Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease

Abstract

Introduction: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.

Methods: A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.

Results: Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.

Discussion: Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.

Highlights: Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.Ceperognastat is both orally available and CNS-penetrant even when given at low doses.Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain.Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.

Keywords: Alzheimer's disease; O‐GlcNAcase inhibition; O‐GlcNAcylation; enzyme occupancy; pharmacokinetics; tau.

FIGURE 1

Relationship between ceperognastat plasma concentration and enzyme occupancy in Sprague‐Dawley rats following a single oral dose of ceperognastat (A) and in P301S mice after 10‐day administration of ceperognastat (B). OGA, O‐GlcNAcase.

FIGURE 2

Relationship of frontal cortex O‐GlcNAc with enzyme occupancy (A) and with tau O‐GlcNAc (B) and for OGA inhibitors. Dashed line in (A) denotes 80% enzyme occupancy and in (B) denotes a linear regression fit. OGA,O‐GlcNAcase; O‐GlcNAc, O‐GlcNAc modification.

FIGURE 3

(A) Arithmetic mean plasma concentration—time profiles following a single dose of ceperognastat from the SAD study (N = 5‐8 per dose group). (B) PET‐based voxel‐wise maps of the distribution volume (VT); Panel A (SD‐PET study): single dose of 1 mg with PET images at baseline, 2‐h, and 24‐h post‐dose. Panel B (MD‐PET study): PET images at baseline and 24 h after the 1st and 14th administration of 1 mg ceperognastat. N = 4 per dose regimen. (C) Relationship between enzyme occupancy and ceperognastat plasma concentration from SD‐PET and MD‐PET studies. Solid line is the median model response. Circles correspond to individual participant values from the SD‐PET (black) and MD‐PET study (white). MD, multiple dose; OGA, O‐linked N‐acetyl glucosaminidase; P, participant; PET, positron emission tomography; SAD, single ascending dose; SD, Sprague Dawley.