The main purpose of this study is to evaluate how much of the study drug (LY3372689), administered as a single dose that has the radioactive substance 14C incorporated into it, passes from blood into urine, feces and expired air in healthy male participants. The study will also measure how much of the study drug gets into the bloodstream, how its broken down, and how long it takes the body to get rid of it. The study will last about 4 weeks. Screening is required within 28 days prior to the start of the study and follow up is required approximately 7 days after discharge.

Start Date24 Feb 2023

Sponsor / Collaborator

Eli Lilly & Co.

NCT05063539

/ CompletedPhase 2

Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic Alzheimer's Disease

The purpose of this study is to assess the safety, tolerability and effect of study drug LY3372689 in participants with early symptomatic Alzheimer's Disease

Start Date16 Sep 2021

Sponsor / Collaborator

Eli Lilly & Co.

NCT04392271

/ CompletedPhase 1

Assessment of Brain O-GlcNAcase (OGA) Enzyme Occupancy After Multiple Oral Doses of LY3372689 as Measured by Positron Emission Tomography (PET) With the Radioligand [18F]LY3316612 in Healthy Subjects

This study uses imaging to evaluate how LY3372689 binds to a protein in the brain. This study will be conducted in healthy participants and will last up to about 10 weeks. Screening must be completed within four weeks prior to enrollment.

Start Date06 Aug 2020

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Ceperognastat

100 Translational Medicine associated with Ceperognastat

100 Patents (Medical) associated with Ceperognastat

Literatures (Medical) associated with Ceperognastat

01 Sep 2025·NEUROCHEMISTRY INTERNATIONAL

Thiamet-G ameliorates Parkinson's disease-associated cognitive impairment via increasing O-GlcNAcylation of STING in the microglia

Article

Author: Zhu, Shanshan ; Chen, Shuyang ; Zou, Ju ; Tan, Sijie ; Wang, Nan

Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclytion is a novel protein post-translational modification with cognitive enhancing effects. This study aimed to investigate the effects of Thiamet-G (TMG), an O-GlcNAcase inhibitor that can increase the intracellular O-GlcNAclytion levels, on PD-associated cognitive impairment and the mechanism related to microglia activation. A PD mouse model was established using rotenone (ROT) and the cognitive functions of these mice were investigated by behavioral tests. The anti-inflammatory effects of TMG were tested in the BV2 microglia cells. TMG treatment significantly improved the cognitive function in the ROT-induced PD mouse model as evidenced by the Y-maze test and objective recognition test. Histological studies showed that TMG decreased the reactive microglia via increasing the total protein O-GlcNAclytion levels in the hippocampus of the PD mice. In the in vitro studies, TMG inhibited ROT-induced inflammation via decreasing the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in BV2 microglia cells. Bioinformatic analysis revealed that STING, a core protein in the innate immunity regulation, might be a novel target of O-GlcNAclytion. The immunoprecipitation experiments further confirmed that TMG inhibited STING phosphorylation via increasing O-GlcNAcylation. Taken together, TMG might ameliorate PD-associated cognitive impairment via increasing O-GlcNAcylation of STING in microglia, which provided evidence supporting that inhibiting the inflammatory response of microglia by elevating the O-GlcNAclytion levels might be an effective strategy for improving the cognitive function in PD.

01 Jun 2025·MINI-REVIEWS IN MEDICINAL CHEMISTRY

Recent Progress of Small-molecule Inhibitors of O-GlcNAcase for Alzheimer’s Disease

Article

Author: wang, Jian ; Ji, Shujie ; Cao, JinFa ; Sun, Sheng

Abstract::

O-GlcNAcylation is a non-canonical form of protein glycosylation that occurs in nuclear, cytoplasmic, and mitochondrial proteins among all multicellular eukaryotes. There are only two enzymes that regulate this post-translational modification, one of which is O-GlcNAcase, a glycoside hydrolase that catalyzes the hydrolytic cleavage of O-GlcNAc from protein substrates. Related studies have shown that the reduction of O-GlcNAc levels is closely related to Alzheimer's disease, which is maintained by reducing the aggregation of tau via inhibiting O-GlcNAcase. Various smallmolecule O-GlcNAcase inhibitors with different chemical structures have been developed and used as chemical probes to explore the O-GlcNAc pathway. Although many reported inhibitors have shown that O-GlcNAcase activity has single-digit nmol IC50 values in binding assays, and molecules, such as LY-3372689, have entered phase II clinical studies, further exploration of novel OGlcNAcase inhibitors with higher inhibitory activity and specificity is still worthy of attention. This article reviews the pathogenesis and therapeutic role of O-GlcNAcase in Alzheimer's disease, as well as the recent progress of O-GlcNAcase small molecule inhibitors, including sugar-derived or non-sugar scaffolds, and summarizes the clinical progress and potential prospects of O-GlcNAcase inhibitors.

01 Mar 2025·JOURNAL OF BIOLOGICAL CHEMISTRY

O-GlcNAc modification differentially regulates microtubule binding and pathological conformations of tau isoforms in vitro

Article

Author: Kanaan, Nicholas M ; Alhadidy, Mohammed M ; Stemmer, Paul M

Tau proteins undergo several posttranslational modifications in physiological and disease conditions. In Alzheimer's disease, O-GlcNAcylation modification of serine/threonine (S/T) residues in tau is reduced. In mouse models of tauopathy, O-GlcNAcase inhibitors lead to increased O-GlcNAcylation and decreased filamentous aggregates of tau. However, various nonfilamentous tau conformations, linked to toxicity and neurodegeneration in tauopathies, involve processes like oligomerization, misfolding, and greater exposure of the phosphatase-activating domain in the amino terminus of tau. Additionally, it is becoming clearer that posttranslational modifications may differently regulate tau pathobiology in an isoform-dependent manner. Therefore, it is crucial to investigate the effects of O-GlcNAcylation on nonfilamentous conformations of both the four-repeat (4R, e.g., hT40) and three-repeat (3R, e.g., hT39) tau isoforms. In this study, we assessed how O-GlcNAcylation impacts pathological tau conformations of the longest 4R and 3R tau isoforms (hT40 and hT39, respectively) using recombinant proteins. Mass spectrometry showed that tau is modified with O-GlcNAc at multiple S/T residues, primarily in the proline-rich domain and the C-terminal region. O-GlcNAcylation of hT40 and hT39 does not affect microtubule polymerization but has opposite effects on hT40 (increases) and hT39 (decreases) binding to preformed microtubules. Although O-GlcNAcylation interferes with forming filamentous hT40 aggregates, it does not alter the formation of pathological nonfilamentous tau conformations. On the other hand, O-GlcNAcylation increases the formation of pathological nonfilamentous hT39 conformations. These findings suggest that O-GlcNAcylation differentially modulates microtubule binding and the adoption of pathological tau conformations in the longest 4R and 3R tau isoforms.

News (Medical) associated with Ceperognastat

17 Jun 2025

·www.businesswire.com

Ferrer Receives FDA Fast Track Designation for FNP-223 in Progressive Supranuclear Palsy (PSP)

BARCELONA, Spain--(BUSINESS WIRE)--Ferrer, a B Corp-certified international pharmaceutical company, has announced that FNP-223, a novel therapy in-licensed from Asceneuron and aimed at slowing the development of progressive supranuclear palsy (PSP), has received Fast Track designation from the US Food & Drug Administration (FDA). FNP-223, a new molecular entity in active development for PSP, is in an ongoing Phase 2 study to evaluate its safety, efficacy, and pharmacokinetics in adult patients with possible or probable PSP-Richardson syndrome (PSP-RS), the most common clinical variant of this neurodegenerative disease1. We are thrilled to receive Fast Track designation from the FDA for FNP-223 in the treatment of PSP. Consistent with our purpose of using business to fight for social justice, we are committed to advancing this promising therapy to patients. “We are thrilled to receive Fast Track designation from the FDA for FNP-223 in the treatment of PSP. Consistent with our purpose of using business to fight for social justice, we are committed to advancing this promising therapy as quickly as possible to benefit as many patients as possible,” said Mario Rovirosa, Chief Executive Officer of Ferrer. Fast Track designation is a significant milestone in the drug development process. It is a program that offers the possibility of having more frequent meetings with the FDA to discuss the drug’s development, eligibility for Accelerated Approval and Priority Review if relevant criteria are met. “This designation underscores the importance of expediting the development and review of FNP-223 to address critical unmet needs in patients with this rare and devastating disease,” said Marta Parmar, Ferrer’s Chief Quality, Regulatory and Pharmacovigilance Officer. Progressive supranuclear palsy manifests in patients with symptoms such as difficulty speaking, imbalance, changes in gait, cognitive problems2-4. PSP has a prevalence of approximately 5 cases per 100,000 people and primarily affects individuals over the age of 603. The disease's etiology is believed to be related to the abnormal accumulation of tau proteins in certain areas of the brain, leading to neurodegeneration3,4. Preclinical models have demonstrated that FNP-223 can prevent the abnormal accumulation of tau proteins in neurons5. Ferrer now aims to show that this molecule is safe and effective in patients with PSP. Oscar Pérez, Chief Scientific Officer of Ferrer, also expressed his enthusiasm: "Receiving Fast Track designation is a significant milestone in our journey to provide a transformative treatment for PSP. We are excited to advance our research and hopefully offer a new therapeutic option earlier for patients living with this challenging condition." About FNP-223 FNP-223 is a new orally administered chemical compound that functions as a reversible and substrate-competitive inhibitor of the O-GlcNAcase (OGA) enzyme5. Mechanistically, FNP-223 binds to the active site of OGA enzyme. As a result, the inhibitor prevents the substrate from accessing the catalytic pocket, thereby impeding the removal of O-GlcNAc modifications from natural client proteins such as the tau protein. Inhibiting O-GlcNAcase is expected to cause a rapid increase of O-GlcNAcylated (glycosylated) tau proteins, ultimately leading to a reduction in abnormal aggregated tau as neurofibrillary tangles (NFT) over a certain period5. Bibliography: 1. ClinicalTrials.gov A Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Assess the Efficacy, Safety, and Pharmacokinetics of FNP-223 (Oral Formulation) to Slow the Disease Progression of Progressive Supranuclear Palsy (PSP) (PROSPER). ClinicalTrials.gov [Internet]. Available from: https://www.clinicaltrials.gov/study/NCT06355531. 2. Coughlin DG, Litvan I. Progressive supranuclear palsy: Advances in diagnosis and management. Parkinsonism Relat Disord. 2020 Apr;73:105-116. doi: 10.1016/j.parkreldis.2020.04.014. Epub 2020 May 25. 3. Agarwal S, Gilbert R. Progressive Supranuclear Palsy. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. Available from: https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/books/NBK526098/. 4. Rowe JB, Holland N, Rittman T. Progressive supranuclear palsy: diagnosis and management. Pract Neurol. 2021;21(5):376-383. doi: 10.1136/practneurol-2020-002794. 5. Permanne B, Sand A, Ousson S, Nény M, Hantson J, Schubert R, et al. D. O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies. ACS Chem Neurosci. 2022 Apr 20;13(8):1296-1314. doi: 10.1021/acschemneuro.2c00057.

Phase 2Fast Track

05 Mar 2025

·www.pharmaceutical-technology.com

Asceneuron halts Alzheimer’s trial adding to tau-targeting setbacks

A build-up of the abnormal tau can contribute to Alzheimer’s disease symptoms. Credit: Andrew Brookes via Getty Images. After Eli Lilly and Biogen’s setbacks in developing O-GlaNAcase (OGA) inhibitors for Alzheimer’s disease, Asceneuron has now halted its own Phase II trial of ASN51, its experimental oral OGA inhibitor. The company disclosed the decision in an update to the federal clinical trials database ClinicalTrials.gov , describing it as “strategic” without providing further details. The trial, which kicked off in October 2024, was expected to run for two years. The study (NCT06677203) was set to evaluate two doses of ASN51 against a placebo in 123 patients with early Alzheimer’s, focusing on safety, tolerability, suicide severity assessment through the Columbia-Suicide Severity Rating Scale (C-SSRS), and tau protein levels in cerebrospinal fluid. Asceneuron had previously said that ASN51 could be a disease-modifying therapy, with applications beyond Alzheimer’s in diseases such as Parkinson’s and amyotrophic lateral sclerosis (ALS). The decision to move ASN51 into this Phase II study was supported by a $100m Series C funding round announced in July 2024. The financing was led by Novo Holdings, the controlling shareholder of Novo Nordisk. Novo Holdings’ senior partner for venture investments Naveed Siddiqi described ASN51 as offering “the potential paradigm shift” in Alzheimer’s treatment at the time of the funding round. Asceneuron had already demonstrated in multiple Phase I studies that ASN51 reaches the nervous system and impacts the OGA enzyme. OGA inhibitors have been explored as a potential new class of disease-modifying treatments for Alzheimer’s and other neurodegenerative diseases due to their ability to target tau protein accumulation. Unlike amyloid-targeting therapies – such as Eisai and Biogen’s Leqembi (lecanemab) – that have dominated Alzheimer’s drug development, OGA inhibitors aim to slow disease progression by preventing the buildup of toxic tau aggregates in the brain. This termination follows setbacks for other OGA inhibitors in development. In August 2024, Eli Lilly disclosed that its OGA inhibitor, LY3372689, failed to meet the primary endpoint in a Phase II trial (NCT05063539) for early symptomatic Alzheimer’s. The study did not show a statistically significant benefit in slowing disease progression as measured by the integrated Alzheimer’s Disease Rating Scale (iADRS). Lilly also previously abandoned its antibody-based tau inhibitor zagotenemab in 2021 while Roche discontinued the development of semorinemab in January 2024. Last month, Biogen discontinued an early-stage OGA inhibitor programme, BIIB113. Beyond ASN51, Asceneuron has another OGA inhibitor, ASN90, which it licensed to Ferrer in February 2023. ASN90 is currently in a Phase II trial (NCT06355531) for progressive supranuclear palsy, a rare tau-related neurodegenerative disorder.

Phase 2Phase 1Clinical Result

08 Aug 2024

·www.fiercebiotech.com

Still feting donanemab approval, Lilly faces phase 2 failure of tau-targeting med

None The confetti is still flying from Eli Lilly’s party celebrating the approval of Alzheimer’s disease therapy donanemab, but the company is yet again facing the harsh reality of the neurodegenerative disease with the failure of an early tau-targeting med.Lilly Chief Scientific Officer and President, Lilly Research Laboratories Daniel Skovronsky, M.D., Ph.D., said the O-GlcNAcase Inhibitor called LY3372689 failed on the primary endpoint of a phase 2 clinical trial recently. The therapy, which targets the OGA enzyme, did not spur a change in baseline to endpoint time in a rating scale of Alzheimer’s severity in either dose tested.“While this negative outcome was disappointing, we remain committed to tap as a high conviction target in Alzheimer's disease and plan to continue studying tau biology,” Skovronsky said, speaking on a second-quarter earnings call Thursday. The executive said the company is currently reviewing the data for presentation at an upcoming medical conference.LY3372689 was a key part of Lilly’s next wave of Alzheimer’s efforts. After getting donanemab approved in July, to be marketed as Kisunla, the company was hoping that tau would be the next front in the fight against the memory-robbing disease. Behind Kisunla, Lilly has remternetug in phase 3 development, which targets amyloid plaques in the brain. Positive allosteric modulator mevidalen is in phase 2 testing. The company also has two undisclosed neurodegeneration medicines in phase 1.Lilly also trimmed around the edges of other programs after getting some early data on a few candidates.They include LOXO-783, a highly mutant-selective, brain-penetrant, allosteric small molecule PI3Kα H1047R inhibitor that was acquired as part of the acquisition of Loxo Oncology. The drug was being investigated in a phase 1 study in patients with PIK3CA H1047R-mutant advanced breast cancer and other solid tumors.Lilly had taken LOXO-783 into the clinic on the basis of preclinical data showing activity without on-target wild-type PI3Kα mediated toxicity.“We evaluated the ongoing clinical data for the program and compared the molecule to next-generation candidates that we have progressed from our discovery efforts,” Skovronsky said on the call. “We believe our next molecules have greater potential benefits to patients.”Also on the discard pile is an unnamed NRG4 agonist. Neuregulin 4 acts locally on brown and white adipose tissue and works to protect against obesity-related inflammatory and hypoxic events. The Big Pharma had halted work on the asset as “the profile is insufficient for further clinical development,” Skovronsky explained. A GITR antagonist has also been removed from the phase 1 immunology pipeline “due to insufficient efficacy,” Skovronsky said. At the time of publication, Lilly had not confirmed to Fierce whether this was LY3461767, a GITR antagonist that was being evaluated in a phase 1 trial of the drug in patients with chronic heart failure with reduced ejection fraction.Acadamic researchers have named glucocorticoid-induced tumor necrosis factor receptor (GITR), a co-stimulatory immune checkpoint protein, as playing a pivotal in cardiovascular disease. It’s also been suggested as a potential target to enhance immunotherapy, in particular immune checkpoint inhibitors.

Phase 1Phase 2Drug ApprovalImmunotherapy

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	United States	Eli Lilly & Co.	16 Sep 2021
Alzheimer Disease	Phase 2	Japan	Eli Lilly & Co.	16 Sep 2021
Alzheimer Disease	Phase 2	Australia	Eli Lilly & Co.	16 Sep 2021
Alzheimer Disease	Phase 2	Canada	Eli Lilly & Co.	16 Sep 2021
Alzheimer Disease	Phase 2	Poland	Eli Lilly & Co.	16 Sep 2021

Clinical Result

Indication

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05063539 (CTgov)	Phase 2	Alzheimer Disease	327	LY3372689 (3 mg LY3372689)	hrbpkivljn(lzdndrwcwy) = cauuwvivib kwskotedjo (itrmvshgyt, cuksusxyzd - mugxugrzur) View more	-	28 Jul 2025
NCT05063539 (CTgov)	Phase 2	Alzheimer Disease	327	Placebo (Placebo)	hrbpkivljn(lzdndrwcwy) = qfuvhdlafu kwskotedjo (itrmvshgyt, mybfzcnghk - pladdohvgb) View more	-	28 Jul 2025
NCT03819270 \| NCT04106206 (AAIC2021)	Phase 1	-	-	LY3372689	ahofvxmxgn(umbqypqydx) = LY3372689 was generally well tolerated up to the highest dose in each study, and no serious AE were reported. In the SAD, 40 treatment-emergent AEs (TEAEs) were reported, which were mostly mild in severity. The most common TEAEs were headache, nausea, pain in extremity, pain of skin, vessel puncture site pain, and limb discomfort. In the MAD, 42 TEAEs were reported, all of which were mild in severity. The most reported TEAE was headache. In both studies, there were no clinically significant changes in safety laboratories, including markers of inflammation, muscle injury, hormones and hepatoxicity. qmtmalengq (bxodcpkehv )	-	31 Dec 2021
NCT03819270 (Literature \| AAIC2020) Manual	Phase 1	-	23	LY3372689	vugyaidxiv(pjvxbuirhk) = jdhwudvknk uahcbumgkz (pkprxlesyn )	Positive	07 Dec 2020

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