Potential ALS therapy, VRG50635, found to be safe in healthy adults

Verge Genomics' proof-of-concept study of oral VRG50635 expected in the fall

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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VRG50635, an experimental oral therapy being developed by Verge Genomics for amyotrophic lateral sclerosis (ALS), was found to be safe and well-tolerated in healthy volunteers, new Phase 1 trial data show.

Top-line data from the trial (ISRCTN14792372) also showed a promising tolerability and pharmacological profile supporting once-daily dosing.

The company is now planning to advance the treatment into a proof-of-concept study in people with sporadic and familial ALS that’s expected to start in the final months of 2023.

“We are extremely encouraged by these initial results which highlight the favorable safety and tolerability profile of VRG50635,” Diego Cadavid, MD, chief medical officer of Verge, said in a company press release.

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VRG50635 works to block PIKfyve, identified by AI as therapeutic target

VRG50635 is a small molecule designed to block the PIKfyve protein, a potential therapeutic target in ALS. PIKfyve was identified by the company’s artificial intelligence (AI) platform after sorting a large amount of biological data stemming from brain and spinal cord samples of ALS patients.

The protein is thought to play a role in the endolysosomal pathway, a kind of recycling system inside cells that helps break down faulty or unneeded molecules to keep the cells clean and functioning properly.

In ALS patients, this recycling system is usually not working as needed, leading to the buildup of toxic protein clumps — a hallmark of the disease known to contribute to the death of motor neurons and the progression of symptoms. Motor neurons are the nerve cells that control muscle movement and are progressively lost in ALS.

VRG50635 advanced from discovery to a first-in-human trial in four years. In the lab, it extended survival of nerve cells from ALS patients and models of motor neuron degeneration.

“The lack of predictive animal models is one of the greatest challenges to developing effective ALS therapies today,” said Alice Zhang, CEO and co-founder of Verge. “This is why we’re excited to advance VRG50635, a drug derived directly from human data, into trials in people with ALS.”

The Phase 1 trial tested VRG50635 versus a placebo in 80 healthy adult volunteers. The therapy was given at different doses once or multiple times over one week, starting with a low dose of 60 mg and gradually increasing it up to 1,800 mg in subsequent groups.

There were no serious side effects, and VRG50635 was considered safe. The therapy was also deemed well-tolerated at the highest planned dose.

Data also showed the maximum concentration of VRG50635 in the body and the total exposure to the drug increased in proportion to the dose. Its active metabolite had a half-life (the time taken for its concentration to reduce by half) of about 37 hours, suggesting that VRG50635 may be taken by mouth once daily.

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Data to be presented at upcoming European conference in Barcelona

More detailed data will be presented at the upcoming European Network to Cure ALS (ENCALS) 2023 meeting, which will be held July 12-14 in Barcelona, Spain.

“We look forward to sharing additional information at the ENCALS meeting in Barcelona next month and anticipate progressing to a proof-of-concept study in patients with sporadic and familial ALS later this year,” Cadavid said.

According to Zhang, the study is “designed to overcome historical challenges in ALS clinical trials by using state of the art technology, such as digital at-home devices and blood-based biomarkers, that can capture richer, higher-fidelity patient data and have the potential to detect efficacy with greater sensitivity.”