Late-onset Alzheimer's disease (AD) is a leading cause of dementia, characterized by synaptic failure and degeneration. While therapies targeting amyloid-β (Aβ) or tau accumulation show promise, they address only limited aspects of AD's complex pathophysiology. An alternative approach involves targeting 'deep biology'—receptors and signaling networks that influence multiple cellular pathways and may normalize various pathological processes. Over two decades of research points to the p75 neurotrophin receptor (p75NTR) as a promising deep biology target for modifying neuronal dysfunction and degeneration in AD. p75NTR, a member of the tumor necrosis factor family, acts as a molecular switch influencing both neuronal survival and degeneration depending on its ligand binding. In its non-liganded state or when bound to proneurotrophins like pro-NGF, it promotes degeneration; however, when bound to mature neurotrophins, it supports cell survival and synaptic plasticity. p75NTR's signaling network significantly overlaps with degenerative networks in AD, particularly those impacting synaptic function. Preclinical studies using p75NTR-mutant mice show resilience against Aβ-related degeneration, and human genetic studies link p75NTR polymorphisms to altered AD risk. Increased p75NTR levels in brain tissue and elevated pro-NGF in CSF of AD patients further support its role in the disease. The highest p75NTR expression is in cell types early affected in AD, such as cholinergic neurons and their targets in the entorhinal cortex and hippocampus. This motivated preclinical research into small-molecule modulation of p75NTR to downregulate its degenerative signaling. LM11A-31, a small molecule mimicking a domain of NGF that interacts with p75NTR, emerged as a promising candidate. Preclinical studies showed LM11A-31 to be well-tolerated, able to cross the blood-brain barrier, and effective in reducing tau pathologies, glial activation, and synaptic loss in AD and tauopathy mouse models. This study aimed to evaluate the safety and potential efficacy of LM11A-31 in a phase 2a trial of patients with mild-to-moderate AD.

The literature extensively supports the involvement of p75NTR in Alzheimer's disease pathogenesis. Studies have shown a correlation between p75NTR polymorphisms and increased AD risk (Cozza et al., 2008; Di Maria et al., 2012; Reitz et al., 2013). Furthermore, research indicates elevated levels of pro-NGF, a ligand that promotes p75NTR-mediated neuronal degeneration, in the brains and CSF of AD patients (Bruno et al., 2009; Fahnestock et al., 2001; Malerba et al., 2021; Tiveron et al., 2013). The selective vulnerability of specific neuronal populations in AD, such as cholinergic neurons of the basal forebrain and neurons in the entorhinal cortex and hippocampus, aligns with the high expression of p75NTR in these regions (Roussarie et al., 2020; Schmitz et al., 2016; Arendt et al., 2015). The upregulation of p75NTR in glial cells during pathological conditions, including AD, further highlights its potential role in neuroinflammation (Cragnolini & Friedman, 2008; Düsedau et al., 2019). Preclinical studies utilizing small-molecule modulation of p75NTR, specifically using LM11A-31, have demonstrated promising results in mitigating various aspects of AD pathology (Longo & Massa, 2008; Massa et al., 2006; Tep et al., 2013; Yang et al., 2008; Nguyen et al., 2014; Simmons et al., 2014; Yang et al., 2020; Knowles et al., 2013). These studies showed reductions in tau pathology, inflammatory responses, and synaptic dysfunction, providing a strong rationale for translating these findings to human clinical trials. The potential impact of p75NTR modulation on the vascular system has also been noted (von Schack et al., 2001; Caporali & Emanueli, 2009), adding another dimension to the investigation of LM11A-31.

This study was a 26-week, multicenter, randomized, placebo-controlled, double-blind, parallel-group phase 2a clinical trial involving 242 participants with mild to moderate AD across 21 sites in five European countries. The trial assessed the safety and exploratory efficacy of LM11A-31, a p75NTR modulator. Participants were randomized 1:1:1 to receive twice-daily oral doses of placebo, 200 mg LM11A-31, or 400 mg LM11A-31. Inclusion criteria included a confirmed AD diagnosis (CSF Aβ42 < 550 ng l⁻¹ or Aβ42/Aβ40 ratio < 0.89), MMSE score between 18 and 26, and absence of major depressive disorder or other significant comorbidities. The primary outcome was safety and tolerability, assessed by adverse event (AE) reporting, physical examinations, and laboratory tests. Secondary outcomes included changes in core AD biomarkers (CSF Aβ40, Aβ42, p-tau181, t-tau, and AChE activity) and cognitive performance (custom neuropsychological test battery, NTB). Prespecified exploratory outcomes comprised CSF synaptic, neurodegenerative, and glial biomarkers; structural MRI (sMRI) and [¹⁸F]-FDG PET to assess brain structure and metabolism; and additional cognitive assessments (ADAS-Cog-13, MMSE, Amunet). CSF samples were analyzed using validated immunoassays for various biomarkers. sMRI and [¹⁸F]-FDG PET data were preprocessed using SPM12 and CAT12, with longitudinal changes analyzed using voxel-wise flexible factorial models within regions identified as AD-vulnerable in an independent ADNI cohort. Cognitive data were analyzed using Wilcoxon rank-sum tests and ANOVA. The sample size was determined based on power calculations, with adjustments made based on observed variability in cognitive data. The study adhered to the Declaration of Helsinki and Good Clinical Practice guidelines, with ethical approval obtained from relevant review boards.

The trial successfully met its primary endpoint, demonstrating the safety and tolerability of LM11A-31. The most common AEs were nasopharyngitis, diarrhea, and headache, mostly mild and transient. A small number of participants experienced transient, asymptomatic eosinophilia, primarily in the higher dose group. Regarding secondary outcomes, LM11A-31 significantly slowed longitudinal increases in CSF Aβ42 (P = 0.037) and Aβ40 (P = 0.009) compared to placebo. However, the Aβ42/Aβ40 ratio remained unchanged. No significant differences were observed in CSF p-tau181 or t-tau between groups. In prespecified exploratory analyses, LM11A-31 significantly slowed longitudinal increases in CSF SNAP25 (P = 0.010) and NG (P = 0.009), suggesting a slowing of presynaptic and postsynaptic loss. A reduction in CSF YKL40 (P = 0.040), a glial marker, also supported the hypothesis of reduced glial activation. sMRI analysis revealed that LM11A-31 slowed rates of gray matter loss in the frontal operculum and posterior parietal cortex compared to placebo (*P* < 0.05, uncorrected). Similarly, [¹⁸F]-FDG PET analysis showed that LM11A-31 slowed the rate of glucose metabolic decline in the entorhinal cortex, hippocampus, insula, and prefrontal cortex (*P* < 0.05, uncorrected). Importantly, post hoc analyses revealed a significant majority of voxels with hypothesis-consistent effects (LM11A-31 slowing disease progression) in both sMRI and [¹⁸F]-FDG PET datasets. No significant differences were observed in cognitive performance between treatment groups.

This phase 2a trial provides initial evidence supporting the safety and potential disease-modifying effects of targeting p75NTR in AD using LM11A-31. The observed slowing of amyloid and synaptic marker increases, along with reduced glial activation and gray matter/metabolic decline in AD-vulnerable brain regions, aligns with preclinical findings demonstrating LM11A-31's ability to enhance synaptic resilience and reduce inflammation. The lack of significant cognitive improvements is not unexpected given the short duration of the trial and the complex nature of cognitive decline in AD. The findings suggest that LM11A-31 may slow the progression of AD-related neuropathology without significantly impacting amyloid plaque burden, aligning with the preclinical observation that LM11A-31 does not affect amyloid plaque levels, potentially through influencing the APP processing pathway. The concordance across multiple biomarker domains (CSF, sMRI, and PET) strongly supports the observed effects. This multi-domain impact of LM11A-31 offers a substantial advantage over single-target AD therapies.

This phase 2a trial demonstrates the safety and tolerability of LM11A-31 in patients with mild-to-moderate AD and provides preliminary evidence suggesting it may slow the progression of several key AD biomarkers. The consistent effects across multiple biomarker domains strengthen the potential of LM11A-31 as a disease-modifying therapy. Larger-scale, longer-duration trials are warranted to confirm these findings and assess the impact of LM11A-31 on cognitive function.

The primary limitation is the relatively short duration (26 weeks) and small sample size of the trial, which may have limited the ability to detect significant effects on cognitive outcomes. The study population was predominantly white participants from European countries, limiting the generalizability of the findings to diverse populations. The lack of in vivo markers for direct p75NTR engagement in humans is also a limitation. Furthermore, the exploratory nature of the study and the lack of multiple comparison correction should be considered when interpreting the findings.