Mechanistic Potential of Synapse-Targeted Agent ALX-001 for Alzheimer Disease: Adam Mecca, MD, PhD

WATCH TIME: 5 minutes

"This compound [ALX-001] basically inhibits the interaction between this beta-amyloid oligomer cellular prion protein complex and the mGluR5. But what’s unique about it is that it does it at an allosteric site where it doesn’t interfere with normal physiologic glutamate signaling."

It has been proposed that Alzheimer disease (AD) and its various stages might be most effectively treated with a combination approach rather than a single therapy. The drug development pipeline for AD is currently filled with a wide range of different agents, each working on a specific mechanism of action. Brain synapse loss, which has been tightly correlated with cognitive symptoms, has been considered a promising avenue to treat, with novel treatments beginning to emerge.

At the recently concluded 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, new phase 1 data was presented on ALX-001, a highly selective, first-in-class, synapse-targeted, disease-modifying therapy. Otherwise known as BMS-984923, the agent does not alter basal or glutamate activity, but does block amyloid-ß oligomer binding to the cellular prion protein activation of metabotropic glutamate receptor subtype 5 (mGluR5) receptor complex. The trial, which featured 36 patients aged 50 to 80 with normal cognition, showed that ALX-001 was safe and tolerable at single doses high enough to achieve significant target development for the treatment of AD, according to study investigators.

Lead author Adam Mecca, MD, PhD, associate professor of psychiatry and associate director of the Alzheimer’s Disease Research Unit at the Yale School of Medicine, sat down with NeurologyLive® at the meeting to discuss the study and its outline. In addition, he spoke about the design of ALX-001, its mechanism of action, and why there’s belief for potential therapeutic impact in AD. Furthermore, he spoke on the origins of the drug and how preclinical findings at Yale led to its discovery.

Click here for more coverage of CTAD 2023.

REFERENCE
1. Mecca AP, Salardini E, Gallezot JD, et al. A phase 1a single ascending dose study of the safety, tolerability, and brain receptor occupancy of BMS-984923 in healthy older adults. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 24-27, 2023; Boston, MA. POSTER OC32