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Daily treatment with <a href="https://www.pharmaust.com/monepantel-for-motor-neurone-disease/">monepantel</a> — a drug widely used in veterinary medicine — was shown to reduce the rate of disease progression by as much as 58% in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) or motor neuron disease (MND), according to top-line data from a Phase 1 trial.
The oral therapy also was found to be generally safe and well tolerated.
The data comes from the completed <a href="https://clinicaltrials.gov/study/NCT04894240">MEND trial (NCT04894240)</a>, which assessed the safety, tolerability, and pharmacological properties of monepantel in 12 adults with ALS or MND at two sites in Australia. MEND also sought to determine any preliminary signs of efficacy for the treatment candidate.
Researchers already have selected the optimal dose for further testing, which will be assessed in a Phase 2/3 clinical study expected to start in the third quarter of this year. That trial may support accelerated U.S. Food and Drug Administration approval in 2026, according to the therapy&#8217;s developer <a href="https://www.pharmaust.com/">PharmAust</a>.
&#8220;This study has shown oral monepantel to be safe and well tolerated by people with MND,&#8221; Susan Mathers, associate professor at Monash University and a principal investigator of the trial, said in a <a href="https://www.prnewswire.com/news-releases/pharmaust-announces-positive-phase-1-mend-study-top-line-results-in-mnd--als-302074155.html">company press release</a>. &#8220;Given the promising findings on preliminary efficacy markers, I look forward to progressing a Phase 2 study as soon as possible.&#8221;
Monepantel is widely used in veterinary medicine as a deworming agent. It has also been reported as a potent <a href="https://www.pharmaust.com/therapeutic-pipeline/">inhibitor of the mTOR signaling pathway</a>, which plays a central role in cell growth and proliferation, as well as autophagy, a process by which cells recycle abnormal or defective components or molecules.
PharmAust scientists believe that by activating this pathway, the medication may help to clear the misfolded proteins that accumulate to toxic levels and contribute to disease progression in virtually all ALS patients.
&#8220;The release of the top-line Phase 1 MEND study results is an exciting milestone for PharmAust as we take a significant step towards helping people diagnosed with this rare and incurable disease,” said Michael Thurn, PhD, CEO at PharmAust.
[recommended-reading id=88913]
<h3>Dosing determined during study&#8217;s extension part</h3>
The MEND trial included two groups of six participants each, all ages 18 to 75. One group received the medication at a low dose, of 2 mg/kg and 6 mg/kg, while the other was given a high dose — 4 mg/kg and 10 mg/kg. All doses were given as oral tablets once daily for 28 days. Dose escalations could then be offered every 28 days, based on recommendations from a safety management committee.
An <a href="https://www.pharmaust.com/additional-phase-1-data-suggest-mpl-may-inhibit-mnd/">interim trial analysis</a> showed that blood levels of a nerve cell damage biomarker called neurofilament light chain remained stable in 11 of the 12 participants for as long as 8.7 months.
The newly reported data comes after all patients received the therapy for 10 to 16 months. After completing the main trial, all continued to receive monepantel in an <a href="https://clinicaltrials.gov/study/NCT06177431">open-label extension study (NCT06177431)</a> for up to one year. In an open-label trial, both researchers and participants know the exact medication and dosage being given.
In this part, monepantel was given at a daily dose of 10 mg/kg, which &#8220;is estimated to produce the most robust mTOR inhibition while still being well tolerated,&#8221; the researchers wrote.
The treatment was deemed generally safe and well tolerated. While 56 treatment-emergent adverse events were reported, only three mild events were considered potentially related to treatment. No patient died during the study.
Regarding efficacy, no significant differences in disease severity, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), were observed from before treatment to the end of the trial, indicating that monepantel slowed the rate of disease progression in these patients.
[recommended-reading id=89867]
<h3>ALS trial comparison confirms slowing of disease progression</h3>
A comparison of data from study participants versus matched controls from previous ALS clinical studies showed that both the low and high doses of monepantel significantly lowered the rate of disease progression. The controls came from the PRO-ACT database, a large repository of data from people who participated in ALS clinical trials and observational studies.
Monepantel-treated patients had a monthly ALSFRS-R of 0.74 points, representing a 39% slowing in disease progression compared with the matched controls. The effect was more evident in the high dose group, where the rate of decline was 0.6 points per month, or 58% slower than the control group.
&#8220;I feel that the monepantel may have slowed my neurological deterioration,&#8221; said a MEND participant in the high-dose group. &#8220;My dosage was increased to 6 [mg/kg] several days ago. There appears to be no side effects with it.&#8221;
[quote=&#8221;center&#8221;]To know that we have potentially prolonged the lives of 12 patients [in this trial] is extremely satisfying and humbling.[/quote]
Using a prognostic model, the researchers estimated that these benefits could translate in a meaningful survival extension, by 13.5 to 56.5 months depending on the severity of the disease at the time of treatment initiation. Approved treatments provide about two to nine months of additional life expectancy, the company said.
“To know that we have potentially prolonged the lives of 12 patients is extremely satisfying and humbling,” Thurn said.
The company <a href="https://alsnewstoday.com/news/fda-pharmaust-discuss-advance-monepantel-als-clinical-trials/">plans to start</a> a Phase 2/3 study to evaluate monepantel against a placebo in ALS/MND patients for 48 weeks (nearly one year). The main goal is to determine changes in disease progression and survival rates in both groups.

Vet drug monepantel slows ALS, MND disease progression in trial

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>.
[recommended-reading id=88361]
<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

<a href="https://quralis.com/" rel="nofollow">QurAlis</a> soon expects to open its ongoing Phase 1 clinical trial testing QRL-201 in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) at sites in various European Union countries, including Germany, Belgium, the Netherlands, and Ireland.
The company&#8217;s announcement comes after these countries reviewed and accepted an application for the study. The <a href="https://www.clinicaltrials.gov/ct2/show/NCT05633459">Phase 1 ANQUR trial (NCT05633459)</a>, which is currently recruiting in Canada, could start enrolling patients at European sites by year&#8217;s end.
&#8220;This EU Clinical Trial Authorisation marks the second regulatory clearance for QRL-201 as we execute our global strategy focused on bringing breakthrough precision medicines to patients with ALS and other neurodegenerative diseases,&#8221; Kasper Roet, PhD, CEO and co-founder of QurAlis, said in a <a href="https://www.prnewswire.com/news-releases/quralis-receives-clinical-trial-authorisation-cta-in-european-union-eu-for-qrl-201-a-first-in-class-stathmin-2-precision-therapy-for-als-301839151.html">company press release</a>.
[recommended-reading id=84924]
<h3>Trial into safety of varying doses of experimental ALS treatment</h3>
ALS is a progressive neurodegenerative disorder that damages motor neurons, the nerve cells that control voluntary movements, leading to muscle weakness and muscle atrophy (shrinkage).
In most ALS cases, toxic aggregates of the TDP-43 protein accumulate in nerve cells, and they are believed to directly contribute to neurodegeneration. This protein normally works to process messenger RNA, an intermediated molecule made when genes are &#8220;read&#8221; to produce proteins.
<a href="https://alsnewstoday.com/news/rescuing-levels-stmn2-potential-new-therapy-als-harvard-study/">Stathmin-2</a> (STMN2) is the protein most significantly regulated by TDP-43 in people. This protein is important for neural repair and stability, and it is abundant in motor neurons. But its levels drop significantly when TDP-43 is faulty, and stathmin-2 is known to be at <a href="https://alsnewstoday.com/news/antisense-oligonucleotide-stathmin-2-levels-lab-grown-motor-neurons-qrl-201-als-quralis/">lower-than-normal levels</a> in nearly all ALS patients.
QRL-201 is a first-in-class experimental therapy designed to raise STMN2 levels in patients. This has been shown to <a href="https://alsnewstoday.com/news/mda-2023-designer-dna-drug-als-shows-promise-early-studies/">lessen the damage caused by TDP-43 aggregates</a>, and to restore nerve cells&#8217; ability to repair damage. As such, QRL-201 could work to slow or prevent ALS progression.
ANQUR is the first trial evaluating a therapy designed to rescue STMN2 production. It aims to test the safety, tolerability, and pharmacological properties of QRL-201 in up to 64 people with ALS.
Participants will be randomly assigned to one of eight increasing doses of the therapy or to a placebo, both given by an injection into the spinal canal (intrathecal injection). Each dosing group will include eight patients, six being treated with QRL-201 and two being given a placebo. A first group in Canada is fully enrolled and dosing is underway.
The company plans to open additional sites in the U.S. and U.K.
&#8220;We believe QRL-201 has the potential to halt disease progression, which could transform the care and treatment of ALS. We are dedicated to ensuring efficient advancement of our ANQUR clinical trial so that we can fulfill our mission to make a meaningful difference in patients&#8217; lives,&#8221; Roet said.

Phase 1 trial of QRL-201 to open for patients at sites across Europe

A first patient has been dosed in a Phase 1 clinical trial evaluating QRL-201, an experimental antisense oligonucleotide (ASO) molecule in treating <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the therapy&#8217;s developer, <a href="https://quralis.com/" rel="nofollow">QurAlis</a>, announced.
Dubbed <a href="https://www.clinicaltrials.gov/ct2/show/NCT05633459">ANQUR (NCT05633459)</a>, the study is reported to be the first into a potential therapy that works to increase production of stathmin-2 (STMN2), a <a href="https://alsnewstoday.com/news/als-progression-linked-stmn2-protein-loss-study/">protein needed for neuronal growth</a> and repair. In nearly all ALS patients, <a href="https://alsnewstoday.com/news/antisense-oligonucleotide-stathmin-2-levels-lab-grown-motor-neurons-qrl-201-als-quralis/">STMN2 </a><a href="https://alsnewstoday.com/news/antisense-oligonucleotide-stathmin-2-levels-lab-grown-motor-neurons-qrl-201-als-quralis/">levels</a><a href="https://alsnewstoday.com/news/antisense-oligonucleotide-stathmin-2-levels-lab-grown-motor-neurons-qrl-201-als-quralis/"> are low</a>.
ANQUR is <a href="https://www.clinicaltrials.gov/ct2/show/NCT05633459#contactlocation">expected to enroll</a> up to 64 adults with ALS, ages 18 to 80, and no SOD1 or FUS gene mutations at sites in Canada, Europe, and the U.S. It is testing the safety and tolerability of multiple ascending doses of QRL-201 against a placebo in groups of patients.
The trial currently is ongoing in Canada, and the first dose was given at the University of Montréal Hospital Centre.
&#8220;QRL-201 recently entered the clinic in Canada and we are pleased to dose our first patient. We look forward to advancing the ANQUR clinical trial of QRL-201 for the treatment of ALS so that we can make a meaningful difference in patients&#8217; lives,&#8221; Angela Genge, MD, chief medical officer at QurAlis, said in a <a href="https://www.prnewswire.com/news-releases/quralis-announces-first-patient-dosed-with-qrl-201-a-first-in-class-stathmin-2-precision-therapy-for-als-301790444.html">company press release</a>.
[recommended-reading id=83378]
<h3>Raising stathmin-2 levels may protect neurons, slow ALS progression</h3>
ALS is a progressive condition that affects motor neurons, the nerve cells that control voluntary movements. The loss of these neurons weakens a person&#8217;s muscles. While a handful of <a href="https://alsnewstoday.com/als-treatment/">ALS therapies are approved</a>, their ability to slow the disease&#8217;s advance is limited.
&#8220;There is great need for therapies that could slow disease progression and improve outcomes,” said Merit Cudkowicz, MD, director of the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital and a member of QurAlis&#8217; clinical advisory board.
Most ALS cases are characterized by abnormalities in the <a href="https://alsnewstoday.com/news/structure-tdp-43-protein-aggregates-characterize-als-identified-first-time/">TDP-43 protein</a>, which forms toxic clumps that damage cells. This protein is normally needed to process messenger RNA, an intermediate molecule that results from genes, which provides the instructions to make proteins.
When TDP-43 is faulty, the mRNA molecule carrying <a href="https://alsnewstoday.com/news/rescuing-levels-stmn2-potential-new-therapy-als-harvard-study/">instructions for stathmin-2 production</a> has an abnormal sequence, resulting in low levels of the STMN2 protein, previous research reported.
Raising stathmin-2 levels also has shown a potential to <a href="https://alsnewstoday.com/news/mda-2023-designer-dna-drug-als-shows-promise-early-studies/">reduce the defects caused by TDP-43 clumping</a> and restore a cell&#8217;s ability to repair neurons. These findings indicate QRL-201 could help to slow disease progression in ALS patients.
&#8220;Stathmin-2 is a well-validated protein important for neural repair and axonal stability and is the most significantly regulated gene by TDP-43 exclusively in humans,&#8221; Genge said. &#8220;Its expression is significantly decreased in nearly all ALS patients and it is the most consistently decreased gene over all sporadic ALS patient data sets.&#8221;
The ongoing trial is testing QRL-201’s safety, tolerability, and pharmacokinetics — how a drug moves into, through, and out of the body — in ALS patients. Participants, in groups of eight people each, will be randomly assigned to one of eight increasing doses of the therapy or to a placebo, both given by intrathecal injection (an injection into the spinal canal).
“This study has the potential to show QRL-201 … could potentially benefit ALS patients who have a loss of STMN2 due to TDP-43 pathology,&#8221; said Cudkowicz, who is also the director and a professor of neurology at Harvard Medical School.

Dosing begins in Phase 1 trial of QRL-201 in promoting neuronal repair

Bosutinib, an inhibitor approved to treat a blood cancer, showed no unexpected safety concerns in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), with some patients experiencing slower disease progression while on the therapy, results from a Phase 1 clinical trial showed.
Larger clinical trials are needed to confirm if bosutinib could be of benefit to people with ALS.
The study, &#8220;<a href="https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00437-0/fulltext">Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial</a>,&#8221; was published in <a href="https://www.thelancet.com/journals/eclinm/home">eClinicalMedicine</a>.
Bosutinib is an oral therapy approved to treat a type of chronic myelogenous leukemia, for which it is marketed under the brand name <a href="https://www.bosulif.com/" rel="nofollow">Bosulif</a> by Pfizer. It belongs to a class of medications called tyrosine kinase inhibitors, commonly called TKIs, and works by blocking the activity of two proteins needed for cell growth called Src and c-Abl.
[recommended-reading id=80731]
<h3>ALS trial of approved treatment for form of leukemia</h3>
Preclinical research has suggested that bosutinib <a href="https://alsnewstoday.com/news/chip-technology-identifies-potential-combo-therapy-for-als-in-study/">may be useful in treating ALS.</a> A research team at Kyoto University, in Japan, in collaboration with Pfizer and other Japanese universities, launched a Phase 1 clinical trial called <a href="https://clinicaltrials.gov/ct2/show/NCT04744532">iDReAM (NCT04744532)</a> to test the therapy in adults with ALS.
The trial&#8217;s main goals were to assess the therapy&#8217;s safety profile in this population, and determine the highest dose that could be given without unacceptable safety concerns.
&#8220;This is the first study to use a Src/c-Abl inhibitor, bosutinib, for patients with ALS,&#8221; the researchers wrote.
After completing a 12-week observation period, a total of 13 people were enrolled in the study and treated with bosutinib for another 12 weeks. All had a one- to three-point decline in their <a href="https://www.alspathways.com/hcp/why-alsfrs-r-matters/">ALS Functional Rating Scale-Revised (ALSFRS-R)</a> scores, a measure of disease severity and progression marked by declining scores, during the three months of observation.
They then were divided into four groups, each receiving a different dose — 100, 200, 300, or 400 mg per day. Trial participants also stopped using their regular <a href="https://alsnewstoday.com/approved-treatments-for-als/">ALS medications</a>, including <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">riluzole</a>, while being treated with bosutinib.
Side effects related to treatment were reported by all 13 participants. The most common were diarrhea, constipation, and liver problems, and most were mild or moderate in severity.
All but one of the 10 people in the three lower dose groups completed the study (the lone discontinuation was for reasons unrelated to bosutinib&#8217;s use). However, all three patients in the 400 mg dose group stopped treatment early due to intolerable side effects.
&#8220;While patients with ALS receiving bosutinib experienced [side effects] with findings consistent with bosutinib&#8217;s known profile, no specific safety profiles or concerns in patients with ALS were observed in this study, and adverse events observed in ALS were also manageable by supportive care or dose modifications,&#8221; the researchers wrote.
On review by a safety committee, all in the 400 mg dosing group were deemed to have experienced dose-limiting toxicities, including two people with signs of liver damage and one with a severe rash. In the lower dose groups, no dose-limiting toxicities were observed.
An exploratory analysis of treatment efficacy was conducted in the three lower dose groups by comparing the change in their ALSFRS-R scores between the observation and treatment periods.
Five out of these nine patients showed stable or a slower decline in ALSFRS-R scores during the 12 weeks of treatment with bosutinib. A similar proportion showed no decline in tests of hand grip strength, and two had no decline in measures of <a href="https://alsnewstoday.com/living-with-als/breathing/">lung function</a>.
<h3>Stable ALSFRS-R scores may link with lower levels of nerve damage marker</h3>
In a post hoc analysis — designed and carried out after all trial data had already been analyzed — the researchers found that patients with a stable outcome on ALSFRS-R generally had lower levels of neurofilament light chain (NfL) in their blood. NfL is a marker of nerve damage.
Based on this finding, the scientists speculated that low initial NfL levels could be a marker of responsiveness to bosutinib treatment. However, they stressed that these results should be interpreted cautiously due to the small number of patients evaluated, and because low NfL levels are generally associated with slower <a href="https://alsnewstoday.com/symptoms-of-als-2/">disease progression</a> in ALS.
&#8220;A subset of patients was found to respond well to bosutinib by appearing to maintain clinical stability during 12 weeks, and the treatment-responsive patients could be distinguished by plasma NFL levels, which may be a potential predictor of drug efficacy,&#8221; the researchers wrote.
In a further set of experiments, the researchers generated motor neuron cells from samples taken from each trial participant. Motor neurons are the nerve cells that control movement and are progressively lost in ALS.
Analyses of these cells showed that neurons from patients with low or high NfL levels showed differences in the expression of several genes, including several <a href="https://alsnewstoday.com/als-and-genetics/">genes known to be related to ALS</a>.
&#8220;The genes and pathways that distinguish these high and low groups may be the target molecules that enhance the efficacy of this study drug, as well as the ALS molecular pathophysiology underlying the NFL levels,&#8221; the researchers wrote. &#8220;Since they are exploratory findings in a small number of cases, further accumulation of case and laboratory data is needed.&#8221;

Tag: Phase 1 clinical trials

Vet drug monepantel slows ALS, MND disease progression in trial

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

Phase 1 trial of QRL-201 to open for patients at sites across Europe

Dosing begins in Phase 1 trial of QRL-201 in promoting neuronal repair

Bosutinib, Blood Cancer Therapy, Safe and May Help Some With ALS