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Stem cell therapy, specifically treatment with mesenchymal stem cells or MSCs, did not substantially alter disease progression among people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to new data from a Phase 2 clinical trial.
However, there was a subset of patients who did appear to experience notable benefits from the treatment, progressing at least 25% slower after stem cell therapy for ALS than before receiving the first MSC injection.
&#8220;We did not see any strong efficacy signal in the overall cohort, but there may be a responder effect when looking at a subset of participants,&#8221; Nathan P. Staff, MD, PhD, a professor of neurology at the Mayo Clinic, said in a talk titled &#8220;<a href="https://www.aan.com/msa/Public/Events/AbstractDetails/55593">Results from a Phase 2 Clinical Trial of Repeated Intrathecal Autologous Adipose-derived MSCs in ALS</a>.&#8221;
Staff&#8217;s presentation took place at the American Academy of Neurology (AAN) 2024 Annual Meeting, which is being held April 13-18, in Colorado and online.
More study is needed, according to the scientist, to help determine which patients will experience that responder effect.
[recommended-reading id=82904]
<h3>Testing the impact of MSC stem cell therapy in ALS</h3>
MSCs are stem cells that reside in the bone marrow and fat tissue. These stem cells are able to grow into certain types of connective tissue cells, and they also secrete a wide range of signaling molecules that can modulate the activity of other nearby cells, including nerve cells.
&#8220;We&#8217;ve been studying MSCs &#8230; for ALS for over a decade now,&#8221; Staff said. &#8220;The reason they were selected for a possible therapy is their ability to secrete growth factors, including neourotrophic [nerve-growth-promoting] factors, and modulate the immune system and neuroinflammation.&#8221;
Staff noted that several pharmaceutical companies are already developing potential ALS therapies based on MSCs. The most well-known stem cell therapy for ALS, called <a href="https://alsnewstoday.com/nurown/">NurOwn</a> (debamestrocel), will enter a <a href="https://alsnewstoday.com/news/fda-oks-phase-eb-trial-design-nurown-less-advanced-als/">Phase 3b clinical trial</a> later this year that could be the basis of a new application seeking the treatment&#8217;s approval in the U.S.
At the AAN meeting, Staff presented data from a <a href="https://clinicaltrials.gov/study/NCT03268603">multisite U.S. trial (NCT03268603</a>) that used MSCs collected from participants&#8217; fat tissue in the belly. The treated cells were then expanded to millions before being delivered back into the patients via injections into the spinal canal, known as intrathecal injections.
The study included 57 people with ALS whose symptoms had started no more than two years before enrollment. About two-thirds of the participants were male, almost all were white, and their average age was 56. Nine of these patients had <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>, in which the disease runs in families.
All of the participants were treated with intrathecal MSC injections every three months for a year, for up to four injections. These injections included somewhere between 10 and 100 million cells, based on certain dose modification criteria.
Staff noted that there was &#8220;quite a bit of dropout&#8221; during the year-long study, with nearly half of patients withdrawing before the study&#8217;s end. There were many reasons for quitting the study, though the most common was due to disease progression.
Nearly half of patients experienced side effects from treatment that were judged moderate or severe. Pain was an especially common side effect of this stem cell therapy for ALS, with about 23 patients experiencing moderate to severe back pain, limb pain, or headache.
For most, the side effects went away after a week or two, and Staff said that, overall, the MSC treatment was &#8220;reasonably well tolerated.&#8221; Still, there were some participants who experienced more long-lasting issues that led them to withdraw from the study.
[recommended-reading id=87114]
<h3>Some patients saw slowing of ALSFRS-R scores of at least 25%</h3>
Disease progression was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), in which higher scores represent better functional abilities.
Prior to starting on MSC treatment, ALSFRS-R scores were rapidly decreasing over time, which is typical in ALS. During the year-long study, the rate of worsening was slightly slower compared with before treatment, but the difference failed to reach statistical significance.
However, 21 of the 57 study participants experienced a slowing of ALSFRS-R score of at least 25% after starting on the MSC treatment, Staff noted. This suggests there may be certain patients who respond to MSC therapy, while others derive no benefit from the treatment.
The team will now conduct further analyses from this study, including biomarker assessments, that may help shed further light on which patients do or do not respond to MSC therapy.

AAN 2024: Stem cell therapy for ALS slows disease in some patients

We often feel isolated now that my husband, Todd, is homebound because of <a href="https://alsnewstoday.com/what-is-als/">ALS</a>. He&#8217;s paralyzed with weak lung function, and it’s just too difficult for him to get out. So we were delighted when some friends planned a game night with us at our home last weekend. We played <a href="https://codenamesgame.com/" rel="nofollow">Codenames</a>, which was a lot of fun because we enjoy word games, and it worked well for Todd because it doesn’t require him to hold cards or manipulate game pieces.
The night was a welcome break from our monotonous routine and an opportunity to connect with others, but when the group left, Todd looked and sounded exhausted.
“Was that too much?” I asked him as I helped him in the bathroom before his nighttime caregiver arrived.
“Three hours might’ve been a bit much,” he said, “but it was worth it.”
[recommended-reading id=88900]
<h3>Holding on to all he can</h3>
Todd has pushed the limits throughout the course of his disease. He kept walking long after I thought it was safe. I worried about him getting a bad head injury, so I implored him to use a wheelchair, but he didn’t want to do it until he absolutely had to. He kept walking even after he fell and bloodied his face, although he did start using a three-wheeled scooter more around the yard.
He continued to mow grass on his zero-turn lawn mower. Once I was nervous for his safety when the kids and I had something planned for the evening and he was set on mowing the yard. He insisted that he&#8217;d be fine, but when I returned home, he was lying on the living room floor.
“At least you fell in here,” I said when I arrived home.
He sheepishly told me that <a href="https://nevastory.com/rolling-home/">he&#8217;d actually fallen outside</a> trying to climb back onto the lawn mower after opening the shed door. The sun had set, the night was getting cold, and coyotes were howling. He barrel-rolled back to the house, kicked the levered door handle to open the door, and shimmied and rolled into the house and onto the living room rug, where he waited until I got home.
After he got his wheelchair, he continued to go to church and out to restaurants, even though his lungs sometimes filled with mucus and I’d have to give him manual assist coughs.
I was scheduled to lead music for preschoolers <a href="https://alsnewstoday.com/columns/breathe-stress-relax/">one Sunday morning</a> at church when Todd&#8217;s lungs weren&#8217;t doing well. I cleared him out and then headed upstairs to sing with the kids after instructing our son to come get me if his dad needed help. When I got done with the music, Todd was out in the lobby. He explained that his lungs had filled up, and he&#8217;d asked a firefighter friend to help him clear them.
Todd kept pushing the limits. He continued to watch the kids in their choir, band, and stage performances, even when it was difficult to traverse snow-covered ground in his power wheelchair. I&#8217;d wait for a lull in pedestrian traffic and then back his accessible van onto the sidewalk near the doors. At times, I&#8217;d have to push Todd’s wheelchair to help it get through the snow.
He kept going out until he became <a href="https://alsnewstoday.com/columns/breathing-easier-support-noninvasive-ventilator/">dependent on his noninvasive ventilator</a>. He doesn’t like to be out in public with it on, and his neck bounces too much to be comfortable riding in our van.
But he still pushes his limits, although he has more of them, and they&#8217;re more severe.
He continues to eat, even though I sometimes need to push on his abdomen to clear food when he chokes. Todd rarely talks on the phone anymore because he gets too winded even with his ventilator, but he still talks to his mother about once per month, because she&#8217;s his mom.
Todd could give up things sooner and avoid risk, but he wants to hold on to all that he enjoys for as long as he can.
<hr />
Note: <a href="https://alsnewstoday.com/">ALS News Today</a> is strictly a news and information website about the disease. It does not provide medical advice, <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis</a>, or <a href="https://alsnewstoday.com/approved-treatments-for-als/">treatment</a>. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of ALS News Today or its parent company, BioNews, and are intended to spark discussion about issues pertaining to ALS.

How my husband keeps pushing the limits with ALS

Researchers have unveiled a new AI-powered avatar platform — one making use of artificial intelligence (AI) technology — that aims to help people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) to communicate, even when the neurodegenerative disease progresses to the point that speaking and moving become difficult or impossible.
The platform was developed through a collaboration between tech companies <a href="https://www.lenovo.com/us/en/">Lenovo</a> and <a href="https://www.deepbrain.io/">DeepBrain AI</a>, as well as the <a href="https://www.scottmorganfoundation.org/">Scott-Morgan Foundation</a>, a nonprofit that focuses on assistive technologies.
“This is a fantastic example of the untapped potential of generative AI to empower individuals and build a more inclusive future,” Scott Tease, vice president and general manager of high-performance computing and AI at Lenovo, said in a <a href="https://www.businesswire.com/news/home/20240109052328/en/AI-Powered-Avatar-from-Lenovo-DeepBrain-AI-and-the-Scott-Morgan-Foundation-Creates-New-Communication-Possibilities-for-People-with-Severe-Disabilities">press release</a>.
The AI-powered platform was revealed at CES 2024, a tech showcase being held Jan. 9-12 in Las Vegas. Andrew Morgan, CEO of the Scott-Morgan Foundation, said the nonprofit&#8217;s vision “is built on a commitment to ensuring a universal right to thrive through technology.&#8221;
&#8220;AI is accelerating work we began years ago, and our brilliant collaborators are helping us completely change the accessibility landscape,&#8221; Morgan said. &#8220;Collectively, we are lighting a beacon for what’s possible—not just for people with ALS, but for everyone.”
[recommended-reading id=87020]
<h3>AI-powered assistive tech platform aims to help those with severe disease</h3>
ALS is characterized by the progressive death and degeneration of the nerve cells that control voluntary movement. This eventually leads to paralysis, which can make it hard for people with the condition to communicate.
DeepBrain has been developing AI-based avatars — video portrayals that capture the look and personality of people. As part of an ongoing collaboration with the Scott-Morgan Foundation, Lenovo spearheaded an effort to adapt this technology to help people with ALS and other disease maintain communication abilities even when they can no longer do so with their own bodies.
&#8220;Leveraging our expansive solutions portfolio and in-house expertise, we love finding these opportunities to reimagine what’s possible and help solve humanity’s greatest challenges,&#8221; Tease said.
Eric Jang, CEO of DeepBrain AI, said his company&#8217;s goal is to use AI-powered tech to &#8220;enable hyper-realistic avatars for everyone.”
“We are constantly amazed at how our partners and clients think of new ways to use AI-generated video,&#8221; Jang said. &#8220;Lenovo had the foresight to share their vision on how this technology could be implemented as a component of an assistive technology platform.”
As a proof-of-concept, Erin Taylor — a 24-year-old woman who last year was diagnosed with ALS — underwent full-body video capture at a studio. That was then used to <a href="https://www.youtube.com/watch?v=4LxqB6gS7Dc&amp;feature=youtu.be">create an avatar for her</a> that offers 96% true-to-life accuracy. The avatar was debuted at CES 2024.
Taylor, who lives in California with her mother, was pursuing a career in botany and forestry when she experienced &#8220;a brief series of escalating symptoms&#8221; that resulted in her diagnosis.
“Feeling so devastated and lost, we were grateful to the Scott-Morgan Foundation for inviting us to help build something new and shape the future,” Taylor said.
[quote=&#8221;center&#8221;]The avatar is incredible, but what matters most to me is that this technology could help change the lives of many more people facing ALS or other diseases — a way of showing how bright the future can still be.[/quote]
Lenovo also has used AI to help develop predictive typing tech, with the aim of making it easier for people with ALS and other motor-limiting diseases to find the right words when a traditional keyboard or voice-to-speech is no longer an option.
Researchers are working to integrate the predictive system along with the avatar and an eye-tracking keyboard, with the ultimate goal of letting people with conditions such as ALS be seen and heard in the digital space.
“I have no doubt this pioneering proof of concept will one day help shape even more staggering innovations,” Morgan said.
“Our foundation was built on the dream that technology, and AI especially, can break through severe disabilities and ensure a right to create, connect, and live life joyfully. We’re making that happen,” Morgan added.
For Taylor, the project is also about the end goal.
“The avatar is incredible, but what matters most to me is that this technology could help change the lives of many more people facing ALS or other diseases — a way of showing how bright the future can still be,&#8221; Taylor said.

Novel AI-powered platform aims to help ALS patients to communicate

Treatment with <a href="https://alsnewstoday.com/ultomiris-ravulizumab-cwvz/">Ultomiris</a> (ravulizumab-cwvz) — a therapy approved for several rare diseases that works by blocking activation of part of the immune system called the complement cascade — failed to slow the progression of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a Phase 3 clinical trial that had been launched in 2020, a new study shows.
The study, which details the findings from the full 50-week trial data, supports the decision, made in 2021, to terminate that trial early.
&#8220;This trial rapidly showed that terminal complement &#8230; inhibition with [Ultomiris] did not slow functional decline in participants with ALS,&#8221; the researchers wrote.
<a href="https://alexion.com/">Alexion</a>, the therapy&#8217;s developer, ultimately stopped the trial in October 2021 after a pre-specified interim analysis failed to demonstrate any signs of efficacy from Ultomiris.
Titled &#8220;<a href="https://jamanetwork.com/journals/jamaneurology/fullarticle/2809453">Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial</a>,&#8221; the study was published in <a href="https://jamanetwork.com/journals/jamaneurology">JAMA Neurology</a>. The work was funded by Alexion, a subsidiary of AstraZeneca.
[recommended-reading id=72320]
<h3>CHAMPION-ALS study had enrolled 382 adults</h3>
The complement cascade is composed of a group of immune proteins that can become activated to destroy threats — but in some disorders, such activation can help to drive disease-causing inflammation.
Ultomiris, which works by blocking a complement protein called C5, is approved to treat several diseases that are driven by overactivation of the complement cascade, including <a href="https://myastheniagravisnews.com/ultomiris-ravulizumab-for-myasthenia-gravis/">myasthenia gravis</a> and <a href="https://pnhnews.com/ultomiris-ravulizumab-for-pnh/">paroxysmal nocturnal hemoglobinuria</a>, known as PNH.
Although the causes of ALS aren&#8217;t well understood, abnormal inflammation is thought to play a role, and some studies had suggested that complement activity may be increased in people with ALS.
Thus, Alexion sponsored a Phase 3 clinical trial called <a href="https://clinicaltrials.gov/ct2/show/NCT04248465">CHAMPION-ALS (NCT04248465</a>) to test whether Ultomiris treatment might be beneficial in ALS. The trial enrolled 382 adults with ALS, whose symptoms had started up to three years prior, and who were randomly assigned to receive Ultomiris or a placebo.
After two loading doses given two weeks apart, patients received treatment every eight weeks for up to 50 weeks, or nearly one year. All participants could then enroll in an open-label extension part and receive Ultomiris for up to 106 weeks, or a little more than two years.
The study&#8217;s main goal was to test whether Ultomiris could slow disease progression, measured by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R).
[recommended-reading id=86121]
<h3>Initial preterm analysis had predicted failure of Ultomiris</h3>
In large studies like this, independent data monitoring committees will regularly conduct interim analyses testing for futility. Simply put, this involves looking at the available data to calculate whether there&#8217;s a reasonable likelihood the trial might have positive results.
In an interim analysis conducted after half of participants had completed their 26-week assessment, researchers found that the average ALSFRS-R score had worsened by 14.67 points for patients on Ultomiris — in fact showing slightly more worsening than the average of 13.33 points seen in the placebo group.
Statistical analyses suggested that the odds the trial would show slower progression with Ultomiris compared with the placebo was less than 0.1%, and the trial was ultimately terminated early.
[quote=&#8221;center&#8221;]There was a clear rationale for testing [Ultomiris] as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression. &#8230; However, the CHAMPION-ALS study was terminated when the week 26 interim analysis showed that the futility criterion had been met.[/quote]
The investigators now shared full analyses of all available trial data.
These results continued to show no effect of Ultomiris compared with a placebo on ALSFRS-R scores. There also was no benefit on other endpoints, including a combined assessment of survival and disease progression, changes in lung function, time to needing ventilatory support, and all-cause mortality.
Measures of muscle strength and markers of nerve damage also failed to improve with Ultomiris treatment.
A total of 80% of patients experienced side effects related to the therapy, the most common of which were headaches, falls, and constipation. Safety data showed no unexpected findings related to Ultomiris compared with what&#8217;s been seen with the therapy in people with other diseases.
&#8220;There was a clear rationale for testing [Ultomiris] as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression,&#8221; the researchers wrote.
&#8220;However,&#8221; they noted, &#8220;the CHAMPION-ALS study was terminated when the week 26 interim analysis showed that the futility criterion had been met.&#8221;
The researchers pointed that pharmacological data from the trial showed Ultomiris was blocking C5 as designed.
&#8220;It is unclear why C5 inhibition did not result in clinical benefit in patients with ALS and whether this lack of benefit might extend to other complement components,&#8221; they wrote.
The team concluded that this trial &#8220;highlights the unmet need for highly effective treatments to slow functional decline and extend survival in patients with ALS.&#8221;

Ultomiris failed to show benefit in ALS in clinical trial, per full data

While eating a high-calorie diet is safe and well tolerated, it does not appear to slow disease progression or reduce the risk of death in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a review of published clinical trials found.
Combining data from multiple trials helps to create a single, more precise estimate of the effect of high-calorie diets in people with ALS. Yet, the review study included only four trials, all of which had few patients and short observations times. Consequently, the available evidence may not be strong enough to establish clear conclusions regarding the use of a high-calorie diet.
“A larger randomized controlled trial with longer observation might be needed to truly establish its efficacy,” which should offer more accurate information to make informed decisions about dietary choices, the researchers wrote.
[recommended-reading id=85831]
The study, “<a href="https://www.sciencedirect.com/science/article/abs/pii/S0035378723009827">Efficacy, safety and tolerability of high caloric diet in amyotrophic lateral sclerosis patients: A systematic review and meta-analysis</a>,” was published in <a href="https://www.sciencedirect.com/journal/revue-neurologique">Revue Neurologique</a>.
ALS affects the motor nerve cells responsible for movement, causing muscles to weaken and waste away over time, making it difficult to walk, speak, eat, and drink.
Poor nutrient intake (malnutrition) and weight loss are common in people with the disease and have been linked with worse survival outcomes. This occurs mainly due to <a href="https://alsnewstoday.com/als-symptoms/difficulty-swallowing/">difficulty swallowing</a>, so establishing a <a href="https://alsnewstoday.com/non-drug-therapies/diet-and-supplements/">proper diet plan</a> can help maintain good nutrition and offer other food options when swallowing becomes harder.
While there is no one-size-fits-all diet, many randomized clinical trials have tested if adding extra calories through sugars (carbohydrates) or fats (lipids) is safe and well tolerated and helps people with ALS live longer.
“However, most of these trials have been small and the results are conflicting,” the researchers wrote.
To draw broader conclusions, a trio of researchers in the Philippines and Canada used a method called meta-analysis to pool data from multiple published studies that had tested high-calorie diets in people with ALS.
<h3>Four studies used in the analysis</h3>
After reviewing the literature, a total of four studies, published between 2013 and 2022, were included in the analysis.
The studies included 311 patients. Of them, 176 followed high-calorie diets with carbohydrate or lipid supplementation, whereas 135 individuals used as controls ate fat-free or moderate-calorie diets.
The four studies lasted between 1-15 months. In all, it was concluded that high-carbohydrate and high-lipid diets “were generally safe and tolerable,” the researchers wrote.
The chances of high-calorie diets causing side effects or leading to dropping out were about the same as they were for controls. However, the results varied widely across studies.
Following high-calorie diets also did not significantly reduce the chances of dying or slow the decline in the revised ALS Functional Rating Scale (ALSFRS-R) score, a measure of how quickly a patient’s functional ability becomes impaired over time.
They also didn’t lead to significant increases in weight versus controls, “even when there was no or there was minimal heterogeneity [variation in results across studies],” the researchers wrote.
<h3>Pooled data was not statistically significant</h3>
While some studies showed beneficial effects of high-calorie diets on certain outcomes, the analysis of pooled data did not reveal statistically significant differences versus controls.
“Current evidence suggests that high calorie supplementation is generally safe and tolerable for patients with ALS. However, it has not been shown to be efficacious in improving weight and functional disability,” the researchers concluded.
However, “the low sample size, high drop-out rate and short observation time in most studies may have affected the result,” they noted, calling for a “larger-scale study, with a longer observation period.”

More evidence needed to support use of high-calorie diet for ALS

Elevated blood levels of the Cystatin C protein are significantly associated with faster disease progression and shorter survival in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a study in China.
The protein may serve as a biomarker to predict disease outcomes in people with ALS and identify those who need more invasive strategies earlier in the disease course, the findings suggest.
Cystatin C “has the potential to be a widely used and reproducible biomarker for monitoring disease progression in ALS,” the researchers wrote in “<a href="https://link.springer.com/article/10.1007/s10072-023-06957-9">Serum Cystatin C is a potential biomarker for predicting amyotrophic lateral sclerosis survival</a>,” which was published in <a href="https://www.springer.com/journal/10072">Neurological Sciences</a>.
ALS is caused by the damage and death of motor neurons, the nerve cells that control voluntary movements. This causes a loss of control of muscle movements, and patients progressively become less able to go about their daily lives without assistance.
About 90% of cases are <a href="https://alsnewstoday.com/sporadic-als/">sporadic</a>, meaning they occur spontaneously. The remaining 10%, which run in families, are called <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>. Although many studies have focused on the genetic causes of familial ALS, less is known about the mechanisms leading to sporadic ALS.
[recommended-reading id=85520]
<h3>Connecting Cystatin C levels to disease progression, survival</h3>
Cystatin C is a small protein used to monitor kidney problems and has also been associated with disease severity in ALS. Yet, studies examining the link between Cystatin C and ALS survival and progression have yielded conflicting results, leading researchers in China to assess the potential biomarker&#8217;s levels in 356 patients with sporadic ALS at their hospital between 2016-2019 to shed more light on this association.
Most participants (57%) were men, with a mean age at disease onset of 53.3 and a mean interval between symptom onset and <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis</a> of 13.8 months. They were followed by neurologists via phone or in-person interviews every six months until January 2022. During that time, 226 patients (63.5%) died and 26 (7.3%) were lost to follow-up.
On average, the levels of Cystatin C in serum (the liquid portion of blood) at diagnosis were 1 mg/L. Based on that average, patients were divided into two groups: those with levels of 1 mg/L or higher and those with levels below the average.
The high Cystatin C group had a significantly higher proportion of men (71.5% vs. 44.5%) and of patients with limb-onset disease (89.1% vs. 55.5%), a form of the disease in which the first <a href="https://alsnewstoday.com/als-symptoms/">symptoms of muscle weakness</a> appear in the limbs. This group was also significantly older at the onset of the disease (57.7 vs. 49.5%).
The participants in the high and low Cystatin C groups also had differences in clinical measures. In fact, the high group had significantly less disease severity, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R), but a faster rate of disease progression.
The higher the Cystatin C levels, the less severe the disease was, but the faster it progressed, according to statistical analyses that looked at Cystatin C levels as a continuous variable.
This suggests “serum [Cystatin C] may be a useful indicator for assessing disease severity, [and that] patients with higher [Cystatin C] levels might have faster disease progression,&#8221; the researchers wrote.
The median survival time for all the patients was 42 months (around 3.5 years). However, consistent with the faster rate of disease progression in those with high Cystatin C levels, this group also had a significantly shorter survival compared with the group with low levels (38 vs. 48 months). In a multivariate analysis, which took into account potential confounding factors such as age and sex, low serum Cystatin C remained associated with a longer survival time with ALS.
Other factors significantly associated with longer survival included a lower age at disease onset, limb onset, a longer time between the appearance of the first symptoms and diagnosis, a slower disease progression rate, and being male.
“Our study found that serum [Cystatin C] seems to be associated with ALS survival and serum [Cystatin C] may be an independent predictor of ALS survival,” the researchers said.

Cystatin C may be biomarker to predict survival, disease progression

Six months of treatment with clenbuterol, an asthma medication, slowed disease progression in adults with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to data from a small U.S.-based Phase 2 clinical trial.
Despite these promising preliminary findings, more than half the participants withdrew from the study due to side effects.
“Nonetheless, this pilot trial provides valuable data for clenbuterol dosing, tolerability, and safety,” the researchers wrote, adding “a large-scale clinical trial is now warranted to determine its potential efficacy.”
The trial’s results were published in the <a href="https://journals.lww.com/jcnmd/pages/currenttoc.aspx">Journal of Clinical Neuromuscular Disease</a> in “<a href="https://journals.lww.com/jcnmd/Fulltext/2023/06000/Clenbuterol_Treatment_Is_Safe_and_Associated_With.5.aspx">Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis</a>.”
Clenbuterol is an oral medication approved for treating asthma outside the U.S. It&#8217;s thought to have muscle strengthening and neuroprotective effects that could slow ALS, which is marked by progressive nerve damage and physical disability.
In a mouse model of ALS, clenbuterol was found to improve motor function and slow disease progression. Also, a previous pilot trial with 16 patients in Italy showed the therapy <a href="https://www.tandfonline.com/doi/abs/10.1080/14660820600600558?journalCode=iafd19">improved limb muscle strength and lung function</a>, while stabilizing disability level.
[recommended-reading id=83744]
<h3>Clenbuterol&#8217;s effect on ALS disease progression</h3>
Building on these promising results, researchers at Duke University, in North Carolina, conducted a <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04245709">Phase 2 trial (NCT04245709)</a> to test the safety and effectiveness of six months of treatment. They enrolled 25 adults diagnosed with possible, probable, or definite ALS between February 2020 and September 2020. Recruitment was temporarily paused due to the COVID-19 pandemic.
Participants had a mean age of 59 and 48% were women. They&#8217;d lived with the disease for a mean of 43 months (about 3.5 years), and 68% were taking the approved ALS therapy riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>, and <a href="https://alsnewstoday.com/tiglutik-riluzole-oral-suspension/">Tiglutik</a>).
All were started on 40 micrograms of clenbuterol a day. This was eventually increased to 80 micrograms twice a day.
Changes in various clinical measures were also assessed, including disease progression using the ALS Functional Rating Score (ALSFRS-R), lung function, and muscle strength. The ALSFRS-R scores range from 0 to 48, with lower scores indicating worse disability.
A total of 14 participants withdrew early, 13 due to side effects. The remaining patient discontinued due to concerns about traveling during the pandemic.
“Patients who discontinued the trial were significantly older and more likely to be male,” the researchers wrote.
The most commonly reported side effects included jitters, tremors, cramps, and insomnia, which were reported as the main reasons for withdrawing. There were no reports of treatment-related severe side effects or concerning laboratory or heart rhythm changes.
<h3>Results among patients who completed 24-week study</h3>
Among the 11 patients who completed the 24-week study, clenbuterol was associated with a slower disease progression, with a mean ALSFRS-R decline rate dropping from 0.56 to 0.17. One patient saw no progression over the six months, while four showed an increase in ALSFRS-R scores, indicating less disability.
The rates of ALSFRS-R decline for each person at the start were also significantly reduced after treatment with clenbuterol.
Ten of these patients had at least two measurements of lung function, as assessed by forced vital capacity (FVC), or the total amount of air that can be forcibly exhaled. The mean rate of FVC decline was slower after treatment (0.25 vs. 0.8), but this difference failed to reach statistical significance. Likewise, FVC rates for each person were not significantly different before and after treatment.
While more than half the participants didn&#8217;t complete treatment, 20 had at least one ALSFRS-R measurement after it started. Among them, 15 had a slower, but nonsignificant, ALSFRS-R decline rate with clenbuterol (0.33 vs. 0.52). Within-individual ALSFRS-R rate differences were also nonsignificant in this analysis.
Similarly, 16 of the initial 25 participants had at least two FVC measurements. Here, mean percent predicted FVC slope was significantly reduced after clenbuterol treatment (0.88 vs. 0.09). Within-individual FVC rates were also significantly different between before and after.
Muscle strength measurements of the lower and upper limbs were highly variable between patients before and after treatment. Most became weaker over six months, data suggested.
Despite these results, a few patients became significantly stronger over time, “which is unusual in the natural history of ALS,” the researchers wrote. “Our study confirms clenbuterol is safe for selected patients with ALS, but it was less tolerable at the doses we chose compared with an earlier Italian [trial], in which 16 patients were treated with 60 [micrograms] daily.&#8221;
A conclusion wasn&#8217;t able to be drawn about clenbuterol&#8217;s effectiveness because of the trial’s small population, large dropout rate, and lack of a placebo group,” said the researchers, who called for larger studies to clarify their results.

Asthma medicine slows ALS disease progression in small trial

<a href="https://alsnewstoday.com/nurown/">NurOwn</a>, an experimental treatment, significantly lowered neurofilament light chain (NfL) levels in the spinal fluid, a marker of nerve damage, and this seems to predict slower disease progression in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients.
That’s according to a new analysis of <a href="https://clinicaltrials.gov/study/NCT03280056">Phase 3 clinical trial (NCT03280056)</a> data that examined changes in multiple biomarkers over about seven months of NurOwn&#8217;s use with in people with fast-progressing ALS.
The analysis was &#8220;motivated&#8221; by the recent U.S. Food and Drug Administration (FDA) decision to conditionally approve <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) for ALS after deeming blood NfL reductions reasonably likely to predict clinical benefit, <a href="https://brainstorm-cell.com" rel="nofollow">BrainStorm Cell Therapeutics</a>, NurOwn&#8217;s developer, stated in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-data-show-treatment-with-nurown-significantly-reduces-nfl-a-key-biomarker-of-neurodegeneration-301871918.html">company press release</a>.
FDA allowance of likely patient benefit with lower NfL levels could impact the agency&#8217;s stance in its ongoing review of NurOwn for possible approval. Analysis findings also further support the use of NfL as a biomarker of clinical benefit in ALS, researchers noted.
[recommended-reading id=85260]
<h3>FDA due to decide on NurOwn in treating ALS in early December</h3>
Stacy Lindborg, PhD, co-CEO at BrainStorm, presented the new findings in the poster “<a href="https://filecache.investorroom.com/mr5ir_brainstorm_cell/188/download/Gordon_Conf_2023_Final%20poster.jpg">CSF biomarkers identified as predictive of clinical outcomes in ALS participants following NurOwn treatment in a phase 3 clinical trial: Reductions in NfL associated with less ALSFRS-R decline</a>” at the Gordon Research Conference, held July 2-7 in Switzerland.
“The data we presented … show that it is equally important to examine biomarker data, particularly [NfL], which is a predictor of disease progression. Treatment-driven reductions in NfL are associated with better clinical outcomes in ALS,” Lindborg said.
The FDA <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">declined to consider NurOwn&#8217;s approval</a> request late last year, citing not enough evidence supporting its clinical benefit. After meeting with the agency, BrainStorm <a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">decided to proceed with the application filing</a>, ensuring that an FDA advisory committee and experts will discuss the treatment&#8217;s potential.
That meeting is <a href="https://alsnewstoday.com/news/fda-final-approval-decision-brainstorms-nurown-als-due-december/">scheduled for Sept. 27</a>, and a final FDA decision is expected by Dec. 8.
NurOwn is a cell-based treatment that involves taking mesenchymal stem cells from a patient’s bone marrow. These stem cells, which can give rise to a variety of cell types, are then grown in the lab to produce large amounts of molecules that help nerve cells thrive.
After being matured and expanded in the lab, the stem cells are returned to the patient via a spinal canal injection. There, they are expected to help prevent nerve cell death, slowing disease progression.
The completed Phase 3 trial included 189 patients rapidly progressing ALS, ages 18 to 60, who received three injections of either NurOwn or a placebo given two months apart.
The study’s main goal was to determine the effect of treatment on disease progression, as measured by the proportion of patients showing at least a 1.25-point slower monthly decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores over 28 weeks (about seven months).
That goal and secondary goals of mean change in ALSFRS-R scores, lung function decline, and a combined assessment of function and survival were not met.
<h3>&#8216;Floor effect&#8217; seen as undermining key goals of NurOwn Phase 3 trial</h3>
According to BrainStorm, these failures likely were due to a large proportion of trial participants having advanced ALS — meaning some patients at trial enrollment already would have the lowest scores on some ALSFRS-R subscales. This creates a <a href="https://alsnewstoday.com/news/mda-2023-issues-als-scale-noted-nurown-trial-failure-analysis/">“floor effect” that prevents changes in disease progression</a> from being properly detected.
In line with that hypothesis, further analysis <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">excluding patients with the lowest scores</a> or <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">including only those with less advanced disease</a> showed evidence that NurOwn may slow disease progression.
The recent presentation focused on a prespecified analysis of 33 biomarkers measured in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord. Among these biomarkers, 16 were related to neuronal inflammation, eight to neurodegeneration, and nine to neuroprotection.
In general, levels of these biomarkers remained stable over time in the placebo group, but about 22 of them changed with NurOwn use.
“Treatment with NurOwn significantly elevates markers of neuroprotection, and lowers markers of neuroinflammation and neurodegeneration over time compared to placebo,” the researchers wrote.
Neurofilaments are proteins that provide structural support to nerve cells and are released to the CSF and blood when nerve cells become damaged. NfL, in particular, is commonly seem as a marker of nerve cell damage and disease progression in people with neurodegenerative conditions.
<h3>Slower ALS progression for treated patients with larger drops in NfL levels</h3>
Results showed that initial (baseline) levels of NfL in patients given a placebo significantly predicted disease progression, with higher levels being significantly associated with greater declines in ALSFRS-R scores after 28 weeks.
However, NfL levels were significantly reduced in NurOwn-treated patients after 20 weeks — the last measurement of CSF biomarkers.
A statistical model found three biomarkers that could be used to predict clinical outcomes in people receiving NurOwn, including baseline levels of NfL and the anti-inflammatory biomarker LAP/TGF beta-1, and changes in the neuroprotective biomarker Galenctin-1.
The team then showed that, after adjusting for the predicted changes due to natural disease progression, greater NfL reductions after treatment with NurOwn significantly associated with slower disease progression over the 28 weeks.
This analysis was done in the subset of patients who did not contribute to the floor effect, meaning those with scores of 1 or higher in all ALSFRS-R subscales. It “provides further &#8230; evidence of the importance of NfL as a prognostic and predictive biomarker for ALS,” the researchers concluded.

Slower ALS progression evident with lower NfL levels: NurOwn trial

<a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava </a>(edaravone) significantly prolongs long-term survival for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to an analysis of nearly 3,000 patients. It didn&#8217;t significantly slow the progression of disease symptoms, as assessed by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R), however.
The results were presented at last week&#8217;s American Academy of Neurology (AAN) 2023 annual meeting in the poster, “<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54324">Survival in Amyotrophic Lateral Sclerosis Patients Treated with Edaravone &#8211; a Pooled Analysis of 2845 Patients</a>.”
Radicava is an approved <a href="https://alsnewstoday.com/als-treatment/">treatment for ALS</a> that&#8217;s thought to reduce oxidative stress — a type of cell damage that plays a major role in driving the disease. It&#8217;s available as an intravenous (into the vein) infusion or in a newer oral formulation called Radicava ORS. Both are sold by <a href="https://www.mt-pharma.co.jp/e/">Mitsubishi Tanabe Pharma</a>, which was not involved with this analysis.
Despite Radicava&#8217;s approval in <a href="https://alsnewstoday.com/news/fda-approves-radicava-first-new-als-therapy-in-20-years-and-cause-for-hope/">the U.S.</a>, <a href="https://alsnewstoday.com/news-posts/2018/10/09/radicava-now-approved-to-treat-als-patients-in-canada/">Canada</a>, Switzerland, and a number of other countries, evidence on its effectiveness <a href="https://alsnewstoday.com/news/radicava-suggests-more-real-world-data-needed-to-determine-efficacy-of-edaravone-in-als/">isn&#8217;t settled</a>, leading scientists at Al-Azhar University, Egypt to analyze pooled data from 12 previously published studies to assess its effect on disease progression and survival.
[recommended-reading id=82936]
The analysis included data on 2,845 patients, among whom, 1,141 were treated with Radicava, sometimes in combination with the older ALS therapy riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek </a>and other formulations). The other 1,704 were given a control treatment, either a placebo or riluzole alone.
After 18 months (1.5 years) of follow-up, the chances of survival were significantly higher, by about 13%, for patients given Radicava. Later analyses also showed a significant survival benefit with Radicava — by 22% at 24 months (two years) and by 17% at 30 months (2.5 years).
At earlier timepoints (six or 12 months), survival tended to be slightly better in the Radicava group, but the difference with the control group was not statistically significant. That means it&#8217;s mathematically plausible the difference could be due to random chance.
Rates of symptom progression, as measured by the change in ALSFRS-R scores, tended to slightly favor Radicava, but weren&#8217;t significantly different from controls. Rates of side effects and other safety issues were comparable in the two groups, leading the scientists to conclude that Radicava “improves long-term survival with no effect on the ALSFRS-R score&#8221; and with a similar rate of adverse events between the groups.

Tag: disease progression