Novel AD Treatment Approach Shows Promise in First Human Trial

Jolynn Tumolo

Exploratory outcomes from a phase 2a trial suggest that the first-in-class small molecule LM11A-31 slowed progression of pathophysiological features of mild to moderate Alzheimer disease (AD) over 26 weeks, according to a study published in Nature Medicine.

LM11A-31 is designed to modulate p75 neurotrophin receptor (p75NTR) signaling pathways, which substantially overlap with degenerative networks in AD, researchers explained. In preclinical models, LM11A-31 helped reduce amyloid-induced and pathological tau-induced synaptic loss.

“The reason this drug is exciting is because it’s directly affecting the ability of the neurons to survive. It promotes their overall integrity, their branching, and their synapses,” said study corresponding author Hayley Shanks, a neuroscience PhD student at Western University Schulich School of Medicine and Dentistry, Ontario, Canada. “In animal models, it was shown that the drug was preserving these neurons or reversing the damage to these neurons, which translated to behavioral improvements, almost reverting the neurons back to a healthy state.”

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The double-blind, phase 2a trial included 242 people with mild to moderate AD. Participants were randomized to placebo, 200-mg LM11A-31, or 400-mg LM11A-31 administered twice daily in capsule form.

The trial met its primary endpoint, which was safety and tolerability of the oral drug. In exploratory outcomes domains that included structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography, and cerebrospinal fluid, researchers found significant differences between treatment with placebo and LM11A-31, suggesting the drug slowed disease progression on multiple measures of brain pathology. Specifically, 2 synaptic biomarkers taken from cerebrospinal fluid showed notable changes.

“We also observed changes in an inflammation biomarker. The drug slowed down the increase of this inflammation marker in the cerebrospinal fluid,” said study lead and corresponding author Taylor W. Schmitz, PhD, a professor in the Western University Schulich School of Medicine and Dentistry. “This is significant because, in the past 5 years, inflammation has become a key factor in understanding AD.”

Although the study found no significant effect on cognitive testing with LM11A-31, researchers considered the trial’s findings promising given the comparatively short 6-month study period. Most phase 3 trials into AD therapies last 2 years, the team pointed out in the study.

“[T]he exploratory findings encourage larger trials of longer treatment duration to address the hypothesis that small-molecule modulation of p75NTR might constitute a disease-modifying therapy in AD,” researchers wrote.