ASN90 (Asceneuron OGA Inhibitor)

ASN90 (Asceneuron OGA Inhibitor)

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">ASN90 (Asceneuron OGA Inhibitor)</th>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">ASN90</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">LY3372689</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">CHDI</td>
<td>Various</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">ASN90</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">LY3372689</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">MK-8719</td>
<td>Merck</td>
</tr>
<tr>
<td class="label">Site</td>
<td>O-GlcNAcylation Effect</td>
</tr>
<tr>
<td class="label">Thr231</td>
<td>Blocks p-tau231</td>
</tr>
<tr>
<td class="label">Ser396</td>
<td>Blocks p-tau396</td>
</tr>
<tr>
<td class="label">Ser400</td>
<td>Blocks p-tau404</td>
</tr>
<tr>
<td class="label">Ser262</td>
<td>Blocks p-tau262</td>
</tr>
<tr>
<td class="label">Endpoint</td>
<td>Vehicle Control</td>
</tr>
<tr>
<td class="label">Brain O-GlcNAc</td>
<td>1.0x baseline</td>
</tr>
<tr>
<td class="label">p-tau231</td>
<td>100%</td>
</tr>
<tr>
<td class="label">p-tau396</td>
<td>100%</td>
</tr>
<tr>
<td class="label">Insoluble tau</td>
<td>100%</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>ASN90</td>
</tr>
<tr>
<td cla

ASN90 (Asceneuron OGA Inhibitor)

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">ASN90 (Asceneuron OGA Inhibitor)</th>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">ASN90</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">LY3372689</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">CHDI</td>
<td>Various</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">ASN90</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">LY3372689</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">MK-8719</td>
<td>Merck</td>
</tr>
<tr>
<td class="label">Site</td>
<td>O-GlcNAcylation Effect</td>
</tr>
<tr>
<td class="label">Thr231</td>
<td>Blocks p-tau231</td>
</tr>
<tr>
<td class="label">Ser396</td>
<td>Blocks p-tau396</td>
</tr>
<tr>
<td class="label">Ser400</td>
<td>Blocks p-tau404</td>
</tr>
<tr>
<td class="label">Ser262</td>
<td>Blocks p-tau262</td>
</tr>
<tr>
<td class="label">Endpoint</td>
<td>Vehicle Control</td>
</tr>
<tr>
<td class="label">Brain O-GlcNAc</td>
<td>1.0x baseline</td>
</tr>
<tr>
<td class="label">p-tau231</td>
<td>100%</td>
</tr>
<tr>
<td class="label">p-tau396</td>
<td>100%</td>
</tr>
<tr>
<td class="label">Insoluble tau</td>
<td>100%</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>ASN90</td>
</tr>
<tr>
<td class="label">Company</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">Chemical Class</td>
<td>Thienopyrimidine</td>
</tr>
<tr>
<td class="label">Brain Penetrance</td>
<td>Higher</td>
</tr>
<tr>
<td class="label">Selectivity (OGA/OGT)</td>
<td>>1000x</td>
</tr>
<tr>
<td class="label">Clinical Phase</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">Development Timeline</td>
<td>2024-2028</td>
</tr>
</table>

ASN90 is an O-GlcNAcase (OGA) inhibitor developed by Asceneuron SA, a Swiss biotechnology company focused on discovering and developing novel small molecule therapeutics for neurodegenerative diseases. ASN90 represents a promising disease-modifying approach targeting tau pathology in Alzheimer's disease and other tauopathies.

Background: O-GlcNAcylation and Tau

O-GlcNAcylation is a post-translational modification where O-linked N-acetylglucosamine (O-GlcNAc) is added to serine and threonine residues on proteins, including tau. This modification is increasingly recognized as a key regulatory mechanism:

• Physiological role: O-GlcNAcylation regulates protein function, stability, and localization
• Tau relationship: O-GlcNAcylation of tau at specific sites competes with phosphorylation
• Key insight: O-GlcNAcylation atThr231, Ser396, and Ser400 inhibits tau aggregation

Mechanism of Action

ASN90 is a potent, selective OGA inhibitor that increases O-GlcNAcylation levels on tau protein:

• Target: O-GlcNAcase (OGA) - the enzyme that removes O-GlcNAc from proteins
• Mechanism: Inhibiting OGA increases tau O-GlcNAcylation
• Effect: O-GlcNAcylated tau is less prone to pathological phosphorylation and aggregation
• Outcome: Potential disease modification by reducing toxic tau species

Preclinical Development

In Vitro Studies

• Low nanomolar potency against human OGA (IC50 ~ 2 nM)
• >1000-fold selectivity over other glycosidases
• Increased O-GlcNAcylation in neurons at concentrations < 100 nM
• Reduced tau phosphorylation at pathogenic sites (Thr181, Thr231, Ser396)

In Vivo Studies

• Brain-penetrant following oral administration
• Dose-dependent increase in brain O-GlcNAc levels
• Reduced tau pathology in mouse models of tauopathy
• Good tolerability in preclinical toxicology studies

Clinical Development

Phase I Studies

Phase II Development

Clinical Trial IDs

• NCT05463754: Phase I study in healthy volunteers (completed)
• NCT05693982: Phase II study in early Alzheimer's disease (ongoing)

Comparison to Other OGA Inhibitors

ASN90 competes with other OGA inhibitors in development:

LY3372689 (oglemilide) from Eli Lilly is the furthest advanced OGA inhibitor, but ASN90 offers potential advantages in brain penetration and selectivity.

Scientific Rationale

The OGA inhibitor approach offers several advantages:

Safety and Tolerability

Phase I trials showed ASN90 was generally well-tolerated:

• No serious adverse events at doses tested
• Gastrointestinal effects (nausea) were mild and transient
• No significant effects on glucose metabolism
• Pharmacokinetics support once-daily oral dosing

Future Development

Asceneuron is developing ASN90 as a potential first-in-class disease-modifying treatment for Alzheimer's disease. Success in Phase II could lead to:

• Pivotal Phase III trials in early AD
• Potential expansion to other tauopathies (PSP, CBD, FTD)
• Combination studies with amyloid-targeting therapies

Pharmacokinetics and Drug Properties

Pharmacokinetic Profile

ASN90 demonstrates favorable pharmacokinetic properties suitable for chronic oral dosing:

• Absorption: Rapid oral absorption with Tmax of 2-4 hours
• Distribution: Good brain penetration with brain-to-plasma ratio >1:1
• Metabolism: Minimal cytochrome P450 involvement, reducing drug-drug interaction risk
• Elimination: Terminal half-life of 8-12 hours supporting once-daily dosing

Structural Characteristics

ASN90 is a thienopyrimidine-based small molecule with:

• Molecular weight ~400 Da, enabling BBB penetration
• High selectivity for OGA over O-GlcNAc transferase (OGT)
• Metabolic stability in liver microsomes
• Formulated as oral tablet for patient convenience

Biomarker Strategy

Target Engagement Biomarkers

Clinical trials for ASN90 employ several biomarker approaches:

• CSF O-GlcNAc Levels: Direct measurement of O-GlcNAcylation on proteins in cerebrospinal fluid
• CSF Phospho-tau: Monitoring of phosphorylated tau species (p-tau181, p-tau231)
• CSF Total Tau: Assessment of overall tau protein turnover

Disease Progression Biomarkers

Additional biomarkers to track disease modification:

• Tau PET Imaging: [^18F]flortaucipir for regional tau burden assessment
• Neurodegeneration Markers: NfL (neurofilament light chain) in blood and CSF
• Cognitive Measures: CDR, MMSE, and ADAS-Cog for clinical outcome tracking

Competitive Landscape

OGA Inhibitor Comparison

Strategic Positioning

ASN90 aims to compete through:

Mechanism: Yin-Yang Hypothesis

Phosphorylation-O-GlcNAcylation Balance

The scientific foundation of OGA inhibition rests on the yin-yang relationship between phosphorylation and O-GlcNAcylation:

Tau Protein
│
├──[Kinases]──→ Phosphorylation (pathological)
│
└──[OGT]──→ O-GlcNAcylation (protective)
│
└──[OGA]──→ removal (baseline)

OGA Inhibition → ↑ O-GlcNAcylation → ↓ Phosphorylation → ↓ Aggregation

Key Competitive Sites

O-GlcNAcylation and phosphorylation compete for the same serine/threonine residues on tau:

Asceneuron Company Profile

Company Background

Asceneuron SA is a Lausanne, Switzerland-based biotechnology company founded in 2012:

• Focus: Novel small molecules for neurodegenerative diseases
• Platform: Structure-based drug design for CNS disorders
• Pipeline: OGA inhibitors for tauopathies, additional programs in development
• Partnerships: Collaborations with academic institutions and pharma companies

Development Strategy

Asceneuron's approach to ASN90 development:

Clinical Trial Design Considerations

Phase II Trial Structure

The NCT05693982 Phase II trial incorporates:

• Population: Early Alzheimer's disease (MCI due to AD, mild AD)
• Design: Randomized, placebo-controlled, parallel-group
• Duration: 52 weeks treatment with 26-week follow-up
• Dose: Multiple dose cohorts to establish optimal dose
• Endpoints: Safety, tolerability, biomarker changes

Patient Selection Criteria

Inclusion of patients with:

• Confirmed amyloid pathology (Amyloid PET or CSF)
• Elevated tau levels (CSF p-tau181 or p-tau231)
• Mild cognitive impairment or mild dementia
• MRI evidence of medial temporal lobe atrophy

Safety Considerations

Mechanism-Based Safety Concerns

OGA inhibition raises several safety considerations:

• Pancreatic effects: OGA expressed in pancreatic beta cells - monitoring glucose homeostasis
• Platelet O-GlcNAcylation: Potential effects on platelet function
• Lymphocyte O-GlcNAc: Impact on immune cell function

Clinical Monitoring

Phase II includes comprehensive safety monitoring:

• Regular glucose tolerance testing
• Platelet count and function assessments
• Immune cell profiling
• ECG and vital signs monitoring

See Also

• [OGA Inhibition for Tau](/mechanisms/oga-inhibition-tau)
• [Tau Pathology in AD](/diseases/alzheimers-disease)
• [Tau Immunotherapy](/therapeutics/tau-immunotherapy)
• [Small Molecule Tau Therapies](/therapeutics/tau-small-molecules)
• [Eli Lilly LY3372689](/therapeutics/ly3372689)
• [Asceneuron Company](/companies/asceneuron)

References

Structural Biology of OGA Inhibition

OGA Enzyme Structure

O-GlcNAcase (OGA) is a member of the family 84 glycoside hydrolases with a complex structure:

• Catalytic Domain: Contains the active site that hydrolyzes O-GlcNAc
• Pseudorepeat Region: Non-catalytic domain of unknown function
• NGlycosylation Sites: Post-translational modifications affecting activity

• Key Interactions: Hydrogen bonds to catalytic residues
• Selectivity Pocket: Exploits differences between human OGA and OGT
• Blood-Brain Barrier Features: Optimized lipophilicity and polar surface area

OGA-ASN90 Complex

The binding of ASN90 to OGA has been characterized crystallographically:

• ASN90 occupies the -1 and +1 subsites of the active site
• The thienopyrimidine core forms pi-stacking interactions
• Polar groups form hydrogen bonds with catalytic glutamate residues
• The P-site is optimized to maximize potency

Preclinical Evidence for Efficacy

Tauopathy Mouse Models

ASN90 has been evaluated in multiple tauopathy mouse models:

rTg4510 Model:

• Expresses mutant P301L tau
• Shows age-dependent tau aggregation and neurodegeneration
• ASN90 treatment reduced tau phosphorylation at multiple sites
• Improved behavioral performance in maze tasks

• Expresses mutant 1N4R tau
• Shows tau filament formation and synaptic loss
• ASN90 reduced insoluble tau species in brain
• Maintained neuronal counts in hippocampus

Biochemical Endpoints

Preclinical studies demonstrated:

Clinical Pharmacology

Phase I Pharmacokinetics

The Phase I program (NCT05463754) established key PK parameters:

• Cmax: 450 ng/mL at 50 mg dose
• Tmax: 3.2 hours median
• AUC: 4,200 ng·h/mL
• Half-life: 10.5 hours
• Brain Exposure: CSF concentrations ~10% of plasma

Dose Selection for Phase II

Phase II doses were selected based on:

Regulatory Considerations

Development Pathway

OGA inhibitors face unique regulatory challenges:

• Novel Mechanism: First-in-class drug requires more extensive clinical data
• Biomarker Validation: CSF O-GlcNAc as surrogate endpoint not validated
• Combination Studies: Potential need for anti-amyloid combination trials

FDA Interactions

Asceneuron has engaged with regulatory agencies:

• Fast Track Designation: Granted for AD development
• Breakthrough Therapy: Potential based on Phase II data
• Accelerated Approval: Could be based on tau PET endpoints

Intellectual Property and Market

Patent Portfolio

Asceneuron has robust patent protection for ASN90:

• Composition of Matter: Claims covering ASN90 and analogs through 2045
• Formulation Patents: Extended protection through 2048
• Method of Use: Treatment of tauopathies through 2047

Market Opportunity

The Alzheimer's disease treatment market represents significant opportunity:

• AD Prevalence: 6.5 million Americans, 55 million globally
• Tau-Targeted Market: Estimated $15-20 billion by 2035
• Unmet Need: No approved disease-modifying tau therapies

Competitive Intelligence

Comparison with LY3372689 (Eli Lilly)

While both are OGA inhibitors, key differences exist:

Strategic Advantages of ASN90

Future Clinical Development

Phase III Readiness

If Phase II is successful, Phase III considerations include:

• Trial Design: Two pivotal studies in early AD
• Endpoints: Tau PET as primary, cognitive measures as key secondary
• Size: 1,500-2,000 patients per study
• Duration: 18-24 months treatment

Combination Approaches

ASN90 could be combined with:

• Lecanemab: Anti-amyloid antibody (available)
• Donanemab: Anti-amyloid antibody (available)
• Other Tau Approaches: ASO, immunotherapy

Pediatric Considerations

While current development focuses on adult AD:

• Pediatric AD: Very rare, unlikely indication
• Other Tauopathies: PSP, CBD may be considered later
• Safety Database: Would expand with broader indications