Synapse-Targeting Agent ALX-001 Ready for Phase 2 Following Early-Stage Progress


ALX-001, a first-in-class compound, will be assessed in an additional cohort of patients with Alzheimer disease as the company continues to plan for phase 2 studies.

Stephen Bloch, MD, chief executive officer and co-founder at Allyx

Stephen Bloch, MD

According to a recent announcement, patient dosing has commenced for part 2 of a phase 1 study (NCT05804383) assessing Allyx Therapeutics investigational, synapse-targeted agent ALX-001 as a potential treatment for Alzheimer disease (AD). In its release, the company noted that they are ready to proceed to phase 2 clinical development, and is not restricted by completion of ongoing studies.1

This second phase, which evaluates the safety of ALX-001 dosed twice daily at either 50 mg or 100 mg vs placebo, features patients with AD between 50 and 80 years of age. It builds off previously completed single- and multiple-ascending dose portions that assessed the efficacy and safety of ALX-001, a silent allosteric modulator of mGluR5, in healthy, cognitively normal volunteers.

ALX-001, which has been in development for more than a decade, is a first-in-class compound that selectively blocks the pathogenic activation of the receptor while preserving the normal physiological glutamate signaling that is requiring for cognition. To date, studies have shown that mGlur5 is essential for mediating synaptic dysfunction and loss caused by multiple misfolded extracellular protein species, and as such, represents a novel approach to treating AD and Parkinson disease (PD).

Stephen Bloch, MD, chief executive officer and co-founder at Allyx, said in a statement, "Administering the first dose in patients is a watershed moment for a new therapeutic, and we are pleased to begin research in patients with Alzheimer disease as we continue to advance clinical development of ALX-001 to become the first-ever disease-modifying small molecule for neurodegenerative diseases."

To date, ALX-001’s clinical program has acquired more than $20 million in grant funding from the National Institutes of Health, the U.S. Government’s highly competitive Small Business Innovation Research programs, the Alzheimer’s Association, and the Michael J. Fox Foundation for Parkinson’s Research, among others. The molecule was originally identified by Bristol Myers Squibb, but the mechanism of action for neurodegenerative diseases was discovered by Allyx scientific founder and Yale University professor Stephen Strittmatter, MD, PhD. In 2021, Allyx officially licensed the agent from Bristol Myers Squibb.

"Every neuroscientist hopes for the moment that an asset they believe in and fight for advances to the critical stage of testing in patients,” Strittmatter said in a statement.1 "The unique mechanism of action of ALX-001 and its promising early data have brought us to this point, and bolster our hope that it has the potential to be a difference-maker in Alzheimer disease."

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Previous data form the phase 1b study, presented at the AD/PD 2024 Conference earlier this year, showed that ALX-001 was safe, with no clinically significant changes in cognitive or psychological symptom scales. The study comprised of 32 participants who completed the single-ascending dose portion who were then randomly assigned 6:2 to either twice daily ALX-001 or placebo. Across the 50, 100, 150, or 225 mg groups, findings showed that the agent maintained a 2.5-fold safety margin relative to the no observed adverse effect level.

Additional findings revealed that 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. All adverse events (AEs) reported were supposedly mild and patients fully recovered.

Following the positive reported data, Tim Siegert, PhD, chief operating officer and co-founder of Allyx, provided commentary, stating, “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."

In terms of how this drug differs from previously approved antiamyloid therapies, he added that “We think we can do better by directly protecting the synapse from the toxic presence of amyloid-b oligomers. Many Alzheimer 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."

1. Allyx Therapeutics announces first Alzheimer’s disease patient treated with lead compound ALX-001. News release. June 11, 2024. Accessed July 2, 2024.
2. Siegert T, Simms P, Post S, Mecca A, van Dyck C, Strittmatter S. A phase 1b multiple ascending dose study of the safety, tolerability, and pharmacokinetics of ALX-001, an mGluR5 silent allosteric modulator, in healthy older adults. Presented at: AD/PD 2024.
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