Background

ASN51 is a small-molecule inhibitor of O-GlycNAcase (OGA), the glycoside hydrolase enzyme that removes O-linked N-acetylglucosamine (N-GlcNAc) from proteins. Asceneuron is developing ASN51 as a potential treatment for Alzheimer’s and Parkinson’s diseases. It is a second-generation version of its lead OGH inhibitor, ASN120290, which is intended to treat the rare tauopathy progressive supranuclear palsy. ASN51 is taken in capsule form.

The rationale for targeting OGA originated in the observation that addition of N-GlcNAc to tau reduces its propensity to form toxic aggregates (Gong et al., 2005; Liu et al., 2004). OGA inhibitors promote glycosylation, prevent aggregation, and appear to stabilize tau in a soluble, nonpathogenic form. O-GlcNAc modification was reported to reduce the aggregation and toxicity of the α-synuclein protein as well (Marotta et al., 2015; Levine et al., 2019). This modification appears to promote formation of an α-synuclein fibril strain that does not propagate and is not neurotoxic in vivo (Balana et al., 2024).Thus, OGA inhibitors could potentially slow or prevent the progression of neurodegeneration due to these proteins.

No preclinical work is published on ASN51. However, Asceneuron has published data on ASN90, their first-generation OGA inhibitor in development for the primary tauopathy progressive supranuclear palsy. In the P301S mouse model of tauopathy, daily oral dosing enhanced brain tau glycosylation, prevented the development of tau tangles, improved motor behavior and breathing, and increased survival (Permanne et al., 2022). In this study, tau glycosylation in peripheral blood cells mirrored modification in the CNS, and thus was suggested as a potential pharmacodynamic marker of OGA inhibition for clinical trials. Also in this work, ASN90 was shown to enhance α-synuclein glycosylation, and slow the progression of motor impairment in a transgenic model of Parkinson’s disease.

A different OGA inhibitor, thiamet G, has also been reported to increase glycosylated tau, reduce tau neurofibrillary tangle numbers, and decrease neuronal cell loss in three different mouse strains expressing P301L mutant human tau (Yuzwa et al., 2012; Graham et al., 2014; Hastings et al., 2017). One lab found that thiamet G treatment resulted in better motor skills, higher body weight, and longer lifespan (Borghgraef et al., 2013). Thiamet G or OGA knockdown was also shown to reduce the uptake of synuclein fibrils by cells (Tavassoly et al., 2020). Fibril uptake is a proposed mechanism for the spread of α-synuclein pathology in the brain.

Findings

In June 2021, Asceneuron began a Phase 1 first-in-human trial in Melbourne, Australia, investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASN51. The placebo-controlled study planned to test single and multiple doses of oral capsules in 64 healthy adults, followed by a 10-day evaluation in 12 people with AD. This study was terminated in August 2022 after completion of the single-dosing portion, and one multiple-dose cohort. The stated reasons were site delays and the impact of COVID.

The company presented results from healthy adults at the December 2022 CTAD conference. Single doses of 20 and 50 mg in young adults and multiple 20 mg doses in eight older adults were safe, with no serious or severe adverse events. The most common side effects were headache and musculoskeletal ache. One person had moderate, transient dizziness. ASN51 produced predictable, dose-proportional plasma PK with a half-life of 40-50 hours, that was unaffected by food or age. CSF concentrations were in the active range, and highly correlated with plasma levels, suggesting the drug freely diffused into the CNS. A pharmacodynamic assay found tau glycosylation to increase in peripheral blood cells after a single 20 or 50 mg dose.

A PET study with an OGA ligand revealed significant target occupancy for up to two days after a single dose of 5 mg or higher. Based on PET results, the investigators estimated that a 10 mg dose would sustain greater than 95 percent brain OGA occupancy for 24 hours.

From February to June of 2023, the company conducted a pharmacokinetic and pharmacodynamic study after repeated dosing in 12 healthy men. According to a presentation at the October 2023 CTAD, 14 days treatment with 10 or 20 mg daily produced no serious adverse events or safety signs, and no study withdrawals. Plasma levels were dose-proportional, reached steady-state by one week, and were maintained for up to a week after dosing stopped. PET revealed greater than 90 percent brain OGA occupancy within hours after the first dose, and three days after the last dose. Two weeks of drug elevated tau glycosylation in peripheral blood cells. Food did not affect this pharmacodynamic marker.

The company is planning a Phase 2 study, to start in 2024.

In February 2025, a study began to assess drug-drug interactions with inhibitors of three cytochrome p450 isotypes. The study will test, in 48 healthy adults, the effect of simultaneous dosing with fluvoxamine, itraconazole, or paroxetine on the pharmacokinetics of ASN51. It will finish in May 2024.

For details on ASN51 trials, see clinicaltrials.gov.