Hayley Renee Christine Shanks, Western University
Shanks, HRC, Chen, K, Reiman, EM, Blennow, K, Cummings, JL, Massa, SM, Longo, FM, Börjesson-Hanson, A, Windisch, M, Schmitz, TW. p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial. Nat Med 30, 1761–1770 (2024). https://doi.org/10.1038/s41591-024-02977-w
Phase 2a clinical trial reveals a small molecule called LM11A-31 is safe and slows progression of many features of Alzheimer’s Disease
Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder for which there is no cure. Therapeutics available to the approximately 734,000 Canadians living with AD provide symptom management without slowing disease progression. Hayley Renee Christine Shanks, working in the laboratory of Dr. Taylor Schmitz at Western University, adopted a novel approach to AD therapeutics by targeting “deep biology” — that is, receptors that control multiple fundamental cellular pathways and may therefore normalize multiple pathological processes underlying AD. This “deep biology” target, called the p75 neurotrophin receptor (p75NTR), plays a critical role in determining whether cells degenerate or survive. This receptor was discovered approximately 30 years ago and is widely studied in the fields of developmental neuroscience and neurology.
In AD, p75NTR is a key receptor that mediates neuronal dysfunction, neurodegeneration, and glial reactivity. Research in AD mouse models indicates that modulation of p75NTR with a small molecule called LM11A-31 promotes neuronal resilience and reduces neuroinflammation. Building on this work, Shanks et al. (2024), Nature Medicine, was the first publication to examine selective modulation of p75NTR in individuals with AD.
This study was a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD dementia. Participants received either placebo or LM11A-31, administered twice daily by oral capsules. While the primary outcome of the trial was safety, key exploratory endpoints were also collected, including brain scans, measurements of biomarkers, and cognitive testing.
The primary outcome was met: LM11A-31 was safe and well tolerated. Moreover, LM11A-31 treatment significantly slowed grey matter degeneration and reduction in metabolism in AD-vulnerable brain regions. LM11A-31 also attenuated progression on AD biomarkers. The study was not powered to detect drug-placebo differences on cognitive tests, and none were observed.
Overall, this research suggests that targeting p75NTR with LM11A-31 is safe and may slow the biological progression of AD. This is the first publication to examine selective modulation of p75NTR in a human disease population. This work may advance a promising AD therapeutic toward further large-scale clinical testing, potentially providing an additional therapeutic option for patients. Moreover, because p75NTR signaling becomes dysfunctional in multiple conditions (for example, Huntington’s disease), these findings in AD patients may translate to other neurodegenerative conditions.
About Hayley Renee Christine Shanks
Hayley Renee Christine Shanks is a Neuroscience PhD student at Western University, conducting research in the laboratory of Dr. Taylor Schmitz with co-supervision from Dr. Stephen Pasternak. During her doctoral work, she collaborated closely with Dr. Frank Longo at Stanford University and Dr. Stephen Massa at the University of California, San Francisco, analyzing data from a clinical trial of a novel Alzheimer’s disease therapeutic. Hayley led key aspects of the project’s analytical development and, in recognition of her substantial contributions, was selected as first author on the resulting manuscript. Looking ahead, Hayley is passionate about advancing therapeutics through clinical research and plans to build a career focused on clinical trial development and execution. Hayley is on LinkedIn and Twitter (X) under the handle @hayleyrcshanks.
Funding
The trial was sponsored and funded by PharmatrophiX (Menlo Park, California) and the National Institute on Aging (NIA AD pilot trial 1R01AG051596). The Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association provided funding for preclinical and phase 1 trials.
For the duration of this work, Hayley was supported by the Jonathan and Joshua Memorial Foundation, the Government of Ontario’s Queen Elizabeth II Graduate Scholarship in Science and Technology, and most recently a Canadian Institutes of Health Research Doctoral Scholarship (FRN 193293). A full list of funding for all trial collaborators is available in the trial publication.
