LY-3372689 LOTUS Trial - Phase 2 in Progressive Supranuclear Palsy

LY-3372689 LOTUS Trial (NCT05682807)

Overview

The LOTUS trial is a Phase 2 clinical study evaluating LY-3372689 (zaniglusemab), an oral O-GlcNAcase (OGA) inhibitor developed by Eli Lilly, in patients with progressive supranuclear palsy (PSP). This is the first OGA inhibitor trial beyond PROSPER to evaluate this mechanism in a pure 4R-tauopathy[@lotus].

LOTUS provides an important competitive benchmark for FNP-223/PROSPER and tests whether OGA inhibition can show clearer benefit in PSP (a pure tauopathy without amyloid comorbidity) compared to AD where MAGNOLIA did not meet its cognitive endpoint. The trial represents a critical test of the hypothesis that pure tauopathies may respond better to tau-directed therapies than Alzheimer's disease where amyloid co-pathology complicates interpretation[@yuzwa2016].

Trial Details

| Parameter | Value |
|-----------|-------|
| Trial ID | NCT05682807 |
| Phase | Phase 2 |
| Status | Active, not recruiting |
| Drug | LY-3372689 (zaniglusemab) |
| Company | Eli Lilly |
| Indication | Progressive Supranuclear Palsy (PSP) |
| Enrollment | ~100 patients |
| Duration | 52 weeks treatment |
| Primary Endpoint | PSPRS change from baseline |
| Secondary Endpoints | Safety, CSF biomarkers, cognitive measures |
| Start Date | 2023 |
| Completion | Q4 2026 |

Background

Tau Biology and O-GlcNAcylation

LY-3372689 LOTUS Trial (NCT05682807)

Overview

The LOTUS trial is a Phase 2 clinical study evaluating LY-3372689 (zaniglusemab), an oral O-GlcNAcase (OGA) inhibitor developed by Eli Lilly, in patients with progressive supranuclear palsy (PSP). This is the first OGA inhibitor trial beyond PROSPER to evaluate this mechanism in a pure 4R-tauopathy[@lotus].

LOTUS provides an important competitive benchmark for FNP-223/PROSPER and tests whether OGA inhibition can show clearer benefit in PSP (a pure tauopathy without amyloid comorbidity) compared to AD where MAGNOLIA did not meet its cognitive endpoint. The trial represents a critical test of the hypothesis that pure tauopathies may respond better to tau-directed therapies than Alzheimer's disease where amyloid co-pathology complicates interpretation[@yuzwa2016].

Trial Details

| Parameter | Value |
|-----------|-------|
| Trial ID | NCT05682807 |
| Phase | Phase 2 |
| Status | Active, not recruiting |
| Drug | LY-3372689 (zaniglusemab) |
| Company | Eli Lilly |
| Indication | Progressive Supranuclear Palsy (PSP) |
| Enrollment | ~100 patients |
| Duration | 52 weeks treatment |
| Primary Endpoint | PSPRS change from baseline |
| Secondary Endpoints | Safety, CSF biomarkers, cognitive measures |
| Start Date | 2023 |
| Completion | Q4 2026 |

Background

Tau Biology and O-GlcNAcylation

Tau protein is a microtubule-associated protein that plays crucial roles in neuronal axonal transport and cytoskeletal stability. In neurodegenerative diseases, tau becomes hyperphosphorylated, leading to aggregation into neurofibrillary tangles (NFTs), which are a hallmark of multiple disorders including AD, PSP, and CBD[@jacobson2020].

O-GlcNAcylation is a post-translational modification where N-acetylglucosamine (GlcNAc) is covalently attached to serine and threonine residues on proteins. This modification is distinct from N-linked or O-linked glycosylation and serves as a dynamic regulatory mechanism akin to phosphorylation:

• Competition with phosphorylation: O-GlcNAcylation and phosphorylation occur on the same serine/threonine residues, creating a competitive relationship
• Tau protection: O-GlcNAcylated tau shows reduced phosphorylation at key pathological epitopes
• Aggregation inhibition: O-GlcNAcylation decreases tau's tendency to form insoluble aggregates
• Neuroprotective effects: Elevated O-GlcNAc levels protect neurons against various stressors

• O-GlcNAc transferase (OGT): Adds O-GlcNAc to proteins
• O-GlcNAcase (OGA): Removes O-GlcNAc from proteins

Why PSP Instead of AD?

The LOTUS trial in PSP was strategically important for several reasons[@west2019][@morizawa2022]:

Comparison: LOTUS vs PROSPER

| Aspect | LOTUS (LY-3372689) | PROSPER (FNP-223) |
|--------|--------------------|--------------------|
| Drug | Zaniglusemab | FNP-223 |
| Company | Eli Lilly | Ferrer |
| Enrollment | ~100 patients | 241 patients |
| Design | Dose-finding | Dose-finding |
| Endpoint | PSPRS | PSPRS |
| Results Expected | Q4 2026 | Q4 2026/Q1 2027 |
| Route | Oral | Oral |

If LOTUS shows clearer benefit than MAGNOLIA (AD), it would support the hypothesis that:

• Pure tauopathies respond better to tau-directed therapies
• Amyloid co-pathology may limit response to single-mechanism approaches
• Combination therapies may be needed in AD
• OGA inhibition is a viable mechanism for 4R-tauopathies

Study Design

Population

• Clinically diagnosed PSP patients (Richardson syndrome)
• Age 40-85 years
• Meet NINDS-SPSP criteria for probable PSP
• Disease duration ≤5 years
• PSPRS score 20-50 at baseline
• Able to undergo lumbar puncture
• Stable PSP medications for ≥4 weeks

Treatment Arms

• LY-3372689: Multiple oral dose levels (dose-finding design)
• Placebo: Matching oral dosing
• Duration: 52 weeks
• Randomization: Double-blind, 1:1 allocation

Endpoints

Primary:

• Change from baseline in PSP Rating Scale (PSPRS) at week 52

• Safety and tolerability assessments
• CSF O-GlcNAc levels (target engagement biomarker)
• CSF p-tau181 (tau pathology burden)
• CSF neurofilament light chain (NfL) (neuroaxonal injury)
• MDS-UPDRS motor examination
• Neuropsychological testing (attention, memory, executive function)

• MRI brain volume measurements
• Plasma biomarkers
• Quality of life measures

Mechanism: OGA Inhibition

LY-3372689 inhibits O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc modifications from proteins including tau. By inhibiting OGA, the drug increases cellular levels of O-GlcNAcylated proteins[@yuzwa2016]:

• Increased tau O-GlcNAcylation competes with pathological phosphorylation
• Reduced tau phosphorylation at key epitopes (Thr231, Ser396, Ser404)
• Decreased tau aggregation and neurofibrillary tangle formation
• Improved neuronal function through cytoskeletal stabilization

• Reduced tau pathology in mouse models with OGA inhibition
• Improved behavioral outcomes in tau transgenic mice
• Direct correlation between CSF O-GlcNAc and target engagement

Biomarker Strategy

Target Engagement

• CSF O-GlcNAc: Direct measure of OGA inhibition
• Dose-response relationship expected
• Changes expected within weeks of treatment initiation

Disease Modification Biomarkers

• CSF p-tau181: Tau pathology burden
• CSF total tau: Neuronal injury marker
• NfL: Neuroaxonal injury marker
• Brain volume: MRI measures of regional atrophy

Clinical Correlations

| Biomarker | Interpretation |
|-----------|----------------|
| Elevated CSF O-GlcNAc | Successful target engagement |
| Reduced p-tau181 | Decreased tau pathology |
| Stable NfL | Neuroprotection |
| Slower brain atrophy | Disease modification |

Clinical Implications

If Positive Results

• Validates OGA inhibition in pure tauopathies
• Supports disease-modifying mechanism through biomarker changes
• Competes with FNP-223 for PSP market opportunity
• May lead to accelerated approval pathway
• Would encourage further trials in other 4R-tauopathies

If Negative Results

• Questions the entire OGA inhibition approach for tauopathies
• Suggests mechanism limitations in advanced disease
• Would shift focus to earlier intervention or combination therapies
• May indicate need for amyloid-clearing combination in AD

Lessons from MAGNOLIA (AD)

The LOTUS trial addresses key learnings from the MAGNOLIA trial in AD:

• PSP without amyloid may show clearer benefit than AD
• Pure 4R-tauopathy is cleaner test of OGA inhibition mechanism
• Earlier stage patients may respond better
• CSF biomarkers may show effects even without clinical benefit

Competitive Position

The OGA inhibitor landscape shows multiple companies pursuing this mechanism:

| Trial | Drug | Company | Indication | Status |
|-------|------|---------|-----------|---------|
| LOTUS | LY-3372689 | Eli Lilly | PSP | Active |
| PROSPER | FNP-223 | Ferrer | PSP | Active |
| MAGNOLIA | LY-3372689 | Eli Lilly | AD | Completed |

Other Tau-Directed Approaches in Development

| Approach | Mechanism | Examples |
|----------|-----------|----------|
| Anti-tau antibodies | Passive immunization | Semorinemab, Tilavonemab, Bepranemab |
| Tau aggregation inhibitors | Small molecule | Methylene blue derivatives |
| OGA inhibitors | Enhance O-GlcNAc | LY-3372689, FNP-223 |
| Kinase inhibitors | Reduce phosphorylation | GSK-3β inhibitors |
| Tau degradation | Autophagy/UPS | Autophagy modulators |

Relationship to Other Trials

• [LY-3372689 MAGNOLIA Trial](/clinical-trials/ly3372689-magnolia-phase2-ad) — Same drug in AD
• [FNP-223 PROSPER Trial](/clinical-trials/fnp223-psp-prosper) — Competing trial in PSP
• [OGA Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape) — Hub page

Current Status (March 2026)

The LOTUS trial is actively following patients with completion expected in Q4 2026. Results will be announced around the same time as PROSPER (FNP-223), enabling direct comparison of two OGA inhibitors in PSP.

Key Milestones:

• 2023: Trial initiated
• 2024: Enrollment complete
• Q1 2025: All patients on treatment
• Q4 2026: Last patient completes 52 weeks
• Q1 2027: Topline results expected

Cross-References

• [LY-3372689 OGA Inhibitor](/therapeutics/ly3372689)
• [OGA Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape)
• [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-psp)
• [PSP Treatment Plan](/therapeutics/personalized-treatment-plan-atypical-parkinsonism)
• [4R-Tauopathies](/diseases/4r-tauopathies-genetics)
• [Tau Biology](/mechanisms/tau-pathology)

References

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Aquaporin-4 Polarization Rescue](/hypothesis/h-c8ccbee8) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: AQP4
• [Microglial Purinergic Reprogramming](/hypothesis/h-5daecb6e) — <span style="color:#81c784;font-weight:600">0.66</span> · Target: P2RY12
• [Sphingolipid Metabolism Reprogramming](/hypothesis/h-6657f7cd) — <span style="color:#81c784;font-weight:600">0.61</span> · Target: CERS2
• [Complement C1q Subtype Switching](/hypothesis/h-5a55aabc) — <span style="color:#ffd54f;font-weight:600">0.59</span> · Target: C1QA
• [Glial Glycocalyx Remodeling Therapy](/hypothesis/h-c35493aa) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: HSPG2
• [Ephrin-B2/EphB4 Axis Manipulation](/hypothesis/h-e6437136) — <span style="color:#ffd54f;font-weight:600">0.56</span> · Target: EPHB4
• [Netrin-1 Gradient Restoration](/hypothesis/h-05b8894a) — <span style="color:#ffd54f;font-weight:600">0.44</span> · Target: NTN1

Related Analyses:

• [4R-tau strain-specific spreading patterns in PSP vs CBD](/analysis/SDA-2026-04-01-gap-005) &#x1f504;

Pathway Diagram

The following diagram shows the key molecular relationships involving LY-3372689 LOTUS Trial - Phase 2 in Progressive Supranuclear Palsy discovered through SciDEX knowledge graph analysis: