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ProJenX has been given the green light to expand its ongoing Phase 1 clinical trial of <a href="https://projenx.com/our-science/">prosetin</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) across the Atlantic Ocean to testing sites in Europe.
The <a href="https://clinicaltrials.gov/study/NCT05279755">PRO-101 trial (NCT05279755)</a>, launched in 2022, is a three-part study evaluating prosetin’s safety, tolerability, and pharmacological properties. Its first two parts — 1a and 1b — involved healthy volunteers and indicated the treatment was generally safe and well tolerated.
Part 1c now is investigating the experimental therapy in people with ALS. The company was <a href="https://alsnewstoday.com/news/phase-1-trial-testing-prosetin-als-patients/">first cleared</a> to launch that portion of the study in Canada, and this authorization allows enrollment to expand to patients in the European Union.
&#8220;This EU clinical trial authorization will allow us to expand the first study of prosetin for people living with ALS to European participants,&#8221; Erin Fleming, <a href="https://projenx.com/">ProJenX</a>’s co-founder and chief operating officer, said in a <a href="https://www.prnewswire.com/news-releases/projenx-receives-european-authorization-for-first-study-of-prosetin-in-people-living-with-als-302061343.html">company press release</a>.
&#8220;We are committed to initiating ALS patient enrollment as quickly as possible,&#8221; Fleming added.
[recommended-reading id=75850]
<h3>Phase 1 trial PRO-101 is 1st to test prosetin in humans</h3>
In ALS, the abnormal folding and clumping of certain proteins is thought to contribute to nerve cell damage and death. In particular, these protein clumps can cause stress in certain cellular compartments, including the endoplasmic reticulum, known as the ER.
This organelle normally works to produce, fold, and transport proteins. But it also can work to help abnormally folded proteins acquire their normal three-dimensional structure — or send them for recycling.
If the ER becomes overwhelmed by the presence of too many unfolded proteins, however, it can lead to cell death.
Prosetin is a first-in-class oral therapy that can reach the brain and reduce ER stress in nerve cells, thereby reducing neuronal damage. It works by blocking a protein called mitogen-activated protein kinase kinase kinase kinase, or MAP4K.
In preclinical studies, ProJenX’s co-founders at Columbia University discovered that blocking MAPK4 protected motor neurons, the cells that are damaged in ALS, in several patient-derived cell models. The team also was able to demonstrate that, by blocking MAPK4, prosetin could reduce inflammation and improve nerve cell survival in several animal models of ALS.
[quote=&#8221;center&#8221;]ALS is a devastating disease, and there is an immense unmet need for therapeutic options to slow or halt its rapid progression.[/quote]
PRO-101 is the first-in-human trial of prosetin. In parts 1a and 1b, healthy volunteers received single or multiple ascending doses of prosetin or a placebo. Part 1c is now evaluating the treatment&#8217;s safety, tolerability, and pharmacological properties in people with ALS.
&#8220;MAP4K inhibition has been shown to protect motor neurons from [ER] stress and other well-established pathological mechanisms of ALS, and we are excited to partner with ProJenX on study PRO-101,&#8221; said Leonard H. van den Berg, MD, PhD, a professor of neurology at UMC Utrecht, chairman of the <a href="https://www.tricals.org/en/">Treatment Research Initiative to Cure ALS</a> (TRICALS), and a PRO-101 study investigator.
TRICALS is the largest European research initiative, encompassing 48 research centers in 16 countries, together with patient organizations and fundraisers, to find effective treatments, and ultimately, a cure for ALS.
According to van den Berg, this is &#8220;the first clinical trial to explore the potential benefits of MAP4K inhibition for ALS patients.&#8221;
Prosetin has been granted <a href="https://alsnewstoday.com/news/prosetin-granted-orphan-drug-designation-for-als/">orphan drug designation</a> by the U.S. Food and Drug Administration for the treatment of ALS. This designation provides several financial incentives, including tax waivers and seven years of marketing exclusivity if the drug ultimately is approved.
&#8220;ALS is a devastating disease, and there is an immense unmet need for therapeutic options to slow or halt its rapid progression,&#8221; van den Berg said.

Phase 1 trial testing prosetin for ALS expands to EU countries

<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

<a href="https://pmneuro.com/" rel="nofollow">PathMaker Neurosystems</a> has launched a Phase 1 clinical trial that will test its experimental noninvasive nerve-modulating device in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
This is the first time that the device — called the <a href="https://pmneuro.com/r-d/alsuppressor/">MyoRegulator</a> and designed to slow disease progression in ALS — will be formally tested in humans. The newly launched trial is being carried out in conjunction with Spaulding Rehabilitation Hospital in Charlestown, Massachusetts.
&#8220;We are tremendously excited to launch this first-in-human trial of MyoRegulator in ALS,&#8221; Nader Yaghoubi, MD, PhD, co-founder and CEO of PathMaker, said in a <a href="https://www.globenewswire.com/news-release/2023/09/14/2743055/0/en/PathMaker-Neurosystems-Announces-Initiation-of-First-in-Human-Trial-in-ALS-for-Non-Invasive-Neuromodulation-Device.html">company press release</a>.
&#8220;Initiating clinical evaluation of our technology in ALS is not only a significant milestone for our company, but a step towards meeting the medical needs of people living with this disease,&#8221; Yaghoubi added.
In a <a href="https://rally.massgeneralbrigham.org/study/als_myoregulator">webpage</a> about the trial, researchers note that &#8220;there are currently a limited number of treatments available for ALS, most of which are pharmaceutical in nature. This study could open a path for a non-invasive, non-pharmaceutical option.&#8221;
[recommended-reading id=81521]
<h3>Device from PathMaker seeks to slow disease progression</h3>
<a href="https://alsnewstoday.com/causes-of-als/">ALS is caused</a> by the progressive dysfunction and death of motor neurons, which are the specialized nerve cells that control movement. The loss of motor neurons disrupts the brain&#8217;s ability to send signals to the body to trigger voluntary movements, ultimately leading to <a href="https://alsnewstoday.com/als-symptoms/">symptoms</a> like weakness and paralysis.
Although it&#8217;s not known exactly what drives motor neuron dysfunction in ALS, one process that&#8217;s thought to play a role is motor neuron hyperexcitability — the tendency for nerve cells to fire, or send electrical signals, more frequently than they should. Hyperexcitability and abnormal nerve firing can put strain on motor neurons, driving damage in the long run.
The PathMaker MyoRegulator device aims to reduce hyperexcitability in ALS motor neurons, with the ultimate goal of helping to preserve motor neuron health to slow disease progression.
The device uses disposable electrodes that are applied to the skin to deliver a gentle electrical current to specific parts of the spinal cord, with the aim of reducing hyperexcitability in spinal motor neurons.
&#8220;Our non-invasive approach seeks to suppress spinal motor neuron hyperexcitability, which is a key characteristic of the ALS disease process that has been found in both sporadic and familial variants of ALS,&#8221; Yaghoubi said.
The Phase 1 trial is a single-arm and open-label study, meaning that all participants will get the same treatment and all will know what treatment they&#8217;re getting, with no placebo or inactive treatment option. It will enroll adult ALS patients at Spaulding who will be required to make 16 visits to the hospital over a 10-week period.
[quote=&#8221;center&#8221;]Our non-invasive approach seeks to suppress spinal motor neuron hyperexcitability, which is a key characteristic of the ALS disease process that has been found in both sporadic and familial variants of ALS.[/quote] 
The study&#8217;s main goal is to assess the safety and feasibility of using the MyoRegulator device in people with ALS. Researchers also aim to collect preliminary data on the efficacy of the device in ALS.
PathMaker is collaborating in the trial with leading experts in the field, including Leon Morales-Quezada, MD, PhD, director of the Integrative Rehabilitation Lab at Spaulding, and Sabrina Paganoni, MD, PhD, professor of physical medicine and rehabilitation at Spaulding and a physician-scientist at Massachusetts General Hospital.
The trial is being financially supported by the <a href="https://alsnewstoday.com/news/mda-600k-support-myoregulator-alternative-als-treatment/">Muscular Dystrophy Association</a> (MDA), with grants also awarded by the <a href="https://alsnewstoday.com/news/private-philanthropy-london-cerf-prizes-als-research-projects/">Cullen Education and Research Fund</a> (CERF) and the <a href="https://alsnewstoday.com/news/nih-awards-pathmaker-371k-advance-als-neuromodulation-therapy/">National Institutes of Health</a> (NIH).

PathMaker launches first human trial to test noninvasive ALS device

An ongoing Phase 1 clinical trial of <a href="https://quralis.com/">QurAlis</a>’ experimental therapy QRL-201 in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is expected to open in the U.K. by the end of the year.
The announcement follows the trial’s clearance by the country’s Medicines and Healthcare Products Regulatory Agency.
“We look forward to advancing ANQUR in the U.K. as part of our global strategy focused on bringing breakthrough precision medicines to patients with ALS and other neurodegenerative diseases,” Kasper Roet, PhD, CEO and co-founder of QurAlis, said in a company <a href="https://www.prnewswire.com/news-releases/quralis-receives-clinical-trial-authorisation-cta-in-the-uk-for-qrl-201-a-first-in-class-stathmin-2-precision-therapy-for-als-301873138.html">press release</a>.
The placebo-controlled <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05633459">Phase 1 ANQUR study (NCT05633459)</a> is recruiting patients at three sites in Canada, but is expected to start enrollment in Germany, Belgium, the Netherlands, and Ireland by the end of the year following its <a href="https://alsnewstoday.com/news/phase-1-trial-experimental-als-treatment-qrl-201-opening-eu/">regulatory clearance</a> in those countries. The company also plans to open sites in the U.S.
According to QurAlis, the trial, which will test several QRL-201 doses, has completed enrollment of the first group in Canada and has already dosed the first patient.
ANQUR’s design was recently presented at the <a href="https://www.encals.eu/meetings/barcelona/">European Network to Cure ALS (ENCALS) meeting</a>, July 12-14 in Barcelona, Spain.
[recommended-reading id=82704]
<h3>QRL-201 works to restore STMN2 levels</h3>
ALS is marked by the progressive dysfunction and death of motor neurons, the nerve cells that control voluntary movements. With neuronal loss, the brain can no longer control movement, leading to muscle weakness and atrophy.
In most patients, toxic aggregates of the TDP-43 protein build up inside nerve cells, including motor neurons, contributing to their degeneration. This protein is found at high levels in the brain and spinal cord and normally regulates the first step of protein production from a gene.
Research by Kevin Eggan, PhD, QurAlis’ co-founder and former Harvard professor, showed <a href="https://alsnewstoday.com/news/rescuing-levels-stmn2-potential-new-therapy-als-harvard-study/">TDP-43 regulates Stathmin-2</a> (STMN2), a protein produced in motor neurons and involved in neuronal repair. Toxic TDP-43 clumps affect the protein’s function, resulting in low STMN2 levels being produced.
QRL-201 is a first-in-class investigational therapy designed to increase STMN2 levels. It was shown to effectively increase STMN2 levels in <a href="https://alsnewstoday.com/news/antisense-oligonucleotide-stathmin-2-levels-lab-grown-motor-neurons-qrl-201-als-quralis/">lab-grown motor neurons</a> and <a href="https://alsnewstoday.com/news/mda-2023-designer-dna-drug-als-shows-promise-early-studies/">mouse models</a>, reversing several neurodegenerative processes. Because of this, the therapy is expected to slow ALS progression.
The first in-human ANQUR trial will test the safety, tolerability, and pharmacokinetics of multiple ascending doses of QRL-201 in up to 64 adults,  ages 18-80, who developed ALS symptoms within the past two years. Pharmacokinetics refers to a therapy’s movement into, through, and out of the body.
Participants will be randomly assigned to receive either QRL-201 at one of eight doses or a placebo via an injection into the spinal canal. The study is expected to be completed in May 2025.

Phase 1 clinical trial of QRL-201 for ALS approved in the UK

Treatment with the investigational therapy DNL343 was generally well-tolerated among people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in an early clinical trial, and biomarker data from the trial suggest that the therapy is working as intended.
Results were presented at the annual meeting of the American Academy of Neurology (AAN), in the poster &#8220;<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54462">The Integrated Stress Response Is Modulated by eIF2B Agonist DNL343: Results From Phase 1 Healthy Subject and Phase 1b ALS Patient Studies</a>.&#8221; The work was funded by DNL343&#8217;s developer <a href="https://www.denalitherapeutics.com/">Denali Therapeutics</a>.
[recommended-reading id=83581]
<h3>How does DNL343 work?</h3>
DNL343 is an oral therapy designed to lower the activity of a molecular pathway called the integrated stress response, or ISR. This pathway is usually turned on when cells are under stress, and then it turns off again once the stressful event has ended. In ALS, it&#8217;s thought that continual activation of the ISR in nerve cells may contribute to disease progression.
DNL343 specifically works by activating a protein called eIF2B, which acts to &#8220;put the brakes&#8221; on the ISR pathway. In animal models, the therapy has been shown to be able to get into the brain and block ISR activation.
Denali sponsored a <a href="https://clinicaltrials.gov/ct2/show/NCT04268784?term=DNL343&amp;draw=2&amp;rank=1">Phase 1 clinical trial (NCT04268784)</a> that tested DNL343 in 95 healthy volunteers. The experimental medicine was well-tolerated, with no serious side effects and no participants quitting the trial due to issues with the medication.
The findings supported the launch of a <a href="https://clinicaltrials.gov/ct2/show/NCT05006352">Phase 1b study (NCT05006352)</a> to test DNL343 in people with ALS, with the primary aim of assessing the safety and tolerability of the therapy. A total of 28 patients were randomly assigned to take a low or high dose of DNL343 or a placebo, either orally or via a feeding tube, daily for about a month.
Study results showed that DNL343 was generally well-tolerated: the most common side effects included headache, fatigue, and a reduced ability to taste (hypogeusia). None of the side effects were rated as serious. One patient given the higher dose of therapy chose to leave the trial due to developing a rash as a side effect.
Pharmacological data from both of these trials were consistent in terms of how the therapy moves through the body, and supported its once-daily dosage.
[recommended-reading id=83646]
<h3>Data support further development of DNL343 for ALS</h3>
Analyses of  blood cells from both ALS patients and healthy volunteers showed that treatment with DNL343 led to reductions in markers of ISR activity, namely ATF4 protein levels and CHAC1 gene expression.
&#8220;DNL343 is generally safe and well-tolerated at doses that demonstrate robust inhibition of ISR,&#8221; the researchers concluded, adding that these data &#8220;support further development of DNL343 as a potential therapeutic for the treatment of ALS.&#8221;
ALS patients who completed the Phase 1b study had the option to enter an open-label extension phase, where all are receiving DNL343 and being monitored for long-term outcomes. At the time of data cut-off in December, patients had been receiving DNL343 in the extension part for a median of four months, with some reaching up to one year of exposure.
DNL343 was <a href="https://alsnewstoday.com/news/dnl343-well-tolerated-interim-als-clinical-trial-data/">recently added</a> to the <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS Platform Trial (NCT04297683)</a>, a study led by the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital that aims to simultaneously evaluate several potential treatments for ALS. Enrollment in the DNL343 arm of the HEALEY trial is expected to start by mid-2023, Denali said in a <a href="https://www.denalitherapeutics.com/investors/press-release?id=9256&amp;type=api">press release</a>.

AAN 2023: DNL343 is safe, appears to work as intended in Phase 1 trial

Utreloxastat (PTC857), an investigational therapy for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), was safe, well tolerated, and displayed promising pharmacological properties in healthy people, according to a first-in-human Phase 1 study.
Based on these findings, the therapy’s developer, <a href="https://www.ptcbio.com/">PTC Therapeutics</a>, has launched a <a href="https://clinicaltrials.gov/ct2/show/NCT05349721">Phase 2 trial (NCT05349721)</a> to evaluate it in up to 258 ALS adults, ages 18–80. <a href="https://clinicaltrials.gov/ct2/show/NCT05349721#contacts">Recruitment is underway</a> at sites in California, Florida, Kansas, and Texas.
Results from the Phase 1 trial were shared in the study, “<a href="https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.1203">First-in-Human Studies of Pharmacokinetics and Safety of Utreloxastat (PTC857), a Novel 15-Lipooxygenase Inhibitor for the Treatment of Amyotrophic Lateral Sclerosis</a>,” which was published in <a href="https://accp1.onlinelibrary.wiley.com/journal/21607648">Clinical Pharmacology in Drug Development</a>.
The nerve cells that control muscle movement, called motor neurons, are lost in ALS, leading to <a href="https://alsnewstoday.com/symptoms-of-als-2/">symptoms</a> of muscle weakness that affect motor function, speaking, swallowing, and eventually, breathing.
A central mechanism behind motor neuron loss is oxidative stress — cell damage caused by an excess of highly reactive oxygen-containing molecules generated by normal cellular processes. Oxidative stress increases the production of an enzyme called 15-lipoxygenase (15-LO), triggering several processes known to contribute to motor neuron death.
Utreloxastat is designed to block the action of 15-LO, reducing further oxidative stress, preventing motor neuron death, and slowing or preventing disease progression. So far, promising preclinical studies in multiple animal models have supported the therapy’s further evaluation in human clinical trials.
PTC launched a first-in-human clinical trial to assess utreloxastat’s safety, tolerability, and pharmacokinetics (PK), or how it moves into, through, and out of the body, in healthy participants.
[recommended-reading id=77752]
<h3>SAD, MAD, and food studies</h3>
The Phase 1 trial had three parts. Part 1 was a single-ascending-dose (SAD) study that included 40 people (19 men, 21 women). Participants were randomly divided into four groups of 10 with eight in each group receiving a single dose of utreloxastat (100, 250, 500, or 1,000 mg), and two receiving a placebo.
A medium-fat breakfast was provided before dosing, and blood samples were collected before and at several points after exposure.
Across all doses, utreloxastat showed dose-dependent increases in maximum concentrations, which were observed in the bloodstream about four hours after dosing. Half-life, the time it takes for utreloxastat levels to be reduced by half, was consistent at all doses, ranging between about 22–25 hours.
Part 2 was a multiple-ascending-dose (MAD) study with 30 people (19 men, 11 women) who were randomly divided into three groups of 10 to receive 14 days of treatment. Participants received utreloxastat at either 250 mg twice daily, 500 mg once daily, 150 mg twice daily/once daily, or a placebo.
Following multiple doses, the rate at which utreloxastat entered the bloodstream and the time to reach maximum levels were similar to the first doses. In the 250 mg twice-daily and 500 mg once-daily regimen groups, concentrations approached continuous exposure after seven consecutive days of dosing.
Part 3 tested the impact of food on utreloxastat’s pharmacological properties in 12 people following a single dose (500 mg) under fasting and low- and high-fat conditions.
Utreloxastat was absorbed into the bloodstream faster with food, but food didn&#8217;t alter the time to reach maximum levels or the drug&#8217;s clearance from the body. There were no differences in exposure between men and women participants, regardless of food intake.
Following a single dose of up to 1,000 mg and multiple doses for 14 days, no marked safety signals were reported. All side effects were considered mild and resolved by the end of the study. No deaths or treatment-emergent serious side effects that led to discontinuation occurred. No abnormal ECG readings for heart function were detected.
During the MAD study, levels of high-density lipoprotein (HDL) — known as good cholesterol — and total cholesterol followed a dose-dependent decrease after multiple utreloxastat doses, but those decreases reversed when exposure stopped. No clinically significant side effects were associated with these observations.
“These PK [pharmacokinetics] and safety data indicate that utreloxastat is an appropriate candidate for further development for the treatment of ALS,” the researchers wrote.
The ongoing Phase 2 study, called CARDINALS, will investigate whether utreloxastat, given twice daily (250 mg) for 24 weeks (about six months), outperforms a placebo at slowing progression.
The main goal is to determine functional decline, as assessed by changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores. Secondary measures include safety, changes in lung function, muscle strength, cognitive abilities, and quality of life, as well as time to breathing support, and survival.
Those who complete CARDINALS can join an open-label extension study and continue receiving utreloxastat for 28 weeks (about seven months).

Phase 1 Safety Study Clears Path to Test Utreloxastat in ALS Patients

A Phase 1 clinical trial has begun dosing adult healthy volunteers to investigate <a href="https://quralis.com/">QurAlis Corporation</a>&#8216;s QRL-101, an oral treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the company announced.
The first-in-human <a href="https://clinicaltrials.gov/ct2/show/NCT05667779?term=NCT05667779&amp;draw=2&amp;rank=1#contacts">Phase 1 trial (NCT05667779)</a> aims to assess the safety, tolerability, and pharmacokinetics — the movement of a drug into, through, and out of the body — of increasing doses of QRL-101 versus a placebo. Ongoing at a single center in The Netherlands, it&#8217;s <a href="https://clinicaltrials.gov/ct2/show/NCT05667779?term=NCT05667779&amp;draw=2&amp;rank=1#contactlocation">enrolling</a> up to 40 participants, ages 18 to 70.
&#8220;We are excited to initiate dosing in this clinical trial of QRL-101,” Kasper Roet, PhD, CEO and co-founder of QurAlis, said in a <a href="https://www.prnewswire.com/news-releases/quralis-announces-first-in-human-dose-in-phase-1-clinical-trial-of-qrl-101-a-first-in-class-kv7-precision-therapy-for-als-301712631.html">company press release</a>.
ALS is a progressive neurological disease that causes dysfunction and death of motor neurons, the nerve cells that control voluntary muscle movement. In about half of patients, this degeneration happens because neurons fire electrical signals more readily than normal (hyperexcitability), which is linked to poor survival.
[recommended-reading id=71088]
&#8220;Motor system hyperexcitability occurs in approximately 50 percent of all ALS patients and is linked to potassium channel dysfunction,” said Leonard H. van den Berg, MD, PhD, professor of neurology at the University Medical Center Utrecht and chair of the Treatment Research Initiative to Cure ALS (TRICALS).
Potassium and other ion channels are proteins in the cell membrane that regulate the entry and exit of charged ions, thereby controlling electrical currents. Researchers believe motor neuron overactivation is linked to the low activity of a potassium channel called Kv7.2/7.3.
In clinical trials, ezogabine, an anticonvulsant that activates Kv7.2/7.3, was able to <a href="https://alsnewstoday.com/news/ezogabine-decreases-motor-neuron-excitability-in-als-clinical-trial/">reduce hyperexcitability</a> in motor neurons of ALS patients. However, it can cause substantial side effects, possibly because it targets other proteins besides Kv7.2/7.3. This caused the medication to be discontinued as an epilepsy treatment.
QRL-101, also known as QRA-244, is an orally available molecule developed to more selectively target Kv7.2/7.3, which could results in fewer side effects compared with ezogabine.
<a href="https://alsnewstoday.com/news/quralis-working-on-new-als-therapy-qra-244-to-harness-benefits-without-side-effects/">Preclinical research</a> in patient-derived motor neurons showed QRL-101 activated these ion channels, but needed a concentration 20 times lower than ezogabine to achieve the same effect.
Furthermore, a head-to-head comparison in rat models showed QRL-101 had a better safety profile, with fewer and less severe side effects than ezogabine. In particular, it didn&#8217;t induce dizziness or fatigue nor affect bladder tissue, known side effects of ezogabine.
“QRL-101 has been shown in preclinical studies to have strong potential to control motor neuron hyperexcitability induced excitotoxicity with significantly fewer side effects than other drug candidates,” Roet said. “QRL-101 has the potential to be a first-in-class effective therapy for ALS patients suffering from hyperexcitability-induced motor neuron degeneration.&#8221;
QurAlis is also developing <a href="https://quralis.com/pipeline/">several other treatment candidates</a> for ALS and frontotempotal dementia, a related disorder. These include its <a href="https://alsnewstoday.com/news/out-of-stealth-quralis-expects-first-trial-2022-als-therapy-qrl-201/">lead candidate QRL-201,</a> designed to increase the production of the stathmin-2 protein to counter the damaging effects of TDP43 toxic clumps.

Tag: Phase 1 Clinical Trial