Alzheimer’s disease is the most common cause of dementia, affecting more than 55 million people worldwide. Currently, the two main treatment approaches to delay its onset or slow its progression target the buildup of amyloid beta peptides (which form plaques in the spaces between nerve cells in the brain) and the buildup of tau protein, which produces tangles that They damage neurons.
However, these strategies only include a limited set of markers and biological mechanisms related to this type of dementia. Now, a team of researchers from Western University, Stanford University and the University of California, San Francisco (UCSF) that has evaluated a new therapeutic strategy to improve the brain’s resilience to multiple forms of Alzheimer’s-related pathology, has obtained promising results for patients with mild to moderate Alzheimer’s in its first human trial.
The drug LM11A-31, developed by Stanford professor Dr. Frank Longo and UCSF professor Dr. Stephen Massa, targets the P75 neurotrophin receptor (P75NTR), located on brain cells. P75NTR helps regulate various processes such as cell survival, growth and death, acting as a traffic controller that decides which signals pass and which do not. The drug improves the passage of signals that promote cell survival and growth.
In 2020, the drug’s developers contacted Taylor Schmitz, assistant professor in the Department of Physiology and Pharmacology, and Hayley Shanks, a doctoral student in neuroscience at Schulich Medicine & Dentistry, to analyze structural MRI data from their phase 2A clinical trial. Their analyzes were increased to include positron emission tomography (PET), PET, and cerebrospinal fluid data.
Alzheimer’s drug demonstrates safety and tolerability
Although the primary goal of the trial was to evaluate the drug’s safety and tolerability in patients with mild to moderate Alzheimer’s, researchers also collected multiple markers of brain pathology to evaluate whether the drug affected disease progression between baseline and follow-up testing. , compared to placebo. The trial met its main objectives: to demonstrate safety and tolerability. Their results have been published in the journal Nature medicine.
The Western team led the analysis of the trial. Despite the relatively short duration of 26 weeks, they showed that the drug slowed disease progression by multiple measures. “In a Phase 2A clinical trial, the goal is to show that the drug does not cause side effects that would be toxic,” said lead author Schmitz.
Researchers are hopeful that the drug could benefit patients, even when given in later stages of the disease. Current treatments such as amyloid monoclonal antibodies that attempt to remove amyloid from the brain are not as effective for patients in the later stages of Alzheimer’s disease because the amyloid has already caused significant damage to neurons.
“The reason this drug is interesting is because it directly affects the ability of neurons to survive. It promotes their overall integrity, their branching and their synapses [donde se conectan y se comunican entre sí]” Shanks said. “In animal models, the drug was shown to preserve these neurons or reverse damage to these neurons, which translated into behavioral improvements, almost returning the neurons to a healthy state.”
“The reason this drug is interesting is because it directly affects the ability of neurons to survive. It promotes their overall integrity, their branching and their synapses [donde se conectan y se comunican entre sí]”
This clinical trial represents the first case of targeting the P75 neurotrophin receptor in a human disease population after 10 years of preclinical work. The trial was carried out in five European countries and included the participation of 242 people who suffered from mild to moderate Alzheimer’s disease.
“We also saw changes in a biomarker of inflammation. The drug slowed the rise of this marker of inflammation in the fluid cerebrospinal system,” Schmitz said. “This is important because, over the past five years, inflammation has become a key factor in understanding Alzheimer’s disease.”
Seeing these results so early is significant and promising. Most Phase 3 trials of Alzheimer’s therapies last about two years, and the six-month interval used in the latest trial typically does not see movement of this degree. In this phase 2 trial, there were significant changes in two synaptic biomarkers taken from the cerebrospinal fluid over a six-month period, Schmitz explained. “This builds confidence that what we’re seeing is real, rather than a false positive,” Shanks added.
At Western, further studies are currently underway to examine the drug using next-generation animal models of Alzheimer’s disease in combination with high-resolution brain imaging on the new 15.2 Tesla MRI at the Center for Functional and Metabolic Mapping . These studies will help improve the efficiency and effectiveness of larger human trials by providing information about when in the disease it is best to start treatment and whether certain Alzheimer’s risk genes may affect response to treatment.
If proven effective in future trials, this drug could help slow the progression of Alzheimer’s in a wide range of patients due to its effects on multiple different types of pathology, its accessibility (taken orally), and its safety against potentially dangerous side effects.
