Allyx Therapeutics is planning a Phase II study to demonstrate proof of concept in Alzheimer’s disease with its lead drug ALX-001 (BMS-984923) using a synaptic approach,

Allyx Therapeutics is currently in the planning stages for a Phase II study. The goal for the Phase II study will be to demonstrate proof of concept in Alzheimer’s disease (AD) patients using a synaptic approach, COO and co-founder Timothy Siegert told Clinical Trials Arena.

The company presented results from the Phase Ia clinical trial (NCT04805983) of ALX-001 evaluating patients with early to mid-stage Alzheimer’s disease at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference on 27 October. The meeting was held in Boston, Massachusetts.

ALX-001 is a silent allosteric modulator designed to block the pathogenic binding of toxic amyloid-β oligomers (AβOs) and cellular prion protein (PrPᶜ) to glutamate receptor, mGluR5, thereby preventing the activation of an intracellular cascade that triggers synaptic dysfunction and synapse loss. In selectively regulating mGluR5, neurons are able to preserve normal glutamate signalling function that is vital to cognition.

Patient diversity is an important target for their Phase II proof of concept study, said Siegert. The majority of enrolled patients (97.2%) in the Phase Ia study, were identified as White, as per the CTAD abstract.

A diverse Phase II study is essential to make sure any observed results will translate effectively into the real world and provide a solution for all patients with Alzheimer’s disease, said Siegert.

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In the open-label, single-ascending dose Phase Ia study, 36 patients were divided equally into six cohorts to receive six sequentially increasing doses of ALX-001. The doses ranged from 10mg to 200mg.

The newly released data showed that ALX-001 met its primary endpoints in safety, tolerability, and pharmacokinetics by the seventh day following the final dosage. The majority of patients (64%) did not experience treatment-emergent adverse events and there were no recorded clinical lab abnormalities or changes in the safety profile of the drug.

In healthy adults, all six dose levels of ALX-001 were tolerable, and in data recorded between zero- and 24-hours following dose administration, the drug demonstrated significant target engagement with the plasma exposure levels being considerably below the no observed adverse effect level (NOAEL).

The potency of ALX-001 required to inhibit mGluR5 binding by 50% and 80% was 34ng/mL and 136ng/mL respectively.

Timothy Siegert PhD, COO and co-founder. Image Credit: Allyx Therapeutics

“We’re really well-positioned to deliver the drug in high concentrations to achieve really high receptor occupancy in the brain and safe doses,” said Siegert.

As the drug was previously tagged with 18F-FPEB, a radioligand that could be detected using positron emission tomography (PET), the study also quantified direct mGluR5 receptor occupancy. The receptor occupancy data allowed the company to build a model between target engagement in the brain and plasma concentrations, said Siegert. Allyx now plans to use the informed model for dose selection in future clinical trials, he added.

“In neuroscience, one of the challenges is always selecting a dose, because the brain is often a black box,” said Siegert. “So you’re really flying blind in dose selection and guessing based on downstream biomarker changes. In this case, we would know very accurately how much is actually hitting the receptor.”

Allyx Therapeutics is also conducting a Phase Ib (NCT05804383) ALX-001 multiple ascending dose and safety study in healthy patients with AD. The study’s expected completion is in November 2024.