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
...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
In PSP and other tauopathies:
- 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:
Blocks pro-NGF/p75NTR binding: Prevents pro-apoptotic signaling cascade
Promotes TrkA co-receptor function: Enhances neurotrophin survival signals
Restores pro-survival balance: Shifts cellular equilibrium toward neuroprotectionMolecular 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:
Shared p75NTR pathway dysregulation in both diseases
Tau-independent neuroprotection - LM11A-31 works even in tau-depleted neurons
Complementary mechanism - can be combined with anti-tau approaches
Preclinical evidence in PSP animal models (though limited to date)
Patient population overlap - PSP patients often have comorbid tau pathologyTrial 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]:
Toxic gain-of-function: Tau aggregates cause neuronal dysfunction
Loss of trophic support: p75NTR activation promotes neuronal deathCurrent 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
[NCT07264283 - The Progressive Supranuclear Palsy Clinical Trial Platform - Regimen B: LM11A-31](https://clinicaltrials.gov/study/NCT07264283)
[Longo FM, Massa SM. p75NTR as a therapeutic target for Alzheimer's disease. Expert Opinion Ther Targets. 2021](https://doi.org/10.1080/14728222.2021.1991313)
[Massa SM, et al. LM11A-31 improves deficits in Alzheimer's disease models. Neurobiol Dis. 2018](https://doi.org/10.1016/j.nbd.2018.05.012)
[Simmons DA, et al. LM11A-31 improves cognition in AD models. Neurotherapeutics. 2022](https://doi.org/10.1007/s13311-022-01238-9)
[Bai Y, et al. Small molecule modulators of p75NTR. J Med Chem. 2020](https://doi.org/10.1021/acs.jmedchem.0c00944)
[Cummings J, et al. Alzheimer's disease drug development pipeline 2024. Alzheimer's & Dementia. 2024](https://doi.org/10.1002/alz.13802)