p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

Hayley R C Shanks; Kewei Chen; Eric M Reiman; Kaj Blennow; Jeffrey L Cummings; Stephen M Massa; Frank M Longo; Anne Börjesson-Hanson; Manfred Windisch; Taylor W Schmitz

doi:10.1038/s41591-024-02977-w

p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

Nat Med. 2024 Jun;30(6):1761-1770. doi: 10.1038/s41591-024-02977-w. Epub 2024 May 17.

Authors

Hayley R C Shanks^{1

2

3}, Kewei Chen^{4

5

6}, Eric M Reiman^{4

5

7

8

9}, Kaj Blennow^{10

11}, Jeffrey L Cummings¹², Stephen M Massa^{13

14}, Frank M Longo¹⁵, Anne Börjesson-Hanson¹⁶, Manfred Windisch¹⁷, Taylor W Schmitz^{18

19

20}

Affiliations

¹ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. [email protected].
² Robarts Research Institute, Western University, London, Ontario, Canada. [email protected].
³ Western Institute for Neuroscience, Western University, London, Ontario, Canada. [email protected].
⁴ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁵ College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA.
⁶ College of Health Solutions, Arizona State University, Downtown, Phoenix, AZ, USA.
⁷ Translational Genomics Research Institute, Phoenix, AZ, USA.
⁸ Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
⁹ ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
¹¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹² Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, NV, USA.
¹³ San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA.
¹⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ PharmatrophiX, Inc., Menlo Park, CA, USA.
¹⁶ Clinical Trials, Department of Aging, Karolinska University Hospital, Stockholm, Sweden.
¹⁷ NeuroScios, GmbH, St. Radegund, Austria.
¹⁸ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. [email protected].
¹⁹ Robarts Research Institute, Western University, London, Ontario, Canada. [email protected].
²⁰ Western Institute for Neuroscience, Western University, London, Ontario, Canada. [email protected].

Abstract

p75 neurotrophin receptor (p75^NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75^NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted 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 with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75^NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .

Publication types

Randomized Controlled Trial
Clinical Trial, Phase II

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / drug therapy
Alzheimer Disease* / pathology
Biomarkers / cerebrospinal fluid
Double-Blind Method
Female
Humans
Isoleucine / analogs & derivatives
Magnetic Resonance Imaging
Male
Middle Aged
Morpholines
Nerve Tissue Proteins
Positron-Emission Tomography*
Receptor, Nerve Growth Factor / metabolism
Receptors, Nerve Growth Factor / metabolism
Treatment Outcome

Substances

LM11A-31
NGFR protein, human
Receptor, Nerve Growth Factor
Receptors, Nerve Growth Factor
Biomarkers
Isoleucine
Morpholines
Nerve Tissue Proteins

Associated data

ClinicalTrials.gov/NCT03069014

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding