p75 Neurotrophin Receptor Modulation Shown to Slow Biomarker Progression, Preserve Visuospatial Function in Alzheimer Disease
Modulation of the p75 neurotrophin receptor using LM11A-31 (PharmatrophiX, Menlo Park, CA), an investigational small molecule agent, may slow disease-related biomarker changes and preserve select cognitive functions in people with Alzheimer disease (AD). The exploratory results of a phase 2a clinical trial (NCT03069014), presented at the 18th annual Clinical Trials on Alzheimer’s Disease (CTAD) conference, suggest that LM11A-31 treatment may have biologically interconnected effects on multiple AD-related processes including reducing tau pathology, attenuating glial activation, and promoting glial activation.
The randomized, double-blind, placebo-controlled trial included 242 individuals with mild to moderate AD, who received oral treatment with LM11A-31 200 mg, LM11A-31 400 mg, or placebo twice daily for 26 weeks. Exploratory outcomes included longitudinal measures of plasma p-tau217, plasma glial fibrillary acidic protein (GFAP), cerebrospinal fluid (CSF) proteomics, and composite cognitive domain scores assessing memory, language, executive function, and visuospatial abilities. Data for the two dose levels of LM11A-31 treatment were combined in the reported results.
Key results reported at CTAD include:
- At 26 weeks, treatment with LM11A-31 was associated with a 31% decrease in plasma p-tau217 levels vs placebo (P=.049).
- LM11A-31 treatment was shown to counteract the direction of change in 5 of 10 CSF proteomic modules (M1 [BBB], M3 [collagen], M2 [postsynaptic], M6 [axonogenesis], and M5 [glycolysis]) compared with placebo, with significant or trend-level effects.
- CSF proteomic analysis identified 241 proteins altered by treatment with LM11A-31; of these, 129 (63%) showed a change in the opposite direction of AD progression, while 75 (37%) showed a change in the same direction as AD progression.
- The proteins affected by LM11A-31 treatment were found to be significantly associated with synaptic structures and synapse-related biological processes.
- In the placebo group, memory and visuospatial scores declined significantly over 26 weeks, while LM11A-31 treatment significantly attenuated decline in visuospatial function at 12 and 26 weeks.
Source: Longo F. Modulation of the p75 neurotrophin receptor in a phase 2a Alzheimer’s disease trial reduces plasma p-tau217, engages the synaptic proteome, and preserves visuospatial cognition. Presented at: 18th annual Clinical Trials on Alzheimer’s Disease Conference; December 1-4, 2025; San Diego, California.