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Having possible symptoms of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) increases the chances of getting an ALS diagnosis by nearly five times, but getting diagnosed is more likely for people in urban areas, who have greater access to specialized care, a U.S. study shows.
People in rural areas are diagnosed at a later age and their diagnosis is more dependent on major ALS-specific <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>, such as muscle weakness and difficulty swallowing or speaking.
The findings underscore the “need to accelerate the detection-to-diagnosis timeline of ALS,” particularly for underserved populations in rural areas, the researchers wrote in “<a href="https://www.tandfonline.com/doi/full/10.1080/21678421.2024.2315185">Rurality modifies the association between symptoms and the diagnosis of amyotrophic lateral sclerosis</a>,” which was published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.
ALS is <a href="https://alsnewstoday.com/causes-of-als/">caused</a> by progressive damage to motor neurons, which are specialized nerve cells responsible for voluntary muscle movements. Evidence suggests early symptoms may appear about a year before the disease is formally diagnosed. These symptoms are often ambiguous, however, and can be missed in many patients, especially where access to specialists is limited, such as rural areas.
Here, researchers in the U.S. studied the association between possible ALS symptoms and a later diagnosis, and whether that association changed in urban or rural areas.
[recommended-reading id=90264]
<h3>Chances of an ALS diagnosis</h3>
The scientists used national insurance claims-based data from 2001 to 2021. The study included 19,226 people newly diagnosed with ALS and a control group of 96,126 people without ALS, who were matched to patients in age, sex, and enrollment period.
The researchers considered eight groups of symptoms as possible signs of ALS: speech problems, swallowing problems, muscle strength, gait problems, involuntary muscle movements, pain, falls, and other symptoms. The symptoms were assessed up to a year before the diagnosis.
A greater proportion of those who were later diagnosed with ALS had at least one possible symptom than those who weren&#8217;t diagnosed with the disease (83.7% vs. 50.7%). There were also more patients than controls with four or more symptoms before a diagnosis (25.5% vs. 4.7%).
Having at least one possible ALS symptom increased the chance of a diagnosis by 4.92 compared with not having a symptom, statistical analyses indicated. Also, as the number of symptoms increased, the likelihood of a diagnosis increased — being 33.2 times more likely in people with five symptoms.
The participants who lived at any time in an urban area were 44% more likely to be diagnosed with ALS than those in rural areas.
Both having possible ALS symptoms and living in an urban area increased the chances of an ALS diagnosis. The difference between urban and rural areas was smaller among those who showed symptoms, however. This means “having a possible ALS symptom reduces the urban bias of ALS,” said the researchers, who then showed the association between possible ALS symptoms and a diagnosis was evident at least a year before a diagnosis, suggesting &#8220;ALS symptoms may start appearing and being noted clinically at least [one] year before the diagnosis of ALS is made.&#8221;
Next, as differences in ALS incidence in urban and rural areas hadn&#8217;t been reported, the researchers hypothesized that the differences in diagnosis resulted from greater access to care in urban areas. This would probably result in being diagnosed at an earlier age in these regions, which analyses confirmed.
“If the age-dependent incidence of ALS is similar between urban and rural places, this finding would suggest people with ALS are being diagnosed earlier in their disease course and with presumably lower symptom burden when they live in urban areas,” wrote the researchers, who noted that “rural populations, which are disproportionately elderly and face limited access to specialist care, are more dependent on major symptoms to arrive at a diagnosis.&#8221;

Rural living may widen gap between early ALS symptoms, diagnosis

While women with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) see a faster functional decline, men have shorter survival times, mostly due to more rapid weight loss and lung function worsening, a study shows.
The findings highlight the importance of considering sex-specific differences when studying the mechanisms leading to ALS and when designing individual  <a href="https://alsnewstoday.com/als-treatment/">treatment plans</a>. The study, “<a href="https://onlinelibrary.wiley.com/doi/10.1002/ana.26933">Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis</a>,” was published in Annals of Neurology.
ALS tends to develop earlier and is <a href="https://alsnewstoday.com/news/als-prevalence-united-states-nearly-2017/">more frequent in men</a> than women. Clinical features may differ too. For example, men are more likely to have flail arm, marked by progressive weakness and atrophy in the arms, as an initial <a href="https://alsnewstoday.com/symptoms-of-als/">symptom of ALS</a>. But women are more often diagnosed with <a href="https://alsnewstoday.com/forms-of-als/#Clinical_onset">bulbar-onset ALS</a>, which first affects the muscles in the head and neck.
Since age and where initial symptoms happen are both strongly associated with survival and the rate of disease progression, researchers at the University of Turin, Italy drew on data from the Piemonte and Valle d&#8217;Aosta Register for ALS (PARALS), which included those <a href="https://alsnewstoday.com/als-diagnosis/">diagnosed with ALS</a> between 2007 and 2019, to better understand how the interaction of sex with these two clinical factors could improve predicting the disease&#8217;s course and survival, and guide treatment.
Of 1,890 patients, more than half (55.2%) were men. On average, men developed ALS at 66.4 years old, while women had their first symptoms about a year later, with bulbar-onset ALS being <a href="https://alsnewstoday.com/news/age-sex-gene-mutations-strongly-influence-als-type-symptoms-study-finds/">more common</a> (41.2% vs. 25.9%). The median diagnostic delay was nine months for both sexes.
[recommended-reading id=89313]
<h3>ALS survival in men, women</h3>
A survival analysis showed men tended to live shorter lives than women, but the difference only became significant when evaluating limb-onset ALS, which is sometimes called spinal ALS, and bulbar-onset ALS separately. This difference persisted even after considering factors like genetic makeup, cognitive function, and age at onset.
At the time of their diagnosis, men had a lower percentage of forced vital capacity (FVC), meaning worse respiratory function than women. Men also lost more weight each month (about 0.15 kg), regardless of having limb-onset or bulbar-onset ALS.
The fact that this occurred despite women having more bulbar symptoms, which often cause <a href="https://alsnewstoday.com/symptoms-of-als/#Breathing_difficulties">trouble breathing</a> and eating, was &#8220;an apparently counterintuitive result,&#8221; wrote the researchers.
A “cause-and-effect” analysis showed the faster declines in respiratory function and weight were the strongest factors contributing to worse survival in men, accounting for about 66% of the sex differences.
&#8220;These findings elucidate that the shorter survival in male ALS patients stems from their faster decline in respiratory function and weight loss, although other factors are involved,&#8221; the researchers wrote.
When men and women were matched for a number of clinical and demographic variables, men continued to have a 19% higher risk of death than women. But this worse survival didn&#8217;t correspond to faster disability progression since women actually progressed faster on the ALS Functional Rating Scale-Revised (ALSFRS-R) scale, a measure of disease severity, by about 0.1 points a month.
This included a significantly faster progression in ALSFRS-R domains of fine motor function, gross motor function, and bulbar function. While there was no difference in the respiratory domain, it took women longer to start noninvasive ventilation to help with breathing.
These findings were confirmed in two additional groups of patients from the <a href="https://ncri1.partners.org/ProACT/Home/Index">Pooled Resource Open-Access ALS Clinical Trials</a> (PRO-ACT) database, which includes data from participants in previous ALS clinical trials, and the <a href="https://www.answerals.org">Answer ALS</a> database.
“The present study casts new light on the multifaceted nature of sex-related differences in ALS prognosis [outlook] and has a direct impact on clinical practice, guiding the management of ALS patients toward sex-personalized care, and improving the design and interpretation of clinical trials,” the researchers said.

ALS women live longer than men despite faster functional decline

The Gary E. Shealy Memorial ALS Clinic in Tennessee has received a $75,000 grant from the <a href="https://www.als.org/">ALS Association</a> to support expanding its clinical care services for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The clinic at East Tennessee State University (ETSU) Health is the only one in the state that offers free multidisciplinary care to ALS patients. Established in partnership with the ALS Association, it relies on voluntary work from different specialty clinicians, serving nearly 100 patients across thousands of visits.
The award, which coincided the clinic&#8217;s seventh anniversary, should help expand services to a full day, increase telehealth availability, help it acquire equipment to loan to patients, and continue educating care providers.
“This funding will go a long way in ensuring we are able to keep up with the increasing demand for services,” Courtney Andrews, professor and clinic coordinator at ETSU Health, said in a <a href="https://www.etsu.edu/etsu-news/2024/04-april/nave-center-shealy-als-clinic-grant.php">university press release</a>. “These services are critically needed in our area and we are committed to doing everything we can to improve the quality of life for those living with ALS in our region.”
[recommended-reading id=90642]
<h3>How ETSU Health&#8217;s ALS Clinic began</h3>
ETSU Health&#8217;s ALS Clinic was established in 2017 with a donation by Faith Akin, PhD, an audiologist at James H. Quillen VA Medical Center, after her husband, Gary E. Shealy, died from ALS in 2016.
Akin said she and her husband had to travel far to other universities to access an ALS clinic, just like other affected families in the region, making a local clinic where patients had access to specialized care urgently needed.
Akin expects the new clinic at ETSU would help reduce the burden on ALS patients and their families by providing coordinated care from several clinicians in one visit, instead of having to make multiple trips to different specialists.
The clinic is based on a multidisciplinary model to offer services from <a href="https://www.etsu.edu/crhs/als-clinic/provider-bio.php">a number of specialists</a>, including a neurologist, a nurse, and physical, occupational, respiratory, and speech-language therapists. It also offers services from a dietitian, a pharmacist, a social worker, an assistive technology professional, and an ALS Association representative.
The clinic is open to everyone with an ALS diagnosis every third Friday of the month from 12 to 4:30 p.m. For appointments, patients or caregivers can contact Andrews by phone at 423-439-4712, by fax at 423-439-4607, or by email at andrewscm@etsu.edu.
Because an ALS diagnosis is often made by excluding a number of other diseases, it offers a second opinion through a partnership with Randy Trudell, MD, whose main office is in Knoxville.
“The Gary E. Shealy Memorial ALS Clinic is a critical lifeline for those in our region seeking care for ALS, and we are incredibly proud to celebrate seven years of care with the support of the ALS Association,” Andrews said.

ETSU ALS clinic receives $75K grant to expand free care services

Treatment with <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) in the real world slowed disease progression in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by SOD1 mutations, a small study reports.
It also stabilized patients&#8217; quality of life and lowered levels of nerve damage-related biomarkers, which is consistent with clinical trial data that supported its approval.
&#8220;Treatment with [Qalsody] was shown to be an effective therapeutic approach,&#8221; the researchers wrote in “<a href="https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00074-9/fulltext">Effects of tofersen treatment in patients with SOD1-ALS in a “real-world” setting – a 12-month multicenter cohort study from the German early access program</a>,” which was published in eClinicalMedicine.
Qalsody was <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">conditionally approved in the U.S.</a> in 2023 for ALS patients who harbor mutations in the SOD1 gene, which are associated with up to 20% of <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> cases and about 2% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic</a> cases. Last month, a committee of the European Medicines Agency (EMA) <a href="https://alsnewstoday.com/news/committee-favors-eu-approval-qalsody-1st-treatment-sod1-als/">recommended</a> that Qalsody be approved in the European Union under exceptional circumstances.
The therapy, which is administered intrathecally, that is, directly into the spinal canal, suppresses the production of mutant SOD1 protein to slow disease progression and extend survival.
Its applications in the U.S. and Europe were based on data from the three-part <a href="https://www.clinicaltrials.gov/ct2/show/NCT02623699">Phase 1/2/3 VALOR trial (NCT02623699)</a> and its ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a>, where Qalsody slowed disease progression, extended survival, and lowered neurofilament light chain (NfL), a marker of nerve damage.
Early access programs (EAPs) were launched in a number of countries based on the findings to provide Qalsody to SOD1-ALS patients outside of clinical trials before its regulatory approval.
[recommended-reading id=90434]
<h3>Qalsody in real-world settings</h3>
Here, researchers report on data from 24 SOD1-ALS patients who received Qalsody under an EAP in Germany between March 2022 and April 2023.
The patients received a median of eight Qalsody doses over a median observation period of six months. Of them, half were women and 58.3% had a family history of the disease.
The median rate of progression, as assessed using the ALS Functional Rating Scale Revised (ALSFRS-R), was slower with Qalsody than at the start of the study, or its baseline. Patients lost a median of 0.11 ALSFRS-R points a month after starting treatment compared with 0.41 monthly points before starting Qalsody.
Seventeen patients had a slower progression rate with treatment compared with the baseline and six had a faster progression.
Those with a faster progression had a shorter disease duration at the time they started Qalsody and higher levels of nerve damage biomarkers, including NfL and phosphorylated neurofilament heavy chain (pNfH). These patients&#8217; observation period was also shorter, “implying that they have received fewer doses of Qalsody,” the researchers wrote. No changes in muscle strength were seen in nine patients with available data.
Self-reported quality of life showed stable results among eight evaluable patients. The participants generally indicated severe problems with mobility and self-care, and slight to moderate levels of pain, discomfort, anxiety, and depression.
Other measures deteriorated from moderate to severe during treatment, including the ability to perform work, study, housework, and family or leisure activities. No changes were observed when the patients were asked to indicate their current state of health on a scale from 0 to 100, however.
In contrast, blood levels of NfL and spinal fluid levels of pNFH significantly dropped with treatment, indicating reduced nerve cell damage.
&#8220;Based on preexisting evidence, treatment with tofersen in SOD1-ALS leads to a reduction in neurofilament levels (NfL),&#8221; the scientists wrote. &#8220;This study provides evidence that these findings can be extended to pNfH in CSF.&#8221;
Two potentially treatment-related serious side effects were reported. One patient was diagnosed with autoimmune-related inflammation of the spinal cord, or myeloradiculitis, and another had short-term weakness in the lower limbs. Both discontinued treatment. No other drug-related side effects were reported, other than those related to the therapy&#8217;s administration into the spinal canal, such as lower back pain, headache, and pain, weakness, numbness, and tingling in the lower limbs.
“The findings of this study suggest that treatment of SOD1-ALS patients with intrathecal administration of [Qalsody] is an effective therapeutic approach,” the researchers wrote.

Qalsody slows ALS disease progression in real-world settings

A double-blind Phase 2 clinical trial that will test Corcept Therapeutics&#8217; oral <a href="https://corcept.com/cortisolmodulation/">cortisol modulator</a> dazucorilant against a placebo in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is now fully enrolled, the company announced in a <a href="https://www.globenewswire.com/news-release/2024/04/15/2862710/0/en/Corcept-Completes-Enrollment-in-Phase-2-DAZALS-Trial-in-Patients-With-Amyotrophic-Lateral-Sclerosis-ALS.html">press release</a>.
Called <a href="https://clinicaltrials.gov/study/NCT05407324">DAZALS (NCT05407324)</a>, the trial involves 249 adults with <a href="https://alsnewstoday.com/forms-of-als/">sporadic or familial ALS</a> across multiple sites in the U.S. and Canada, and in Europe.
Participants are randomly assigned to receive one of two dazucorilant doses (150 or 300 mg), or a placebo, with neither researchers nor patients knowing who gets which one. Treatment is given as four softgel capsules once daily for 24 weeks, or about six months, in addition to standard <a href="https://alsnewstoday.com/als-treatment/">ALS treatments</a>.
The trial&#8217;s main goals are to assess dazucorilant&#8217;s safety and tolerability, as well as changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, which measure a person&#8217;s ability to perform everyday tasks. The researchers also will evaluate changes in muscle strength, lung function, and quality of life after 24 weeks.
“Fully enrolling DAZALS is an important step toward understanding dazucorilant&#8217;s potential for significantly improving outcomes for people living with this devastating disease,”  said Bill Guyer, <a href="https://corcept.com/">Corcept</a>’s chief development officer. Early data from the trial is expected later this year, Guyer said.
[recommended-reading id=90892]
<h3>Fully enrolled human trial follows positive results in animal study</h3>
People with ALS often show signs of having overactive adrenal glands. These small glands, located atop the kidneys, are responsible for producing cortisol and other hormones.
Cortisol is a steroid hormone that is released into circulation in the body to help manage stressful conditions. However, prolonged elevations in cortisol levels can promote inflammation and nerve cell death, which is thought to drive ALS progression.
Consistently, high levels of cortisol seem to be particularly present in ALS patients with rapid <a href="https://alsnewstoday.com/stages-of-als/">disease progression</a>.
Dazucorilant is a cortisol modulator that binds to glucocorticoid receptors to prevent their interaction with cortisol, preventing the cascade of events that cause neuronal inflammation and death. This is expected to reduce the negative effects of excessive cortisol in ALS patients.
In <a href="https://www.sciencedirect.com/science/article/abs/pii/S0006899319306055">preclinical studies</a> using animal models of ALS, the scientists found that daily treatment with dazucorilant eased inflammation and nerve cell death. Mice also had better motor function and less muscle wasting, as compared with untreated mice.
Now, Corcept aims to see if the therapy is safe and effective in humans at either of two doses.
[quote=&#8221;center&#8221;]Better treatments for ALS are urgently needed. &#8230; Dazucorilant showed great promise in an animal model of ALS – improving motor performance and reducing neuroinflammation and muscular atrophy.[/quote]
The Phase 2 trial, now fully enrolled, has study sites in four U.S. states and eight European countries, as well as locations in Ontario and Quebec. Participants who complete the trial will then be eligible to enter an open-label extension study, in which they can receive a 300 mg daily dose of the active treatment for an additional 132 weeks, or about 2.5 years.
“Better treatments for ALS are urgently needed,” Guyer said, noting that “dazucorilant showed great promise in an animal model of ALS – improving motor performance and reducing neuroinflammation and muscular atrophy.”

Phase 2 trial testing dazucorilant in ALS patients now fully enrolled

Treatment with <a href="https://brainstorm-cell.com/science/#msc-cells">NurOwn</a> (debamestrocel), which BrainStorm Cell Therapeutics is developing for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), may bring about changes in biomarkers of inflammation and neurodegeneration that predict clinical outcomes.
The findings come from the <a href="https://clinicaltrials.gov/study/NCT03280056">Phase 3 trial (NCT03280056)</a> that tested NurOwn against a placebo in 189 adults with rapidly progressing ALS. The trial <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed to meet its main goal</a> of slowing disease progression, but showed <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">promise</a> in those with less advanced disease.
“These findings are encouraging and provide preliminary evidence that debamestrocel may be effective in treating ALS. The impact on biomarkers suggests debamestrocel targets inflammation and neurodegeneration,” Chaim Lebovits, president and CEO of <a href="https://brainstorm-cell.com">BrainStorm</a>, said in a <a href="https://ir.brainstorm-cell.com/2024-04-10-BrainStorm-Cell-Therapeutics-Announces-Peer-reviewed-Publication-of-Biomarker-Data-from-NurOwns-R-Phase-3-Clinical-Trial-in-ALS">company press release</a>.
The study, “<a href="https://onlinelibrary.wiley.com/doi/10.1002/mus.28093">Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes</a>,” was published in Muscle &amp; Nerve. It was funded by BrainStorm.
NurOwn is a cell-based therapy that involves harvesting mesenchymal stem cells from a patient’s bone marrow. These stem cells, which can develop into a variety of cell types, are then grown in a lab to secrete large amounts of neurotrophic factors, or molecules that boost nerve cell heath and survival.
After the modified stem cells are expanded into the millions, they are returned to the patient via an injection into the spinal canal, where they should produce high levels of neurotrophic factors and help slow disease progression.
The previous Phase 3 trial tested the therapy in adults with rapidly progressing ALS, most of whom had advanced disease. An analysis showed that levels of neurofilament light chain (NfL), a biomarker of nerve cell damage, in the spinal fluid were significantly lower after treatment with NurOwn and this reduction was <a href="https://alsnewstoday.com/news/nurown-trial-slower-als-progression-tied-lower-nfl-levels/">linked to slower disease progression</a>.
[recommended-reading id=91103]
<h3>NurOwn&#8217;s effect on disease biomarkers</h3>
To know more about the impact of NurOwn on disease biomarkers, researchers examined 45 biomarkers in spinal fluid samples from 185 of the participants.
Compared with a placebo, NurOwn resulted in significant changes in 16 biomarkers of neuroinflammation, eight biomarkers of neurodegeneration, and nine biomarkers of neuroprotection after 20 weeks.
Similar findings were obtained with the participants with less advanced ALS who saw the greatest clinical benefits with NurOwn, but also in those with more advanced disease, &#8220;suggesting debamestrocel remains biologically active regardless of clinical progression,&#8221; the researchers wrote. &#8220;The results &#8230; highlight a pattern across biomarkers relative to placebo, with debamestrocel reducing levels of neuroinflammation (reducing pro-inflammatory biomarkers, and elevating anti-inflammatory biomarkers), lowering markers of neurodegeneration, and elevating neuroprotective biomarkers.&#8221;
The researchers identified three biomarkers that seemed to predict clinical responses to NurOwn. For example, lower levels of NfL at the start of the study, that is, its baseline, predicted slower rates of disease progression. Also, the greater the reduction in NfL after NurOwn treatment, the smaller the disease severity progression.
The other two biomarkers were baseline levels of TGF-beta1, which indicated less neuroinflammation, and changes in galectin-1 that indicated greater neuroprotection, both of which also predicted slower disease progression.
“The identification of biomarkers across different pathways could be an indication of the mechanism of action of debamestrocel of balancing the immune response through modulation of inflammation while at the same time preserving the dynamics of the interplay with neurodegenerative processes,” the researchers wrote.
“The publication of these findings is important, because it demonstrates a potential biologic mechanism by which modified mesenchymal stem cells (debamestrocel) may benefit patients with ALS,” said Anthony J. Windebank, MD, a professor of neurology at Mayo Clinic College of Medicine and Science in Rochester, and one of the study authors.
While data from the Phase 3 trial were <a href="https://alsnewstoday.com/news/fda-advisory-committee-votes-not-enough-efficacy-nurown-als/">deemed insufficient</a> to support an approval by the U.S. Food and Drug Administration (FDA), leading BrainStorm to <a href="https://alsnewstoday.com/news/brainstorm-drops-application-nurown-als-regroup/">withdraw its application</a> in October, the company plans a Phase 3b trial to test NurOwn in people with less advanced disease.
The two-part trial will enroll about 200 participants whose symptoms started within the last two years. They will receive NurOwn or a placebo for six months along with standard ALS treatments. For the next six months, all will then receive the experimental medication.
The trial&#8217;s protocol and planned statistical analyses have been reviewed by the FDA under a special protocol assessment and deemed adequate to support a future regulatory application.
“Biomarkers are becoming an increasingly important part of drug development in ALS,” said Stacy Lindborg, PhD, co-CEO of BrainStorm. “We look forward to confirming these findings in our upcoming Phase 3b trial, which is in planning for the most expeditious path forward to bring NurOwn to people living with ALS.”

Certain spinal fluid biomarkers may predict responses to NurOwn

Troriluzole, a new formulation of the approved <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) treatment riluzole, can be taken with or without food and appears to have better pharmacological properties than approved versions of the medication that allow once daily administration.
That&#8217;s according to data from three studies in healthy volunteers presented by Heather Sevinsky, executive director of clinical pharmacology and pharmacometrics at <a href="https://www.biohaven.com/">Biohaven Pharmaceuticals</a>, which is developing troriluzole.
Sevinsky&#8217;s talk, &#8220;<a href="https://www.aan.com/msa/Public/Events/AbstractDetails/55596">Next Generation Prodrug Troriluzole: Increased Bioavailability of Riluzole with No Food Effect in Healthy Subjects</a>,&#8221; took place at the American Academy of Neurology (AAN) 2024 Annual Meeting held April 13-18 in Denver, Colorado, and online.
Riluzole was approved in the 1990s as the first treatment for ALS. An oral therapy thought to reduce nerve damage by altering neurological signaling, it was originally authorized under the brand name <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, which is sold as tablets. Other formulations taken as an oral suspension (<a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>) or an oral film (<a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>) have also been approved in more recent years.
Although riluzole has been proven to slow the <a href="https://alsnewstoday.com/stages-of-als/">progression of ALS</a>, the therapy has some notable drawbacks. It can cause liver damage, requires twice daily administration, and has to be taken on an empty stomach because food can prevent the medication from being absorbed properly.
[recommended-reading id=90863]
<h3>Aim is safer, easier formulation</h3>
Troriluzole is a prodrug, an inactive agent that is converted into therapeutic riluzole once inside the body. Biohaven is developing the therapy with the goal of creating a new riluzole formulation that&#8217;s safer and easier to take.
&#8220;Trorilulozole is a novel prodrug that was designed to overcome the shortcomings of oral riluzole,&#8221; Sevinsky said.
Biohaven has conducted three, single-center studies to test the safety and pharmacological effects of a single dose of troriluzole in healthy volunteers.
The first study, which involved 24 participants, compared the bioavailability of troriluzole, at a dose of 100 or 280 mg, against that of oral riluzole at the approved dose of 50 mg. Bioavailability refers to how much of the drug is absorbed into the body.
Results showed that the maximum concentration of active riluzole in the bloodstream was similar for oral riluzole compared with any of the troriluzole doses tested. However, levels stayed higher for longer with troriluzole, such that the total amount of active riluzole in the blood over time was 40% to 50% higher with troriluzole.
Sevinsky noted that troriluzole also led to markedly less variability in levels of riluzole in the bloodstream. Levels varied by about 40% with troriluzole, compared with more than 50% with oral riluzole.
The other two studies, which collectively involved 26 volunteers, tested whether taking troriluzole with food alters how the body absorbs the drug.
Results indicated that, when the 280 mg dose of troriluzole was taken with a fatty meal, the time it took for blood riluzole levels to reach a peak was delayed by about two hours, and the maximum concentration was 20% lower compared with taking the therapy on an empty stomach.
Nonetheless, when considering the total amount of the medication in the bloodstream over time, &#8220;the overall riluzole absorption &#8230; was unaffected by food,&#8221; Sevinsky said.
To put those results in perspective, Sevinsky said that when oral riluzole is taken with a fatty meal, the total amount of drug in the bloodstream over time is reduced by about 20%.
Collectively, these three studies &#8220;confirm higher bioavailability of riluzole when administered as troriluzole and demonstrate troriluzole may be taken without regard to food,&#8221; Sevinsky said.
&#8220;Additionally, results show lower variability of riluzole, representing an optimized profile allowing once daily administration,&#8221; she added, noting that the findings support further development of the new treatment formulation.

AAN 2024: Troriluzole may be taken with food, data suggest

NeuroSense Therapeutics&#8217; investigational therapy <a href="https://www.neurosense-tx.com/primec/">PrimeC</a> tends to reduce blood levels of neurofilament light chain (NfL), a biomarker of nerve damage, in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — especially when given earlier in the course of the disease.
That&#8217;s according to data from the <a href="https://clinicaltrials.gov/study/NCT05357950">PARADIGM Phase 2b trial (NCT05357950)</a>, in which the oral treatment — also found in this study to be well tolerated — was able to <a href="https://alsnewstoday.com/news/primec-safe-shows-trends-slowing-als-progression-paradigm-trial/">significantly slow disease progression</a> among patients who adhered to the study&#8217;s protocol.
<a href="https://www.neurosense-tx.com/">NeuroSense</a> had previously <a href="https://alsnewstoday.com/news/primec-potential-als-therapy-earns-patents-in-europe-japan-israel/">indicated plans</a> to launch a Phase 3 trial in 2024 should the Phase 2 findings be positive.
“We feel strongly that this is now ready to go forward to another … Phase 3 trial,” Merit E. Cudkowicz, MD, the director of the Sean M. Healey &amp; AMG Center for ALS, said in a talk titled “<a href="https://www.aan.com/msa/Public/Events/AbstractDetails/57911">PrimeC Meets Primary and Secondary Endpoints in a Phase 2b Trial</a>.”
Cudkowicz gave the presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting, held this past week in Colorado, and virtually. 
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<h3>PARADIGM trial tested PrimeC in patients within 2.5 years of symptom onset</h3>
PrimeC is a fixed-dose combination of two medications individually approved in the U.S. — the anti-inflammatory drug celecoxib and ciprofloxacin, an antibiotic. Together, they are thought to slow ALS progression by targeting key cellular processes implicated in the degeneration of motor nerve cells that characterizes the disease.
In PARADIGM, 68 adults with ALS were randomly assigned to receive a long-acting formulation of PrimeC or a placebo for six months, while remaining on their standard <a href="https://alsnewstoday.com/als-treatment/">ALS therapy regimen</a>. Treatment was given twice daily, with a total of four tablets per day.
About 90% of the participants were being treated with riluzole (e.g. <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>) during the trial, according to Cudkowicz. All participants also were within 30 months, or 2.5 years, of <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptom</a> onset.
The study&#8217;s main goals were to evaluate PrimeC’s safety and tolerability, as well as its effects on certain disease-associated biomarkers. Secondary efficacy endpoints included measures of disease progression, lung function, quality of life, and survival.
As reported late last year, top-line data showed that the therapy was tolerated well by patients, meeting one of the study’s main goals. Side effects, all of which were mild and temporary, were all “expected based on what’s known about the two drugs,” Cudkowicz said.
Across the full study population, PrimeC also led to a meaningful — although not statistically significant — 29.2% slower disease progression relative to the placebo, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R).
Analyses that focused solely on the trial’s so-called per protocol population — the 62 people who complied with the trial’s initial rules — indicated that PrimeC was associated with a significant, 37.4% reduction in functional declines compared with the placebo. A per protocol population is thought to more accurately reflect how a treatment works when used exactly as intended.
In this population, the data showed a mean difference of 3.22 ALSFRS-R points between the PrimeC and placebo groups after six months, indicating less advanced disease in the treated group.
Across both groups, benefits of PrimeC tended to be observed across ALSFRS-R subdomains, although statistical significance was only observed in the per protocol population for the respiratory domain, according to Cudkowicz.
Previous trial analyses have also indicated that PrimeC is associated with non-significant slowing of lung function declines, <a href="https://alsnewstoday.com/news/primec-shown-extend-complication-free-survival-als-patients/">improved life quality, and prolonged complication-free survival</a>.
“We saw a consistently positive effect in all clinical outcomes,” said Cudkowicz, who also is chief of the department of neurology at Massachusetts General Hospital, and professor of neurology at Harvard Medical School.
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<h3>New data analyses focus on blood biomarker levels over study&#8217;s course</h3>
Blood levels of NfL were evaluated in an exploratory manner. Across the entire study population, PrimeC was associated with a small, 4.3% reduction in NfL levels after six months relative to the placebo, without statistical significance.
The reductions in NfL were greatest in patients who were earlier in the disease course, and grew increasingly smaller with longer ALS duration. Individuals within nine months of symptom onset experienced an average 29.1% NfL drop relative to the placebo. That compared with an average decline of 17.1% for patients within a year of symptom onset, and 5.1% for those within 1.5 years. An average decline of 3.6% was seen for patients within two years of the start of symptoms.
“What we can learn from this is that, particularly in the people who started the drug earlier in their illness, that’s where we saw the largest difference,&#8221; Cudkowicz said, noting &#8220;this is still a work in progress.”
Analyses of additional biomarkers — one of the study&#8217;s main outcome measures — are ongoing, with results expected in the coming months.
[quote=&#8221;center&#8221;]What we can learn from this is that, particularly in the people who started the drug earlier in their illness, that’s where we saw the largest difference.[/quote]
After the main trial, participants were enrolled in an ongoing open-label extension study, where all are receiving PrimeC.
“We’re very thankful for the trial participants, their family, and caregivers for being part of the study and all the site investigators and their coordinators … that enrolled these patients,“ Cudkowicz concluded.

AAN 2024: PrimeC found to lower nerve damage biomarker in trial

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.
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<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.
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<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.

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