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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.
[recommended-reading id=85141]
<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

Magnetic stimulation restored the health of lab-grown motor neurons — the muscle-controlling nerve cells that die in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — derived from people with familial ALS, according to a proof-of-concept study.
The approach improved several biological processes in motor neurons, including the movement of cellular components along nerve fibers, or axons, and the growth of new axons.
“In the numerous series of experiments, we were able to demonstrate that the motor neurons from ALS patients respond to the magnetic fields,” Arun Pal, a cell biologist at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) research center, in Germany, who served as the study&#8217;s co-senior author, said in a <a href="https://www.hzdr.de/db/Cms?pNid=99&amp;pOid=69393">university press release</a>.
Thomas Herrmannsdörfer, PhD, another study author from the HZDR, noted that “detailed follow-up studies are required to corroborate [these] findings,” but added, “We regard these … results as an encouraging approach on the path to a potential novel therapy for ALS as well as other neurogenerative diseases.”
The study, “<a href="https://www.mdpi.com/2073-4409/12/11/1502">Restoring Axonal Organelle Motility and Regeneration in Cultured FUS-ALS Motoneurons through Magnetic Field Stimulation Suggests an Alternative Therapeutic Approach</a>,” was published in the journal <a href="https://www.mdpi.com/journal/cells">Cells</a>.
[recommended-reading id=79602]
<h3>Magnetic stimulation applied to lab-grown motor neurons</h3>
Motor neurons are nerve cells in the brain and spinal cord that send signals to muscles to perform various bodily functions, including movement, speaking, swallowing, and breathing. Their <a href="https://qbi.uq.edu.au/brain/brain-anatomy/axons-cable-transmission-neurons">axons</a> — the cable-like part that snakes away from the main part of the cell — are the longest in the body and can stretch from the spinal cord to the toes.
Most cases of ALS are characterized by the sporadic and progressive loss of motor neurons. In about 10% of cases, however, inherited genetic mutations are responsible for motor neuron death.
Magnetic stimulation is a non-invasive procedure that uses magnetic fields to stimulate nerve cells. It&#8217;s been approved for use in psychiatric disorders, such as depression.
A small clinical trial recently showed that <a href="https://www.nature.com/articles/s41598-019-39313-z">magnetic stimulation slowed muscle function decline</a> in ALS patients.
To investigate its impact at the cellular level, researchers in Germany now applied magnetic stimulation directly to lab-grown motor neurons derived from three ALS patients carrying inherited <a href="https://alsnewstoday.com/causes-of-als/">disease-causing mutations in the FUS gene</a>.
Motor neurons were grown from patient-derived induced pluripotent stem cells, called iPSCs. Such iPSCs are generated from fully matured cells that are reprogrammed back to a stem cell-like state, where they can give rise to almost every type of human cell.
The team previously showed the movement of cellular components, or organelles, along axons was <a href="https://alsnewstoday.com/news/neurodegenratioals-patients-linnked-faulty-dna-repair/">impaired in spinal motoneurons</a> derived from FUS-ALS patients. These <a href="https://www.nature.com/articles/s41467-017-02299-1#:~:text=we%20observed%20the%20appearance%20of%20an%20axonal%20phenotype%20in%20FUS%2DALS%20with%20a%20virtual%20arrest%20of%20mitochondria%20and%20lysosomes%20distally%20as%20opposed%20to%20normal%20motility%20proximally">organelles included</a> mitochondria, the cell’s energy producers, and lysosomes, the cell’s recycling centers.
Now the researchers found that magnetic stimulation restored the movement of these organelles in lab-grown patient-derived motor neurons without affecting cells derived from three healthy people. Restoration depended on the frequency of the magnetic field, with a combination of 2 and 10 Hz (cycles per second) generating the best results.
“The axonal transport of mitochondria (the power stations of the cell) and other organelles that are impaired in ALS cells is reactivated by stimulation with magnetic fields,” Pal said.
[recommended-reading id=82060]
<h3>Scientists now planning clinical pilot studies</h3>
In FUS-ALS mouse models, the growth, branching, and distribution of axons — which go on to form connections to other nerve cells as well as muscle cells — have been shown to be impaired.
Consistently, untreated patient-derived motor neurons showed slower outgrowth than those derived from healthy controls.
With the 10 Hz treatment, axons of patient-derived motor neurons grew as fast as control cells, while the 2 Hz and 2/10 Hz combination did not show significant changes. No evidence of magnetic stimulation-related adverse effects on patient and control motor neurons was observed.
These findings showed that, with magnetic stimulation treatment, “axonal regeneration — which is the ability to regrow and reconnect — can be restored,” Pal said.
The shape of nerve cells is unique, with axons extending from the cell body. This shape is dictated by the cytoskeleton, a complex network of interlinking proteins called microtubules that helps cells maintain their shape and internal organization.
The levels of a microtubule stabilization marker were significantly lower in FUS-ALS motor neurons relative to controls. With magnetic stimulation, marker levels in patient cells rose back to control levels, pointing to “an improvement of microtubule stability that is feasibly beneficial for deficient axonal organelle trafficking and regeneration,” the researchers wrote.
“This work provides proof of concept demonstrating that magnetic field treatments are powerful in restoring several hallmarks of ALS [development] recapitulated in our cultured disease model of human iPSC-derived spinal [motor neurons],” the team concluded.
“Long-term and [living organism] studies are required to further substantiate the therapeutic potential of magnetic field treatments,” they added.
The scientists are now planning clinical pilot studies to assess the therapeutic potential of magnetic simulation, applied with specialized equipment.

Magnetic stimulation seen to restore ALS motor neurons in cell study

Four people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) each experienced a marked slowing in disease progression with COYA 302, an experimental immune-modulating therapy tested in a small proof-of-concept clinical trial, according to <a href="https://www.coyatherapeutics.com/">Coya Therapeutics</a>, its developer.
Based on these findings, Coya is planning to start work on further trials to test the therapy candidate in larger groups of ALS patients. Pending regulatory approvals, the company hopes to begin Phase 1b/2 clinical testing later this year or early next year.
&#8220;We believe the results of this initial proof-of-concept study in a small number of ALS patients are encouraging and warrant conducting a larger and controlled industry-sponsored study,&#8221; Adrian Hepner, MD, chief medical officer of Coya, said in a <a href="https://www.businesswire.com/news/home/20230321005042/en/Coya-Therapeutics-Inc.-Announces-Positive-Results-from-a-Proof-of-Concept-Academic-Clinical-Study-for-COYA-302-in-Amyotrophic-Lateral-Sclerosis-ALS">company press release</a>.
Stanley Appel, MD, chair of Coya’s scientific advisory board and a trial investigator at Houston Methodist Research Institute, in Texas, shared the study&#8217;s findings at the Muscular Dystrophy Association&#8217;s MDA Clinical &amp; Scientific Conference, held March 19-22 in Dallas. His talk was titled, &#8220;Novel Treg-modulating Immunotherapy Targets Inflammation in ALS.&#8221; The work was funded in part by Coya.
[recommended-reading id=77518]
<h3>Seeking to slow disease progression in ALS</h3>
COYA 302 contains a combination of the immune signaling molecule IL-2 and a fusion protein known as CTLA4-Ig or abatacept. It is administered via subcutaneous (under-the-skin) injection.
The therapy is designed to reduce inflammation by increasing the activity of regulatory T-cells — a type of anti-inflammatory immune cells known as Tregs — while simultaneously decreasing the activity of pro-inflammatory immune cells
Inflammation in the nervous system, termed neuroinflammation, is &#8220;an extremely important part in propagating neuronal injury in ALS,&#8221; Appel said.
Coya recently forged an agreement with a global pharmaceutical company known as Dr. Reddy’s Laboratories for the production of COYA 302. Under the agreement, Coya will produce the IL-2 component of the therapy — which the company is also developing separately under the name COYA 301 — while Dr. Reddy&#8217;s will provide the CTLA4-Ig part of COYA 302.
&#8220;We believe that the combined resources of both organizations strengthens our chances to bring this therapeutic modality to patients with neurodegenerative diseases if approved by regulatory authorities,&#8221; Howard Berman, PhD, Coya&#8217;s CEO, said in a <a href="https://www.businesswire.com/news/home/20230317005028/en/Coya-Therapeutics-Inc.-Announces-an-Agreement-with-Dr.-Reddy%E2%80%99s-Laboratories-Ltd.-to-License-its-proposed-biosimilar-Abatacept-for-the-Development-and-Commercialization-of-COYA-302-for-the-Treatment-of-Neurodegenerative-Diseases">press release</a> announcing the agreement.
In the proof-of-concept clinical trial, four ALS patients were treated with COYA 302 for 48 weeks, or about one year. The participants then were followed for an additional eight weeks (about two months) after they stopped receiving the medication.
The therapy was generally well tolerated, with no serious side effects reported. The most common side effects were injection site reactions that were mostly rated as mild.
&#8220;Safety and tolerability went very very well in these patients,&#8221; Appel said, noting that the injection reactions seen were similar to reactions that are common with other injectable therapies like insulin.
[recommended-reading id=71573]
<h3>ALS progression slowed, ALSFRS-R scores show</h3>
The participants&#8217; symptom severity and functional abilities were measured with the ALS Functional Rating Scale (ALSFRS-R), in which higher scores indicate a better ability to function. Prior to starting the study, the participants&#8217; ALSFRS-R scores were decreasing at a rate of about 1.1 points per month on average.
At the start of the study (baseline), the average ALSFRS-R score was 33.5 points. Halfway through the study, at week 24, the average score was stable at 33.75 points. After 48 weeks of treatment, the average score had declined less than two points to 32. The difference in scores from the start of the trial to its end was not statistically significant.
These results indicate that ALS progression was slowed considerably while patients were receiving treatment with COYA 302. However, after treatment with COYA 302 stopped, patients showed rates of disease progression resembling those before treatment, going from 32 points in the ALSFRS-R scale to 30 in about eight weeks.
&#8220;The average patient decline, as measured by ALSFRS-R, is approximately -1-point/month. In the present study there was no average decline from baseline to 24 weeks and we observed minimal average decline from baseline to 48 weeks,&#8221; Appel said.
&#8220;To us, this was truly exciting to go 48 weeks and have the patients doing as well as they were, with good safety and good tolerability,&#8221; he said.
[quote align=&#8221;center&#8221;]We believe the results of this initial proof-of-concept study in a small number of ALS patients are encouraging and warrant conducting a larger and controlled industry-sponsored study.[/quote]
Analyses of immune cell function indicated that the therapy was working as designed: data suggested that Treg activity increased during the 48 weeks of treatment with COYA 302, then decreased again once patients were off the therapy. Other markers of inflammation and oxidative stress — a type of cell damage associated with inflammation — also decreased with COYA 302 treatment.
&#8220;The therapy was well tolerated, and most significantly it enhanced [Treg] suppressive functions, suppressed markers of oxidative stress, and ameliorated disease progression over 48 weeks,&#8221; Appel said. He added that these findings suggest COYA 302 &#8220;may provide a potentially meaningful approach for the &#8216;unmet need&#8217; in ALS.&#8221;
Appel stressed that further studies will be needed to conclusively evaluate the efficacy of COYA 302.
But he added, &#8220;We&#8217;re very excited about where we are as the preliminary proof of concept.&#8221;
Coya also is developing a cell therapy called COYA 101, in which Treg cells are administered as a form of treatment. Data from early trials of that therapy also have suggested <a href="https://alsnewstoday.com/news/coya-treg-therapy-als001-als-reduces-inflammation-early-trial/">reductions in oxidative stress</a> and <a href="https://alsnewstoday.com/news/treg-therapy-found-safe-effective-slowing-als-small-trial/">slower ALS disease progression</a>.

MDA 2023: COYA 302 therapy slows ALS progression in early trial

A CRISPR/Cas9 gene editing system can be used to remove the repeat expansion in the C9ORF72 gene, the most common genetic cause of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a new study reports.
The system showed positive proof-of-concept effects in mouse models and in human cells, reducing the amount of faulty RNA molecules and small proteins that contribute to nerve cell death in ALS. RNA is the intermediate molecule produced from a DNA sequence that serves as a template for protein production.
The study, &#8220;<a href="https://www.nature.com/articles/s41467-022-33332-7">CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro</a>,&#8221; was published in <a href="https://www.nature.com/ncomms">Nature Communications</a>.
[recommended-reading id=80380]
<h3>ALS-causing C9ORF72 mutations involve abnormal repeats of DNA sequence</h3>
The <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> are not completely understood, but some cases are associated with <a href="https://alsnewstoday.com/als-and-genetics/">genetic mutations</a>. Mutations in a gene called C9ORF72 are the most common genetic cause of ALS, found in about 40% of <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial</a> cases and 5% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic</a> cases.
ALS-causing mutations in C9ORF72 mainly involve an abnormal repeat of a certain sequence of DNA, called an hexanucleotide repeat expansion (HRE). In the gene, there is a region where six nucleotides (the &#8220;letter&#8221; of the genetic code), namely GGGGCC, are repeated multiple times. In healthy versions of the C9ORF72 gene, there are about two dozen repeats, but in ALS-causing mutations, there can be hundreds or even thousands of these repeats.
The HRE interferes with production of the C9ORF72 protein and leads to the formation of toxic RNA intermediate molecules and small proteins, all of which is thought to contribute to the progression of ALS.
CRISPR/Cas9 was developed by manipulating a similar system that bacteria use to defend themselves against viral infection. Very simplistically, CRISPR/Cas9 gene editing can be used to &#8220;cut out&#8221; a specific region of DNA.
[quote=&#8221;center&#8221;]These proof-of-concept findings support the view that CRISPR methodologies should be explored as a strategy to halt or slow disease progression in [ALS] patients, and potentially other disorders caused by expanded domains of repeated DNA[/quote]
In the study, researchers developed a CRISPR/Cas9 system to &#8220;cut out&#8221; the HRE in an ALS-mutant version of the C9ORF72 gene, without affecting the parts of the gene that provide instructions for making the C9ORF72 protein.
To deliver the system to cells, it was packaged in adeno-associated virus (AAV) vectors. AAV is commonly used in gene therapy applications because it can effectively deliver genetic cargo to human cells and is easy to manipulate in a laboratory, but it doesn&#8217;t cause notable illness in people.
&#8220;AAV has many advantages and is presently regarded as the safest and most effective gene therapy vector for the [brain and spinal cord], with potentially a long-lived therapeutic effect following a single treatment,&#8221; the researchers wrote. However, they stressed that the viral vector they used was &#8220;merely a delivery tool for a proof-of-mechanism,&#8221; noting that other delivery tools will likely be better suited for clinical applications.
After designing the system and conducting initial proof-of-concept and refinement tests in cell lines, the researchers tested the system in several models of ALS.
First, in a battery of experiments done in mouse cell models, the researchers demonstrated that the system could efficiently remove the HRE from nerve cells harboring the ALS-causing mutation in C9ORF72. As designed, the CRISPR/Cas9 system did not interfere with production of the C9ORF72 protein, but it markedly reduced the production of toxic intermediate molecules made from the HRE.
[recommended-reading id=80664]
<h3>CRISPR/Cas9 was able to reduce production of toxic molecules</h3>
Additional experiments done in three mouse models of ALS yielded generally consistent results, with the system effectively removing the HRE and decreasing toxic intermediate production, without affecting C9ORF72 protein levels.
Of note, because the CRISPR/Cas9 system was relatively large, it needed to be delivered to the mice using two separate AAV vectors. Analyses showed that most of the mice&#8217;s cells were delivered genetic cargo from both vectors.
In a final set of experiments, the researchers tested the system in human nerve cells derived from people with ALS caused by C9ORF72 mutations. Consistent with the mouse experiments, results showed that the system could reduce the production of toxic molecules without interfering with C9ORF72 protein levels — in fact, data suggested the system may increase C9ORF72 protein expression in human cells.
&#8220;These proof-of-concept findings support the view that CRISPR methodologies should be explored as a strategy to halt or slow disease progression in [ALS] patients, and potentially other disorders caused by expanded domains of repeated DNA,&#8221; the researchers concluded.

Tag: proof-of-concept study

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

Magnetic stimulation seen to restore ALS motor neurons in cell study

MDA 2023: COYA 302 therapy slows ALS progression in early trial

CRISPR/Cas9 Gene Editing Used to ‘Cut Out’ ALS Mutation: Early Study