Eli Lilly and Company — Neuroscience and Tauopathy Programs

Eli Lilly and Company

Path: /companies/eli-lilly Status: Public (NYSE: LLY) Headquarters: Indianapolis, Indiana, USA Founded: 1876 CEO: David A. Ricks Market Cap: ~$800B (2025) Website: [lilly.com](https://www.lilly.com)

Overview

Eli Lilly and Company is one of the world's largest pharmaceutical companies, with a significant investment in neuroscience and neurodegenerative disease therapeutics. The company gained a leading position in the tauopathy space through its acquisition of Swiss biotech Asceneuron in 2023, adding OGA inhibitors to its pipeline.

Neuroscience Focus

Lilly's neuroscience division has grown to become one of its highest-priority therapeutic areas:

Current Pipeline

| Drug | Mechanism | Indication | Stage |
|------|----------|-----------|--------|
| Zaniglusemab (LY3372689) | OGA inhibitor | PSP | Phase 2 (LOTUS) |
| Zaniglusemab (LY3372689) | OGA inhibitor | AD (MAGNOLIA) | Phase 2 |
| Remternetug | Anti-tau antibody | AD | Phase 3 |
| LY3891044 | Tau aggregation inhibitor | Preclinical | Research |

PSP Program: Zaniglusemab (LY3372689)

Background

Zaniglusemab (formerly ASN90) is an O-GlcNAcase (OGA) inhibitor developed by Asceneuron and acquired by Lilly in 2023. The drug targets tau pathology by reducing tau hyperphosphorylation through O-GlcNAc modification.

Development Timeline

Eli Lilly and Company

Path: /companies/eli-lilly Status: Public (NYSE: LLY) Headquarters: Indianapolis, Indiana, USA Founded: 1876 CEO: David A. Ricks Market Cap: ~$800B (2025) Website: [lilly.com](https://www.lilly.com)

Overview

Eli Lilly and Company is one of the world's largest pharmaceutical companies, with a significant investment in neuroscience and neurodegenerative disease therapeutics. The company gained a leading position in the tauopathy space through its acquisition of Swiss biotech Asceneuron in 2023, adding OGA inhibitors to its pipeline.

Neuroscience Focus

Lilly's neuroscience division has grown to become one of its highest-priority therapeutic areas:

Current Pipeline

| Drug | Mechanism | Indication | Stage |
|------|----------|-----------|--------|
| Zaniglusemab (LY3372689) | OGA inhibitor | PSP | Phase 2 (LOTUS) |
| Zaniglusemab (LY3372689) | OGA inhibitor | AD (MAGNOLIA) | Phase 2 |
| Remternetug | Anti-tau antibody | AD | Phase 3 |
| LY3891044 | Tau aggregation inhibitor | Preclinical | Research |

PSP Program: Zaniglusemab (LY3372689)

Background

Zaniglusemab (formerly ASN90) is an O-GlcNAcase (OGA) inhibitor developed by Asceneuron and acquired by Lilly in 2023. The drug targets tau pathology by reducing tau hyperphosphorylation through O-GlcNAc modification.

Development Timeline

| Milestone | Date | Notes |
|----------|------|------|
| Discovery | 2015-2019 | Asceneuron OGA inhibitor program |
| Phase 1 | 2020 | Safety, PK, CSF target engagement |
| Phase 2 AD (MAGNOLIA) | 2021-2024 | Early AD, biomarker effects confirmed |
| Lilly Acquisition | 2023 | $60M upfront + milestones |
| Phase 2 PSP (LOTUS) | 2022-Present | First OGA inhibitor in PSP |
| Expected Results | Q4 2026 | LOTUS primary endpoint |

LOTUS Trial (NCT05433740)

LOTUS (Lyming OGA inhibitor Trial in PSP) is the pivotal Phase 2 study:

• Design: Randomized, double-blind, placebo-controlled
• Enrollment: ~200 patients with PSP
• Primary Endpoint: change in PSP Rating Scale (PSPRS)
• Secondary Endpoints: CSF O-GlcNAc, neuroimaging, cognition

MAGNOLIA Trial (AD)

The MAGNOLIA Phase 2 study in early Alzheimer's disease:

• Results: Biomarker effects (CSF tau reduction) confirmed
• Outcome: Did not meet primary cognitive endpoint
• Biomarker findings: Validated target engagement

Mechanism of Action

O-GlcNAcase Inhibition

Zaniglusemab works by inhibiting O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc modifications from proteins:

• Tau hyperphosphorylation: Reduced O-GlcNAc leads to increased tau phosphorylation
• OGA inhibition: Increases tau O-GlcNAcylation, reducing hyperphosphorylation
• Aggregation prevention: Modified tau less likely to form aggregates

Rationale for PSP

PSP and other 4R-tauopathies show:

• Tau aggregation: 4R tau forms insoluble aggregates
• OGA activity: Elevated OGA in tauopathies
• Therapeutic angle: OGA inhibition may slow aggregation

Corporate Strategy

Acquisition of Asceneuron

The 2023 acquisition of Asceneuron reflects Lilly's tauopathy strategy:

• Strategic rationale: Add OGA inhibitor platform
• Complementary to remternetug: Antibody + small molecule tau approach
• Swiss presence: Basel neuroscience research site
• Team retention: Key Asceneuron scientists joined Lilly

Portfolio Approach

Lilly is pursuing a multi-mechanism tau strategy:

Financial Impact

Pipeline Investment

Lilly's neuroscience investment:

• R&D: ~$8B annually (all programs)
• Tauopathy programs: Significant portion of neuroscience budget
• Acquisition cost: $60M upfront (Asceneuron)

Market Position

The tauopathy market represents significant opportunity:

• PSP: ~$1B potential peak sales
• AD: >$10B potential
• Competitive landscape: Multiple mechanisms in development

Partnerships

Academic Collaborations

• University of Pennsylvania: Biomarker development
• UCL Institute of Neurology: Clinical trial site
• Mayo Clinic Florida: PSP expertise

Industry Partnerships

• CurePSP: Clinical trial promotion
• Coalition for 4R-Tau: Industry consortium

Cross-References

• [Asceneuron](/researchers/asceneuron) — Acquired biotech
• [OGA Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape)
• [LY3372689 PSP Trial](/clinical-trials/ly3372689-lotus-psp)
• [CurePSP](/organizations/curepsp) — Trial sponsor
• [4R-Tauopathies](/mechanisms/4r-tauopathies)

References