NCT07264283: PSP Clinical Trial Platform - Regimen B (LM11A-31)

The Progressive Supranuclear Palsy Clinical Trial Platform - Regimen B: LM11A-31 (NCT07264283)

Overview

NCT07264283 is a Phase 2 clinical trial evaluating LM11A-31 (also known as BMS-902464), a small molecule modulator of the p75 neurotrophin receptor (p75NTR), as a treatment for [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP). This trial is part of the PSP Clinical Trial Platform (NCT07173803), a master protocol designed to efficiently evaluate multiple investigational products for PSP simultaneously[@nct].

LM11A-31 represents a novel neuroprotective approach that targets neuronal survival pathways rather than tau pathology directly. By modulating p75NTR signaling, the compound promotes pro-survival pathways while blocking pro-apoptotic cascades activated by tau pathology.

Trial Details

| Field | Value |
|-------|-------|
| NCT ID | NCT07264283 |
| Status | Not Yet Recruiting |
| Phase | Phase 2 |
| Sponsor | University of Pennsylvania |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Blinding | Triple (Participant, Investigator, Outcomes Assessor) |
| Estimated Enrollment | ~200 participants |
| Start Date | 2024 |
| Estimated Completion | ~2028 |

Mechanism of Action

p75NTR Signaling in Neurodegeneration

The Progressive Supranuclear Palsy Clinical Trial Platform - Regimen B: LM11A-31 (NCT07264283)

Overview

NCT07264283 is a Phase 2 clinical trial evaluating LM11A-31 (also known as BMS-902464), a small molecule modulator of the p75 neurotrophin receptor (p75NTR), as a treatment for [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP). This trial is part of the PSP Clinical Trial Platform (NCT07173803), a master protocol designed to efficiently evaluate multiple investigational products for PSP simultaneously[@nct].

LM11A-31 represents a novel neuroprotective approach that targets neuronal survival pathways rather than tau pathology directly. By modulating p75NTR signaling, the compound promotes pro-survival pathways while blocking pro-apoptotic cascades activated by tau pathology.

Trial Details

| Field | Value |
|-------|-------|
| NCT ID | NCT07264283 |
| Status | Not Yet Recruiting |
| Phase | Phase 2 |
| Sponsor | University of Pennsylvania |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Blinding | Triple (Participant, Investigator, Outcomes Assessor) |
| Estimated Enrollment | ~200 participants |
| Start Date | 2024 |
| Estimated Completion | ~2028 |

Mechanism of Action

p75NTR Signaling in Neurodegeneration

The p75 neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor superfamily that plays complex roles in neuronal survival and death[@longo2021][@bai2020]. Unlike tropomyosin receptor kinase (Trk) receptors which mediate pro-survival signals, p75NTR can:

• Promote apoptosis when bound by pro-neurotrophins (pro-NGF, pro-BDNF)
• Enhance Trk signaling when co-expressed with Trk receptors
• Mediate tau toxicity through downstream pathways that promote neuronal death

• Tau pathology activates pro-apoptotic p75NTR signaling
• Elevated pro-NGF levels are found in affected brain regions
• p75NTR activation exacerbates neuronal loss beyond tau toxicity alone

LM11A-31: Neuroprotective Modulation

LM11A-31 is a small molecule p75NTR modulator developed by Astellas Pharma (formerly Bristol-Myers Squibb)[@nct]. The compound:

Molecular target: p75NTR extracellular domain - specifically the cysteine-rich domain (CRD) II where pro-NGF binds[@massa2018]

Downstream Effects

LM11A-31 modulation of p75NTR leads to[@simmons2022]:

• Inhibition of JNK/p53 apoptotic pathway
• Reduced caspase-3 activation
• Preservation of mitochondrial integrity
• Enhanced neurite outgrowth and synaptic function

Clinical Development History

Preclinical Studies

Extensive preclinical work demonstrated LM11A-31's neuroprotective potential:

• Reduced tau phosphorylation and aggregation in cellular models
• Improved cognitive performance in tau transgenic mouse models
• Restored synaptic markers and hippocampal long-term potentiation
• Good blood-brain barrier penetration with favorable pharmacokinetics

Phase 1 in Alzheimer's Disease (Completed)

LM11A-31 completed Phase 1 testing in patients with mild-to-moderate AD[@longo2021]:

• Good safety and tolerability at all doses tested
• Target engagement demonstrated via CSF biomarkers
• No dose-limiting toxicities observed
• Pharmacokinetic profile suitable for oral dosing (once or twice daily)

Translational Rationale for PSP

The translation from AD to PSP is supported by:

Trial Design

Master Protocol Structure

NCT07264283 is conducted under the PSP Clinical Trial Platform (NCT07173803) master protocol[@nct]. Key design features:

• Shared placebo control: Single placebo group serves all active treatment arms
• Adaptive design: Interim analyses allow early stopping for futility or efficacy
• Core biomarker panel: Common biomarkers across all treatment arms
• Common outcome measures: Consistent PSPRS as primary endpoint for cross-arm comparison

Inclusion Criteria

Likely inclusion criteria for the LM11A-31 regimen:

• Age 40-85 years
• Diagnosis of probable PSP (MDS PSP criteria)
• PSP Rating Scale score 20-60
• Disease duration 1-7 years
• Stable background medications for 30 days
• No significant vascular dementia or other exclusions

Exclusion Criteria

Likely exclusion criteria:

• Other neurodegenerative diseases (AD, PD, CBS)
• Active major depression or psychiatric disorders
• Contraindications to MRI
• History of malignancy (except non-melanoma skin cancer)
• Impaired liver or kidney function

Outcome Measures

Primary Endpoint

• Change from baseline in PSP Rating Scale (PSPRS) at 52 weeks
• 100-point validated scale measuring disease severity across domains:
• Mentation and behavior (7 points)
• Bulbar function (7 points)
• Axial function (14 points)
• Limb motor function (14 points)
• Gait and balance (58 points)

Secondary Endpoints

| Measure | Timepoint | Purpose |
|---------|-----------|---------|
| Clinical Global Impression of Change (CGI-C) | 52 weeks | Global clinical assessment |
| Montreal Cognitive Assessment (MoCA) | 52 weeks | Cognitive function |
| Timed Up and Go Test (TUG) | 52 weeks | Mobility/balance assessment |
| MDS-UPDRS Part III | 52 weeks | Motor examination |
| Quality of Life (PSP-QoL) | 52 weeks | Patient-reported outcomes |

Biomarker Endpoints

• Tau PET imaging: 4R-tau selective ligand quantification
• CSF biomarkers: Total tau, phospho-tau (p-tau181, p-tau217), NfL
• Plasma biomarkers: Neurofilament light chain (NfL), pro-NGF levels
• PK/PD assessments: Plasma drug levels for exposure-response analysis

Safety Monitoring

Adverse Event Monitoring

Comprehensive safety monitoring including:

• Solicited and unsolicited adverse events
• Serious adverse event (SAE) reporting with causality
• Clinical laboratory monitoring (hematology, chemistry, lipids)
• Vital signs and physical examinations
• Neurological assessments for new deficits

PK/PD Monitoring

Pharmacokinetic monitoring to ensure:

• Adequate drug exposure across patient population
• Compliance with oral dosing regimen
• No unexpected drug accumulation

Independent Oversight

An independent Data Safety Monitoring Board (DSMB) provides:

• Periodic safety data review
• Randomized, unblinded interim efficacy analysis
• Protocol adherence monitoring

Comparison with Other Neuroprotective Approaches

| Agent | Mechanism | Target | Trial Status |
|-------|-----------|--------|--------------|
| LM11A-31 (NCT07264283) | p75NTR modulator | Neuronal survival | Not Yet Recruiting |
| Tilavonemab | Anti-tau mAb | Extracellular tau | Failed |
| BIIB080 | ASO | MAPT mRNA | Recruiting |
| Neuroprotective small molecules | Various | Mitochondria/oxidative stress | Varying stages |

Scientific Rationale

Why Neuroprotection in PSP

PSP progression involves two parallel mechanisms[@cummings2024]:

Current anti-tau therapies target mechanism #1. LM11A-31 targets mechanism #2, offering:

• Complementary approach that may synergize with anti-tau therapies
• Potential to preserve neurons even if tau pathology persists
• Disease-modifying potential beyond symptom management

Dual-Mechanism Strategy

The PSP Platform trial allows future combination studies where:

• AADvac1 + LM11A-31 could be evaluated together
• Targeting tau pathology AND neuronal survival simultaneously
• Potentially greater efficacy than single-mechanism approaches

Current Status

As of early 2026, this trial is not yet recruiting. Updates will be tracked as enrollment begins.

Anticipated Timeline

| Milestone | Expected Timeframe |
|-----------|-------------------|
| IRB approval and site activation | 2025-2026 |
| First patient enrolled | 2026 Q1-Q2 |
| Enrollment completion | 2027 Q4 |
| Primary endpoint readout | 2028 Q1 |

References