Potential of mGluR5 Modifier ALX-001 in Neurodegenerative Disorders

Commentary
Article

Tim Siegert, PhD, chief operating officer and co-founder of Allyx Therapeutics, provided commentary on the recently announced positive phase 1b results for ALX-001, an agent in development for Alzheimer and Parkinson disease.

Tim Siegert, PhD, chief operating officer and co-founder of Allyx

Tim Siegert, PhD

ALX-001 (Allyx Therapeutics), previously known as BMS-984923, is a silent allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), and is a first-in-class compound that selectively blocks the pathogenic activation of the receptor while preserving the normal physiological glutamate signaling that is required for cognition. Previous research has shown that mGluR5 is involved in regulating integrative brain function and synaptic transmission, and that aberrant mGluR5 signaling may play a key role in the initial pathophysiological mechanism of Alzheimer disease (AD).

Recently, Allyx Therapeutics announced positive topline data from its phase 1b study assessing ALX-001 in cognitively normal older adults. In the trial, 32 participants aged 50 to 80 years old were randomized to receive 50 mg (n = 8), 100 mg (n = 8), 100 mg (n = 8), or 150 mg (n = 8) of either ALX-001 or placebo. At the doses studied, the agent was safe and generally well tolerated, with no clinically significant changes observed in cognitive of psychological symptom scales. In addition, 50 mg BID of ALX-001 achieved a 2-fold coverage of IC80 mGluR5 receptor and 100 mg BID mean Ctrough provided a 6-fold coverage of IC80 mGluR5 receptor occupancy.

The company has already begun to initiate 2 small, grant-funded pilot patient studies assessing ALX-001 in AD and Parkinson disease. Following the announcement of the positive data, NeurologyLive® reached out to Tim Siegert, PhD, chief operating officer and co-founder of Allyx, to provided commentary. He spoke on the safety profile of the agent, some of the key findings from the study, and how ALX-001 differs from other therapies with similar mechanisms of action.

NeurologyLive®: How does the phase 1b data add to the profile of ALX-001?

Tim Siegert, PhD: The phase 1b data expands our safety and pharmacokinetic understanding of ALX-001. This was our first study with repeated dose administration. We successfully demonstrated all doses were safe out to 20 days of dosing in healthy volunteers. From a safety perspective, all doses were well-tolerated with no serious adverse events. Importantly, ALX-001 did not show any neuropsychiatric or cognitive adverse events that are common with high concentrations of mGluR5 negative allosteric modulators. This demonstrates that ALX-001 is a unique, first-in-class, silent allosteric modulator which preserves normal glutamate function and is selective for disease pathology. We have defined a range of safe doses and exposures to advance ALX-001 into trials with Alzheimer and Parkinson disease. We plan to further investigate the 50 and 100mg doses in additional studies in patients.

What is the significance of the more than 2-fold coverage of IC80 seen across the treatment groups?

For ALX-001, we are able to measure target engagement by imaging receptor occupancy with PET. This takes the guesswork out of dose translation and selection, which has been a challenge in CNS diseases. This is significant because our preclinical studies showed that 80% occupancy of the mGluR5 receptors rescued learning and memory deficits and reversed synapse loss in transgenic and knock-in mouse models of Alzheimer’s disease. From our human phase 1a receptor occupancy study, we know achieving 136 ng/mL plasma concentration results in 80% receptor occupancy (defining the IC80 concentration). This indicates that, even at the lowest dose (50mg BID), ALX-001 can be expected to demonstrate a therapeutic effect.

How does this agent differ from others that have a similar mechanism of action?

Targeting amyloid-b oligomer toxicity is one of the most interesting areas of Alzheimer’s disease clinical development. Biogen and Eisai’s lecanamab validated that amyloid-b oligomers are neurotoxic and that removing them can deliver some therapeutic benefit to patients. We think we can do better by directly protecting the synapse from the toxic presence of amyloid-b oligomers. Many Alzheimer’s programs are now focused on more highly selective amyloid-b oligomer targeted monoclonal antibodies, but clinical benefits are likely to be limited due to selectivity, dosing and safety challenges. This has been reinforced by slow clinical adoption of new therapies so far. Allyx’s approach is different. ALX-001 is a first-in-class oral therapy for neuroprotection from toxic oligomers. Instead of targeting amyloid-b oligomers, ALX-001 blocks amyloid-β oligomer synaptic receptor signaling to protect synapses and halt dysfunction and loss. ALX-001 avoids the known risks of direct amyloid binding, increasing the likelihood of better efficacy and safety in an oral therapy. Even with comparable efficacy, an oral treatment would significantly improve access and administration across healthcare settings.

What will the phase 2 studies in AD and PD look like?

Allyx Therapeutics has initiated a 28-day safety study of ALX-001 in Alzheimer’s disease patients (NCT05804383) and is initiating a study in patients with Parkinson disease as well. Allyx’s phase 1b results support the advancement of ALX-001 into phase 2 studies. Allyx is designing its phase 2 trials to best leverage advancements in biomarkers and clinical tests with input from Alzheimer’s KOLs, investors, and the scientific community.

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