 2 multi-center PROSPECT-ALZ study (AAIC 2024) - P2 | "Our study evaluated baseline GM microstructure and WM integrity measures in the PROSPECT-ALZ trial (NCT05063539) of LY3372689, an O-GlcNAcase (OGA) inhibitor... DTI was successfully implemented in phase 2 multi-center PROSPECT-ALZ study. Cross-sectional analysis suggests that DTI measures can differentiate individuals based on global tau burden and cognition, presumably capturing differences in cortical microstructure. Future work will focus on multimodal evaluation of longitudinal changes in DTI, tau, and cognition."

Biomarker • Clinical • P2 data • Alzheimer's Disease • CNS Disorders • OGA

DISCOVERY AND EARLY CLINICAL DEVELOPMENT OF ORAL ANTI-TAU THERAPIES AS THE NEXT GENERATION OF DISEASE-MODIFYING TREATMENTS (ADPD 2024) - "Inhibition of the O-GlcNAcase (OGA) enzyme is proposed to delay the progression of tau-related diseases by slowing the accumulation of hyper-phosphorylated, insoluble tau filaments. We will present the discovery and our innovative approach to clinical development of LY3372689, a low dose, central nervous system (CNS) penetrant OGA inhibitor currently under investigation in a phase 2 clinical trial in patients with early symptomatic AD."

Clinical • Alzheimer's Disease • CNS Disorders • MAPT • OGA

Use of plasma P-tau217 for enrichment in the Phase 2 PROSPECT-ALZ study of LY3372689 in early symptomatic Alzheimer’s disease: Cohort selection and baseline characteristics (AAIC 2023) - "As blood-based biomarkers become more accessible, their use in selecting participants for clinical research is desirable. The PROSPECT-ALZ study successfully implemented plasma P-tau217 in sequence with tau PET to improve efficiency in identifying trial participants. This study of LY3372689, the first orally administered OGA inhibitor to be investigated in AD, has topline trial results anticipated in 2024."

P2 data • Alzheimer's Disease • CNS Disorders

A Study of Carbon-14-Labelled [14C] LY3372689 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

A Study of Carbon-14-Labelled [14C] LY3372689 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Active, not recruiting

Enrollment closed

A Study of Carbon-14-Labelled [14C] LY3372689 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial

A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer's Disease (clinicaltrials.gov) - P2 | N=330 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders

"Kudos to @LillyPad for largest series I've ever seen of closely bunched WOs against same OGA target. At least LY-3372689 seems to be progressing #lorraSAR https://t.co/oSaDd8dTtx" (@cdsouthan)

Discovery and Early Clinical Development of LY3372689, an O-GlcNAcase (OGA) Enzyme Inhibitor (ACS-Sp 2022) - "Increased tau O-GlcNAcylation reduces tau aggregation and studies have found that OGA inhibition decreased the accumulation of hyperphosphorylated, aggregated tau in different tau-overexpression mice. This presentation will describe the discovery and early clinical development of LY3372689, a potent OGA inhibitor capable of achieving enzyme occupancy > 90% in humans at low doses."

Clinical • Alzheimer's Disease • CNS Disorders • MAPT • OGA

[VIRTUAL] Brain target occupancy of LY3372689, an inhibitor of the O-GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers (CTAD 2021) - P1 | "PET studies using the radioligand 18F-LY3316612 demonstrated that LY3372689 can achieve high brain OGA EO in HV. LY3372689 target engagement as measured by OGA EO was maintained following repeated dosing, thus supporting its use in longer duration clinical trials. The pharmacodynamic data from the PET studies will support LY3372869 dose selection for efficacy trials in tauopathies."

Clinical • Alzheimer's Disease • CNS Disorders • OGA

[VIRTUAL] Single and multiple ascending dose studies in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of the O-GlcNAcase (OGA) enzyme (CTAD 2021) - P1 | "LY3372689 demonstrated an acceptable safety and PK profile following single and multiple doses of LY3372689 in HV. These results support investigation of LY3372689 in efficacy trials for tauopathies and help support dose selection for those trials."

Clinical • Alzheimer's Disease • Back Pain • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Musculoskeletal Pain • Pain • Respiratory Diseases • OGA

A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer's Disease (clinicaltrials.gov) - P2; N=330; Recruiting; Sponsor: Eli Lilly and Company

Clinical • New P2 trial • Alzheimer's Disease • CNS Disorders • MRI

[VIRTUAL] Brain target occupancy of LY3372689, an inhibitor of the O-GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers (AAIC 2021) - P1 | "PET studies in healthy volunteers demonstrated that LY3372689 can achieve high brain target occupancy of the OGA enzyme. Brain OGA EO was maintained after multiple dosing, supporting the durability of target engagement for longer clinical trials. The human PET data will be used to support LY3372869 dose selection for efficacy trials in tauopathies."

Clinical • Alzheimer's Disease • CNS Disorders • OGA

[VIRTUAL] Single and multiple ascending dose studies in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of the O-GlcNAcase (OGA) enzyme (AAIC 2021) - P1 | "LY3372689 demonstrated an acceptable safety and PK profile following single and multiple doses of LY3372689 in HV. These results support investigation of LY3372689 in efficacy trials for tauopathies and help support dose selection for those trials."

Clinical • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation • Pain • OGA

"Updated safety data for LY-3372689 study in healthy volunteers disclosed at #AAIC21" (@Cortellis)

Clinical

A Study of the Effects of Multiple Doses of LY3372689 on the Brain in Healthy Participants (clinicaltrials.gov) - P1; N=4; Completed; Sponsor: Eli Lilly and Company; Recruiting ➔ Completed; N=12 ➔ 4

Clinical • Enrollment change • Trial completion • OGA

A Study of the Effects of Multiple Doses of LY3372689 on the Brain in Healthy Participants (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Eli Lilly and Company; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

[VIRTUAL] Brain target occupancy of LY3372689, an inhibitor of the O-GlcNAcase (OGA) enzyme: translation from rat to human (AAIC 2020) - P1 | "Non-clinical and clinical EO studies demonstrated that occupancy of the OGA enzyme effectively translated from rats to humans after single doses of LY3372689. The human PET data can be used to support LY3372869 dose selection for efficacy trials in tauopathies."

Preclinical • Alzheimer's Disease • CNS Disorders

[VIRTUAL] A single ascending dose study in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of O-GlcNAcase (OGA) enzyme (AAIC 2020) - P1 | "LY3372689 demonstrated an acceptable safety and PK profile following single oral doses of LY3372689 in HV, which supports further investigation of LY3372689 as a potential treatment for tauopathies."

Clinical • Alzheimer's Disease • CNS Disorders • Fatigue • Pain

Data from Lilly at Alzheimer's Association International Conference 2020 (AAIC 2020) to Showcase Clinical Advances in Alzheimer's Research (PRNewswire) - "Eli Lilly and Company...today announced that new results from 17 research studies will be presented at the upcoming Alzheimer's Association International Conference® 2020 (AAIC® 2020) which will be held virtually July 27-31, 2020."

Biomarker • Diagnostic • P2/3 data • P3 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Parkinson's Disease

A Study of the Effects of Multiple Doses of LY3372689 on the Brain in Healthy Participants (clinicaltrials.gov) - P1; N=12; Not yet recruiting; Sponsor: Eli Lilly and Company

Clinical • New P1 trial