LM11A-31 Meets Primary End Point in Exploratory Trial of Alzheimer Disease


In addition to demonstrating safety and tolerability, treatment with LM11A-31 resulted in significant differences in Aß40 and Aß42, although the ratio of Aß42 and Aß40 was not affected.

Taylor Schmitz, PhD, an assistant professor in the department of physiology and pharmacology at Western University

Taylor Schmitz, PhD

Results from an exploratory phase 2a trial (NCT03069014) showed that LM11A-31 (PharmatrophiX), an investigational agent targeting p75 neurotrophin receptor (p75NTR), met its primary end point of safety and tolerability in a cohort of individuals with mild to moderate Alzheimer disease (AD). Published in Nature Medicine, the therapy showed significant drug-placebo differences on prespecified secondary and exploratory outcomes, warranting further investigation in larger-scale clinical trials of longer duration.1

Of the 242 participants enrolled in the trial, 221 completed the study as outlined in the protocol and 211 completed the study at the 26-week visit. Among those who completed, patients were on either placebo (n = 76), LM11A-31 200 mg (n = 75) or LM11A-31 400 mg (n = 70). The study was not sufficiently powered to reliably assess effects of LM11A-31 on potentially slowing the loss of cognitive function, and thus, cognitive measures were included as secondary or exploratory outcomes.

The study, which received funding by the Alzheimer’s Drug Discovery Foundation (ADDF), met its primary prespecified end point of demonstrating safety and tolerability of LM11A-31. In order, the most frequently observed adverse events (AEs) were nasopharyngitis, diarrhea, headache, and eosinophilia. Overall, there were more total discontinuations in the 400-mg group (12 participants) than in the 200-mg (3 participants) and placebo (5 participants) groups. MRI did not detect findings that raised concern regarding drug safety, including amyloid-related imaging abnormalities (ARIA).

Led by senior author Taylor Schmitz, PhD, an assistant professor in the department of physiology and pharmacology at Western University, secondary and exploratory data analyses pooled participants from the 200-mg and 400-mg arms into a single LM11A-31 group. Secondary cerebrospinal fluid (CSF) outcomes, which included total tau (t-tau), phosphorylated tau 181 (p-tau181), and amyloid-ß (Aß)40 and 42, showed significant longitudinal differences between LM11A-31 and placebo (P rank sum = 0.037). Treatment with LM11A-31 resulted in relative changes of –6.98% (95% CI, –14.22% to –1.45%) and –8.98 (95% CI, –17.60% to –1.29%) in Aß42 and Aß40, respectively, compared with placebo.

In exploratory end points of synaptic degeneration, treatment with LM11A-31 resulted in significant slowing of longitudinal increases in CSF SNAP25 compared with placebo (P = 0.10). The difference in median annual percent change between LM11A-31 and placebo for SNAP25 was −19.20% (95% CI, −32.19% to −1.47%). LM11A-31 also significantly showed longitudinal increases in the postsynaptic NG biomarker compared with placebo (P = .009). Overall, these data suggested that the agent slows progression of presynaptic and postsynaptic loss, as measured by CSF SNAP25 and NG.


Between LM11A-31- and placebo-treated patients, the difference in median annual percent change of neurofilament light was 3.13% (95% CI, –8.64% to 16.31%), which was considered not significant. In terms of glial activation, LM11A-31 demonstrated significant slowing of YKL40 relative to placebo (–5.19%; 95% CI, –14.80% to 2.49%; P = .040), whereas there was no significant difference in the percent change of sTREM2 (–4.29%; 95% CI, –13.12% to 3.15%; P = .172). There were no between-group differences in spatial memory, demonstrated through Amunet scores (P >.10 for all 4 Amunet memory subdomains).

To examine whether LM11A-31 slows longitudinal changes in gray matter integrity, a voxel-wise analyses of variance (ANOVAs) was conducted, with selected participants from the AD Neuroimaging Initiative (ADNI) used to define AD-vulnerable brain regions. Overall, a significant hypothesis-consistent treatment group-by-time interaction effect was detected at an uncorrected threshold of P <.001. Compared with placebo, LM11A-31 slowed rates of gray matter loss in the frontal operculum and posterior parietal cortex.

These clusters were projected at a more liberal uncorrected threshold of P <.05; however, when detected at the P <.001 threshold there were no hypothesis-inconsistent voxels. For the [18F]-FDG PET analysis of brain glucose metabolism, no voxels exhibited a treatment group-by-time interaction effect at the uncorrected threshold of P < 0.001. At a more liberal threshold of P < 0.05, a hypothesis-consistent treatment group-by-time interaction was detected, where administration of LM11A-31 slowed rates of glucose metabolic decline in regions such as the entorhinal cortex and surrounding temporal cortex, hippocampus, insula and prefrontal cortex.

Overall, there was no significant change in the ratio of Aß42 to Aß40 over the 26-week treatment period. Similarly, investigators found no between-group differences in changes in CSF p-tau181 (P = .201) and longitudinal CSF t-tau (P = .068). Although the study wasn’t powered for cognition, the placebo and LM11A-31 groups did not differ in longitudinal cognitive decline on the NTB global z-score at 12 weeks (P = .156) or 26 weeks (P = .185). Furthermore, longitudinal changes in acetylcholinesterase activity did not differ between the 2 groups (P = .295).

1. Shanks HRC, Chen K, Reiman EM, et al. p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial. Nature Med. 2024; Published online May 17, 2024. doi:10.1038/s41591-024-02977-w
Related Videos
Patricia K. Coyle, MD
Video 2 - 5 KOLs are featured in "Natural History of Spinal Muscular Atrophy"
Video 1 - 5 KOLs are featured in "Clinical Features and Phenotypes of Spinal Muscular Atrophy"
Aliza Ben-Zacharia, PhD, DNP, ANP-BC, FAAN
 Brian G. Weinshenker, MD, FRCP
© 2024 MJH Life Sciences

All rights reserved.