Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 1)
Company: Asceneuron SA
ASN120290 is an inhibitor of O-GlcNAcase, the glycoside hydrolase enzyme that removes O-linked N-acetylglucosamine (N-GlcNAc) from proteins. The function of numerous proteins is regulated by O-linked glycosylation of serine and threonine residues, which is reversed by O-GlcNAcase.
N-GlcNAcylation of the microtubule-associated protein tau reduces its propensity to form toxic aggregates (Gong et al., 2005; Liu et al., 2004). A similar anti-aggregation effect of O-GlcNAc modification was recently reported for α-synuclein protein (Levine et al., 2019).
By increasing tau glycosylation, inhibitors of the O-GlcNAcase enzyme appear to stabilize tau in a soluble, nonpathogenic form. ASN120290 is being developed as a potential treatment for progressive supranuclear palsy and other tau-related dementias.
In two different mouse strains expressing P301L mutant human tau, the OGA inhibitor thiamet G was reported to increase N-GlcNAc-modified tau, reduce tau neurofibrillary tangle numbers, and decreased neuronal cell loss (Yuzwa et al., 2012; Graham et al., 2014; Hastings et al., 2017). One lab found that thiamet G treatment of a third mutant tau strain resulted in better motor skills, higher body weight, and longer lifespan (Borghgraef et al., 2013).
No preclinical results have been formally published with ASN120290, previously known as ASN-561. Animal data presented at meetings indicated it penetrates the blood-brain barrier better than thiamet G. In P301L human tau mice, the compound reportedly evokes a 12-fold increase in brain tau O-GlcNAcylation, a 40 percent reduction in insoluble paired helical filaments, and 80 percent fewer neurofibrillary tangles (Aug 2014 conference news; Apr 2017 conference news).
In 2017, Asceneuron conducted a randomized, placebo-controlled Phase I safety and tolerability study of oral ASN120290 in healthy adult and aged volunteers. As presented July 2018 at AAIC, it enrolled 61 subjects, who received single ascending doses, or multiple doses for up to 10 days. The drug was reported to be have been well tolerated at single doses of up to 1,000 mg, or 500 mg twice a day. No dose-limiting toxicities, severe adverse events, or dropouts due to adverse events were reported. Plasma pharmacokinetics were dose-proportional and affected by food. In aged participants, ASN120290 rapidly appeared in the cerebrospinal fluid after dosing, at concentrations similar to those in plasma (see abstract). Data were not published in a peer-reviewed journal.
In July 2018, ASN120290 received orphan drug designation by the U.S. FDA for treatment of the primary tauopathy, progressive supranuclear palsy.
In November 2018, the company announced a trial using PET imaging with labeled ASN120290. This study will assess target engagement by quantifying binding of a radioactive ASN120290 tracer in the brains of healthy volunteers, both alone and after pre-administration of the inhibitor (see press release). According to results presented at the July 2021 AAIC, the tracer displayed high binding throughout the human brain and was fully displaced by a single, oral dose of 500 or 300 mg ASN120290.
Asceneuron is also developing a second generation OGA inhibitor. ASN51 is claimed to be a longer-acting form of ASN120290, suitable for once-a-day dosing. It is in Phase 1 testing for Alzheimer’s and Parkinson’s disease.
Last Updated: 11 Aug 2021
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