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<a href="https://www.vergegenomics.com/">Verge Genomics</a> has launched a proof-of-concept trial to test whether VRG50635, its oral PIKfyve inhibitor therapy, can be used as a potential treatment for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The Phase 1b study will assess the safety and tolerability of escalating doses of VRG50635 — which works by blocking a protein called PIKfyve — in people with sporadic and familial <a href="https://alsnewstoday.com/forms-of-als/">types of ALS</a>.
In addition to using traditional measures of ALS progression, the trial will employ digital devices to objectively evaluate disease-relevant changes in patients — including changes in mobility, breathing, and sleeping — which may help detect disease progression and treatment responses much earlier than with conventional physician rating scales.
“Incorporating cutting-edge technology into our ALS proof-of-concept study is a necessity born from the urgent unmet need to efficiently study promising therapeutics for people battling this devastating disease,” Diego Cadavid, MD, Verge’s chief medical officer, said in a <a href="https://www.globenewswire.com/news-release/2024/01/09/2806185/0/en/Verge-Genomics-Announces-Initiation-of-Proof-of-Concept-Study-for-the-Treatment-of-Amyotrophic-Lateral-Sclerosis-ALS-with-VRG50635.html">company press release</a>.
This “will make it possible to collect dense amounts of unbiased, objective disease-relevant data to properly assess the safety, tolerability, and potential efficacy, including dose-response, early in clinical development,” Cadavid added.
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<h3>Trial of VRG50635 PIKfyve inhibitor to use digital tools in testing</h3>
ALS is characterized by progressive damage to motor neurons, which are the specialized nerve cells that control voluntary movements. This damage results in muscle weakness and wasting, leading patients to experience progressively worsening issues with mobility and balance, breathing, and speaking.
VRG50635 is designed to slow ALS progression and potentially extend survival in patients by helping motor neurons clear out the toxic protein aggregates, or clumps, that contribute to nerve cell damage.
This PIKfyve inhibitor, which blocks the protein, was identified as a potential treatment target in ALS by Verge&#8217;s artificial intelligence (AI) platform <a href="https://www.vergegenomics.com/approach">ConVERGE</a>. This platform goes through large amounts of biological data from people with a given disease to identify novel therapeutic targets, and then predicts new drugs with a higher probability of clinical success.
PIKfyve&#8217;s function in ALS was described in a <a href="https://pubmed.ncbi.nlm.nih.gov/29400714/">landmark 2018 study</a>. Researchers showed that blocking this protein increased the number of lysosomes, which are cellular organelles that break down faulty or unwanted molecules, and are essential to prevent the accumulation of toxic proteins.
Given that lysosomes are faulty in ALS, inhibiting the activity of PIKfyve could restore their function and improve the clearance of toxic protein clumps, it was thought.
Those discoveries led to the development of VRG50635.
[quote=&#8221;center&#8221;]Initiating our proof-of-concept study marks another important milestone for Verge and further demonstrates that by leveraging our AI-enabled platform in combination with patient data using a novel study design we are able to more efficiently discover and develop potential drugs for deadly diseases like ALS.[/quote]
The therapy has been shown to extended survival of nerve cells from ALS patients and in models of motor neuron degeneration. It also was deemed safe and well tolerated at multiple doses in healthy volunteers who participated in a <a href="https://www.isrctn.com/ISRCTN14792372">Phase 1 clinical trial (ISRCTN14792372)</a>. In these participants, the therapy showed a pharmacological profile that supported once-daily dosing.
“Initiating our proof-of-concept study marks another important milestone for Verge and further demonstrates that by leveraging our AI-enabled platform in combination with patient data using a novel study design we are able to more efficiently discover and develop potential drugs for deadly diseases like ALS,” said Alice Zhang, MD, PhD, Verge’s co-founder and CEO.
In ALS clinical trials, disease progression is often measured with physician-rated scales, such as the ALS Functional Rating Scale Revised (ALSFRS-R). However, these can only be measured in clinical appointments, meaning there&#8217;s only scarce data to monitor disease progression. Such scales also tend to relate poorly to treatment responses.
To address that, Verge will use digital devices to measure changes in functionality in the patients&#8217; own homes. The company also <a href="https://alsnewstoday.com/news/upcoming-als-therapy-trial-monitor-speech-changes-patients/">announced in December</a> it would use <a href="https://modality.ai/">Modality.AI</a>, a computer-based tool for automated assessments of language and speech patterns, in the trial.
The platform uses machine learning to analyze what patients say and how they say it. It does not require specialized equipment and can be done using home devices like smartphones and laptops. According to Verge, this can deliver more precise and comprehensive insights into how VRG50635 may benefit ALS patients.
Other clinicians voiced their support for the VRG50635 study.
“I applaud Verge for creating a bold proof-of-concept design that incorporates cutting-edge technology and scientific innovation in their efforts to create groundbreaking therapies for ALS,” said Angela Genge, MD, director of the ALS Centre of Excellence for Research and Patient Care, at the Montreal Neurological Institute-Hospital.

Verge launches Phase 1 trial to test PIKfyve inhibitor therapy in ALS

A Phase 1b proof-of-concept clinical trial of the experimental oral therapy VRG50635 in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is expected to launch in the coming months, according to the therapy&#8217;s developer, <a href="https://www.vergegenomics.com/" rel="nofollow">Verge Genomics</a>.
Verge also announced that the upcoming trial will use <a href="https://modality.ai/" rel="nofollow">Modality.AI</a>, a computer-based tool that performs automated assessments of language and speech patterns.
“Gradually deteriorating vocal communication is one of the major issues many people with ALS experience. It is, therefore, crucial for us to capture objective data to quantify changes in speech during therapeutic trials and explore how this data can be used to better understand the potential benefits of VRG50635,” Diego Cadavid, MD, Verge&#8217;s chief medical officer, said in a <a href="https://www.globenewswire.com/news-release/2023/11/29/2787605/0/en/Verge-Genomics-Will-Use-Modality-AI-in-Its-ALS-Phase-1b-Clinical-Trial-of-Its-Lead-Drug-Candidate-VRG50635.html">company press release</a>.
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<h3>ALS weakens muscles of mouth and throat, affecting speech</h3>
Clinical trials are the gold standard for testing <a href="https://alsnewstoday.com/experimental-treatments-for-als/">potential disease treatments</a>. One of the most important aspects to consider when designing these studies is determining their endpoints — that is, what measurements will be used to determine whether or not the experimental treatment is working.
&#8220;Endpoints used in ALS trials are often subjective, biased, and only limited objective biomarkers of neurological function are available,&#8221; said Anil Tarachandani, PhD, vice president and head of translational medicine at Verge.
ALS is characterized by the progressive death and dysfunction of motor neurons, the nerve cells that control voluntary movements. Degeneration of motor neurons impairs communication with muscles, leading to muscle weakness and atrophy (shrinkage). When muscles in the mouth and throat are affected, patients typically experience <a href="https://alsnewstoday.com/symptoms-of-als/#Speech_problems">problems with speech</a>, among the common <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms of ALS</a>.
Modality.AI uses a multimodal platform where a computer analyzes what patients say and how they say it. The platform doesn&#8217;t require a doctor or specialized equipment; it can be done using home devices like smartphones and laptops.
To analyze vocal recordings, Modality.AI uses machine learning, a branch of artificial intelligence, in which a computer is given a set of mathematical rules, called algorithms, alongside a heap of data. The computer uses the algorithms to &#8220;learn&#8221; from these data by detecting patterns, and patterns then be can applied to build models that help in understanding new data.
&#8220;There are several publications already on the ability of Modality’s platform to measure vocal communication in ALS. Using speech as an objective endpoint in ALS trials can provide evidence of the efficacy of potential therapeutic interventions, such as VRG50635,&#8221; Tarachandani said.
The platform &#8220;has been extensively used by the broader ALS community and can provide insights into ALS disease progression,&#8221; he added.
<h3>Trial in healthy adults supports VRG50635 tolerability and safety</h3>
VRG50635 is designed to block the activity of a protein called PIKfyve, which Verge identified as a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112156/">potential treatment target in ALS</a> using a machine learning analysis of biological data.
“At the core of both Verge Genomics and Modality.AI is the use of machine learning in combination with proprietary data sets to optimize drug development,” said David Suendermann-Oeft, PhD, founder and CEO of Modality.AI.
&#8220;While the Verge platform is designed to predict new drugs with a higher probability of clinical success, Modality.AI’s multimodal platform reduces inefficiencies in clinical trials of these new drugs, increasing the success probability … by delivering more accurate and comprehensive insights into how these drugs may benefit people with ALS,&#8221; he added.
Verge reported top-line data from a <a href="https://www.isrctn.com/ISRCTN14792372">Phase 1 trial (ISRCTN14792372)</a> of VRG50635 in healthy adults earlier this year. Results showed that the experimental <a href="https://alsnewstoday.com/news/potential-oral-therapy-vrg50635-found-safe-healthy-adults/">treatment was generally well tolerated</a> at varying doses and may be given once daily.
In addition to working with Modality.AI, Verge previously <a href="https://www.businesswire.com/news/home/20230523005354/en/Verge-Genomics-to-Incorporate-Emerald-Digital-Health-Technology-into-its-ALS-Phase-1b-Proof-of-Concept-Clinical-Trial" rel="nofollow">announced a collaboration</a> with <a href="https://emeraldinno.com/" rel="nofollow">Emerald Innovations</a> for the upcoming trial of VRG50635 in ALS patients.
Under this earlier collaboration, the trial will incorporate digital sensors made by Emerald in study participants&#8217; homes, allowing continuous monitoring of breathing, sleeping, walking, and other aspects of daily life that are impacted by ALS.

Changes in speech with ALS to be monitored in planned Phase 1b trial

VRG50635, an experimental oral therapy being developed by <a href="https://www.vergegenomics.com">Verge Genomics</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), was found to be safe and well-tolerated in healthy volunteers, new Phase 1 trial data show.
Top-line data from the <a href="https://www.isrctn.com/ISRCTN14792372">trial (ISRCTN14792372)</a> 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 <a href="https://alsnewstoday.com/sporadic-als/">sporadic</a> and <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> 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 <a href="https://www.businesswire.com/news/home/20230615018038/en/Verge-Genomics-Announces-Positive-Safety-and-Tolerability-Data-from-the-Phase-1-Clinical-Trial-of-VRG50635-a-Potential-Best-in-Class-Therapeutic-for-All-Forms-of-ALS">company press release</a>.
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<h3>VRG50635 works to block PIKfyve, identified by AI as therapeutic target</h3>
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 <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>. Motor neurons are the nerve cells that control muscle movement and are progressively lost in ALS.
VRG50635 <a href="https://alsnewstoday.com/news/verge-starts-first-human-trial-pikfyve-inhibitor-als/">advanced from discovery</a> 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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<h3>Data to be presented at upcoming European conference in Barcelona</h3>
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.”

Tag: VRG50635

Verge launches Phase 1 trial to test PIKfyve inhibitor therapy in ALS

Changes in speech with ALS to be monitored in planned Phase 1b trial

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