ALX001 to Advance to Phase 2 Studies Following Positive Phase 1b MAD Data

Tim Siegert, PhD

At the AD/PD 2024 Conference, Allyx Therapeutics presented new phase 1b data from its multiple-ascending dose study (NCT05804383) assessing ALX-001, a first-in-class, synapse-targeted, disease-modifying therapy in development for neurodegenerative diseases. All told, the agent was safe in cognitively normal older adults at all doses investigated, and will be advanced into phase 2 studies of Parkinson disease (PD) and Alzheimer disease (AD).^1,2

Following the single-ascending dose (SAD) portion of the study, all 32 participants moved on to phase 1b of the study, where they were randomly assigned 6:2 to either twice daily ALX-001 or placebo. Phase 1b included 4 cohorts of healthy adults aged 50 to 80 years old who received either 50 mg (n = 8), 100 mg (n = 8), 100 mg (n = 8), or 150 mg (n = 8) of either treatment. The goal of the study was to establish the safety, tolerability, and pharmacokinetics of ALX-001, a silent allosteric modulator of metabotropic glutamate receptor subtype 5 (mGluR5).

The study comprised of older adults, with a mean age of 61 (SD, 7.26) years old, who were mostly White (90.6%). Safety assessments included vital signs, physical exams, ECGs, Montreal Cognitive Assessment, Neuropsychiatric Inventory, GDS, GCS, safety labs, and adverse events (AEs). All told, no clinically significant changes in cognitive or psychological symptom scales were recorded. Additionally, all AEs were mild and patients fully recovered.

"We are excited to begin the next phase of development with the initiation of two 28-day patient studies, the first studies of ALX-001 in people living with Alzheimer’s and Parkinson’s disease," Tim Siegert, PhD, chief operating officer and co-founder of Allyx, said in a statement. "We believe that the results from the Phase 1b MAD study directly support larger scale Phase 2 clinical development to more fully understand the potential for ALX-001 to become the first-ever disease-modifying small molecule for neurodegenerative diseases."

At the doses studies, findings from the study showed that the agent maintained a 2.5-fold safety margin relative to the no observed adverse effect level (NOAEL). 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. Notably, ALX-001 achieved high target engagement while avoiding mGluR5 related AEs typically seen from other agents in this class.

In the phase 1a single-ascending dose portion, presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, results showed that ALX-001 was safe and well tolerated at all doses. In single doses of 10 mg to 200 mg, there were no serious AEs and 7 mild grade 1 possibly related AEs. The study confirmed oral bioavailability and validated target engagement via mGluR5 PET imaging.³

READ MORE: Short Questionnaire Accurate in Identifying Parkinson Disease-Associated Psychosis

"The data show that ALX-001 achieved high target engagement without any adverse events related to mGluR5, which supports our vision to mediate synaptic dysfunction and loss while avoiding the on-target toxicity observed with other treatment modalities," Stephen Strittmatter, MD, PhD, professor and chair of Neuroscience, Yale University School of Medicine, and scientific founder of Allyx Therapeutics, said in a statement.¹

The company has already begun to initiate 2 small, grant-funded pilot patient studies assessing ALX-001 in AD and PD. Both studies are similar in design, testing a 3-arm parallel dose at 50 mg BID, 100 mg BID, and placebo for a 28-day period. The AD trial is funded by the National Institutes of Health while the PD study is funded by the Michael J. Parkinson’s Foundation for Parkinson’s Research.

Brain synapse loss in 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 recovered synapses density, restored long term potentiation, and returned memory performance to wild-type levels.

At CTAD 2023, principal investigator Adam Mecca, MD, PhD, associate director of the Alzheimer’s Disease Research Unit at the Yale School of Medicine, told NeurologyLive®, "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."

REFERENCES
1. Allyx Therapeutics announces positive phase 1b multiple ascending dose data and advances ALX-001 to patients. News release. March 11, 2024. Accessed March 12, 2024. https://finance.yahoo.com/news/allyx-therapeutics-announces-positive-phase-120500339.html
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.
3. 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