A single ascending dose study in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of O‐GlcNAcase (OGA) enzyme

Abstract

Background LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein we report the first clinical study that assessed safety and pharmacokinetics (PK) of LY3372689 after single oral doses in healthy volunteers (HV). Method The phase 1 clinical trial (NCT03819270) was a single ascending dose, randomized, crossover, placebo controlled, investigator‐ and subject‐blind study. Each HV received up to 3 escalating single doses of LY3372689 or placebo over 3 study periods with an approximately 7‐day follow‐up period after each dose, such that a total of 6 LY3372689 dose levels were evaluated. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma PK was assessed up to 48 hours after LY3372689 administration. Result A total of 23 HV (15 males, 8 females; 22 – 63 years) participated in the study, of which 18 completed and 5 did not complete due to loss to follow up procedures or did not meet randomization criteria. LY3372689 was generally well tolerated up to the maximum dose administered. There were no serious AE reported and no subjects discontinued the study because of an AE. A total of 13 treatment‐emergent AE reported by 5 subjects considered as possibly related to study treatment were mostly mild in severity, and included pain of skin, headache, limb discomfort, pain in extremity, chest discomfort, muscle fatigue, nausea, and rash macular. The PK of LY3372689 supported daily dosing and was generally dose proportional based on AUC and Cmax. Conclusion 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.

Chemical Biology Approaches to Understanding Neuronal O−GlcNAcylation

“…In addition to their power to elucidate normal neurobiological processes, chemical methods show great promise in manipulating O−GlcNAc for future clinical benefit in nervous system injuries and pathologies. Recent studies have employed these tools to probe therapeutic potential in numerous disease models and human clinical trials [18,146–151] . In particular, there has been significant progress in the pharmacological targeting of O−GlcNAcylation on tau [88,89,38,90,91,63,92,93] and α‐synuclein [123–126] for AD, PD and related disorders.…”

“…These results led to Phase I human trials, which showed low toxicity in healthy volunteers [149] . Second, LY3372689 (Eli Lilly) has been tested as a potential treatment for AD and other tauopathies, with promising safety and pharmacokinetic parameters after single and multiple oral doses in healthy volunteers [146,147, 150] . Third, ASN90 (Asceneuron S.A.) potently inhibits rodent and human OGA, crosses the blood‐brain barrier, and exhibits favorable drug‐like properties for the central nervous system [39] .…”

A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies

“…The pharmacokinetics were deemed supportive of once-a-day dosing. 192 Two other Phase 1 studies were carried out to measure LY3372689 binding in the brain through displacement of the OGA-specific PET ligand 18 F-LSN3316612. 193 The primary outcome of the studies was the percent of OGA occupancy before and after dosing.…”

“…The drug appeared to be well tolerated at all doses, without serious adverse events or discontinuations due to adverse events. The pharmacokinetics were deemed supportive of once‐a‐day dosing 192 . Two other Phase 1 studies were carried out to measure LY3372689 binding in the brain through displacement of the OGA‐specific PET ligand 18 F‐LSN3316612 193 .…”

O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations

“…For example, multiple reports showed that elevating O−GlcNAcylation via treatment with the small molecule OGA inhibitor Thiamet-G 69 reduced proteotoxicity, cognitive deficits, and behavioral dysfunction in AD rodent models 70,71 . Based on these and other promising pre-clinical data 68,72 , at least three OGA inhibitors (MK-8719, LY3372689, ASN90) have entered human clinical trials 73-75 , paving the way for future pharmacological modulation of O-GlcNAc on substrates, such as NF proteins, in human patients. However, despite its potential clinical significance, the functional impact of O-GlcNAcylation on human NF proteins has never been studied systematically.…”