NeuroVoices: Adam Mecca, MD, PhD, on mGlurR5 Modulator ALX-001 as Potential Treatment for Alzheimer Disease

Adam Mecca, MD, PhD

Brain synapse loss in Alzheimer disease (AD) has been tightly correlated with cognitive symptoms and developing drugs that preserve or restore synapses is an important therapeutic goal. In preclinical mouse models of AD, treatment with ALX-001, an investigational agent developed by Allyx Therapeutics, recovered synapses density, restored long term potentiation, and returned memory performance to wild-type levels. Previously known as BMS-984923, ALX-001 is a silent allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5) receptor complex.

At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, Allyx presented new phase 1 data from a single-ascending dose study assessing the agent in 30 patients with normal cognition. Six cohorts of 6 participants were administered a single dose of either 10, 40, 70, 100, 150, or 200 mg, with monitoring that occurred for 7 days after administration. All told, the therapy was well tolerated with no serious adverse events (AEs). Plasma exposure increased linearly with increasing oral doses of the therapy, further supporting its development in older adults and patients with AD.

To learn more about the mechanism of action of ALX-001 and how it may be beneficial to patients with AD, NeurologyLive® sat down with principal investigator Adam Mecca, MD, PhD, associate director of the Alzheimer’s Disease Research Unit at the Yale School of Medicine. As part of a new iteration of NeuroVoices, Mecca gave thoughts on the emergence of mGluR5 inhibitors, the role of synaptic plasticity in AD, and how these mechanisms may interplay with other prominent AD biomarkers.

NeurologyLive®: Can you provide some background on the study and what it entailed?

Adam Mecca, MD, PhD: This is a first-in-human study with this drug. The design aims to dose six different cohorts, starting from 10 milligrams and working up to 200 milligrams, giving a single dose. Participants, aged 55 to 80, were screened for cognitive health. Each cohort, for at least the first dose, also underwent PET scans to measure the receptor occupancy of the drug. This was a unique aspect accomplished at our site at Yale. We were very interested in being involved for this reason. People would come in, stay in an inpatient unit for heavy monitoring for days one, two, and three. Then, they would undergo outpatient monitoring through day seven, and the trial was completed after day seven.

Regarding the mechanism of action of ALX-001, why do we believe it has potential?

The drug's mechanism is based on preclinical work done by Stephen Strittmatter, MD, PhD, AB, at Yale. It focuses on the metabotropic glutamate receptor subtype (mGluR5). In normal situations, it's thought to regulate synapses through calcium regulation. However, in Alzheimer's disease models, amyloid beta oligomers exert a pathologic signaling through mGluR5. The drug, known as BMS984923, inhibits this interaction at an allosteric site, where it doesn't interfere with normal physiologic glutamate signaling. This is crucial because other molecules that bind to receptors are either positive or negative allosteric modulators, affecting normal physiologic activity to increase or decrease it. This drug doesn't seem to change normal physiologic mGluR5 signaling. This is important because inhibiting normal physiologic mGluR5 signaling, in animal models, might be helpful in Alzheimer's disease. However, drugs that do that have a narrow therapeutic index because they start to exert toxicity. This is due to the need for normal glutamate signaling for normal functioning. This drug can interfere with the interaction without causing an impact on normal physiologic glutamate signaling, giving it a potentially large therapeutic index. This could allow for high target engagement and a drug that has the potential to be dosed at sufficient levels to be effective in Alzheimer's disease in humans.

How do you envision this therapy working with other antiamyloid agents?

The mechanism focuses on the fact that early amyloid species, the soluble amyloid beta oligomers, exert synaptic toxicity. This drug aims to block those oligomers from causing toxicity, providing a different mechanism than drugs clearing amyloid. It seems reasonable that targeting different aspects of amyloid toxicity pathways could be relevant. Also, it's still not known what the connection is between things like inflammation and amyloid accumulation and tau accumulation. There's evidence that this pathway is involved in pathologic phosphorylation of tau and tau deposition. So, it's possible that there can be synergy there. At the very least, there could be some synergy in some kind of combination of treatments, including a drug like this.

In what ways has the literature and understanding of synaptic plasticity grown?

The basis for thinking about synapses and synaptic loss in Alzheimer's disease goes back to human pathologic studies, post-mortem studies that are 20 to 30 years old. Recent advancements include using PET tracers to measure synapse density more directly, targeting a protein called SVP2. This protein is found on synaptic vesicles, and targeting it with a PET tracer allows for measuring the abundance of synapses. This technology is used to confirm expected changes with Alzheimer's disease, correlate changes with cognitive loss, correlate changes with the accumulation of tau protein, and show synaptic change convincingly. The synaptic markers might be useful for assessing the effectiveness of certain drugs. For example, this drug is thought to prevent synapse toxicity and restore synapses in animal models. So, the next step is to do a phase one study, which is already underway. It's a multiple ascending dose study in humans, moving into early Alzheimer's disease. The study assesses safety and tolerability but also collects some pilot data using Synaptic PET imaging before and then a month after treatment.

Is there anything else noteworthy you’d like to mention?

We're excited to continue down this pathway. Things are moving along smoothly. I should also acknowledge our funders. The National Institutes of Aging has funded both the phase one A and B, along with the Alzheimer's Association. We're very grateful for their support.

Transcript edited by artificial intelligence.