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Up to about 2.5 years of treatment with <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> in an open-label extension of the HEALEY ALS platform trial significantly reduced the risk of death for individuals with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) relative to a historical placebo group of patients from previous ALS clinical trials, according to new analyses.
These long-term analyses add to previous findings from the platform trial, which found the experimental therapy from <a href="https://clene.com/">Clene Nanomedicine</a> reduced the risk of death for these ALS patients by more than 90% compared with a placebo in the first six months.
Similar results were observed when pooled data from <a href="https://clinicaltrials.gov/ct2/show/NCT04414345">CNMAu8&#8217;s arm in HEALEY (NCT04414345)</a> and the <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS Phase 2 clinical trial (NCT04098406)</a> were compared with the historical placebo-treated patients.
“To show such profound survival improvement using the HEALEY ALS Platform Trial data set alone and a pooled HEALEY and RESCUE data set is remarkable,&#8221; Benjamin Greenberg, MD, head of medical at Clene, said in a <a href="https://www.globenewswire.com/news-release/2023/09/25/2748500/0/en/Clene-Reports-Significant-Long-Term-Survival-Improvement-From-CNM-Au8-Treatment-in-HEALEY-ALS-Platform-Trial-Compared-to-PRO-ACT-Historical-Controls.html">company press release</a>.
&#8220;Clene is extremely gratified to see this consistent long-term survival data from the HEALEY ALS Platform Trial [open-label extension], with a continued clean safety profile, adding to the totality of the survival evidence,” Greenberg added.
[recommended-reading id=83732]
<h3>New analyses also used data from RESCUE-ALS Phase 2 trial</h3>
CNM-Au8 is an oral liquid suspension of gold nanocrystals, which is expected to support the energetic needs of nerve cells and protect them against forms of cellular stress implicated in the neurodegenerative disease.
The ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1">HEALEY ALS Platform Trial (NCT04297683)</a>, launched in 2020, is designed to simultaneously test multiple <a href="https://alsnewstoday.com/experimental-treatments-for-als/">ALS treatment candidates</a> using a shared placebo group. This strategy helps to cut costs and accelerate therapeutic development.
Adults with ALS, with symptom onset in the prior three years, are screened through the trial&#8217;s master protocol, and if eligible, are randomly assigned to one of the trial arms that is actively enrolling. <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1#contacts">Recruitment</a> is ongoing across 67 study locations in U.S. sites.
A CNM-Au8 arm was among the trial&#8217;s first, and ultimately enrolled 161 patients. Of them, about 75% were randomly assigned to receive CNM-Au8 at doses of 30 mg or 60 mg for six months, while the other 25% were given a placebo. After the main trial, 92% of the participants continued on in an open-label extension (OLE) trial, where all were given CNM-Au8 at the 30 mg dose.
The main trial did not meet its main goal of slowing functional declines, nor did it demonstrate benefit in measures of lung function.
Still, exploratory analyses indicated that the 30 mg dose was associated with a more than 90% <a href="https://alsnewstoday.com/news/cnm-au8-found-lower-risk-death-als-healey-platform-trial/">lower risk of death</a> and combined risk of death or need for permanently assisted ventilation relative to a placebo after six months. It also was associated with a <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">74% lower risk</a> of overall clinical worsening.
Because the therapy&#8217;s placebo-controlled portion was just six months, it would be difficult to ascertain CNM-Au8&#8217;s potential long-term survival benefits for ALS patients across the OLE portion. A common solution to this issue is to compare the therapy to an external, historical placebo group.
In the new analyses, the researchers compared CMN-Au8 treatment data from the HEALEY trial with placebo-treated patients from PRO-ACT, the largest U.S. clinical database of previous ALS trials.
The database contains data from 29 completed Phase 2 and 3 ALS clinical trials, including records from more than 11,600 ALS patients.
[recommended-reading id=78394]
<h3>Treatment with CNM-Au9 led to 49% lower risk of death for patients</h3>
For the analysis, 59 people who were originally treated with CNM-Au8 30 mg in the placebo-controlled part of HEALEY were compared with matched placebo participants in the PRO-ACT database.
These results showed that CNM-Au8-treated participants demonstrated a statistically significant, 49% lower risk of death compared with PRO-ACT participants with up to 133 weeks, or about 2.5 years, of treatment.
A similar analysis was performed that pooled 82 CNM-Au8-treated patients across the HEALEY and RESCUE trials. Again, the therapy was associated with a statistically significant 59% reduction in mortality risk relative to matched placebo-treated patients from PRO-ACT.
[quote=&#8221;center&#8221;]Improved survival status is an important measure of drug effect. &#8230; We are pleased to see these data from our long-term follow-up as further support of a survival signal in our HEALEY ALS Platform Trial.[/quote]
Previous analyses from RESCUE and its <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension trial (NCT05299658)</a> have similarly indicated a <a href="https://alsnewstoday.com/news/cnm-au8-seen-to-extend-survival-by-more-than-1-5-years-in-als-trial/">survival benefit of CNM-Au8</a>.
&#8220;Improved survival status is an important measure of drug effect,&#8221; said Merit Cudkowicz, MD, neurology chair at Massachusetts General Hospital, director of the Sean M. Healey &amp; AMG Center for ALS, and the principal investigator of the HEALEY ALS Platform Trial.
&#8220;We are pleased to see these data from our long-term follow-up as further support of a survival signal in our HEALEY ALS Platform Trial,&#8221; Cudkowicz said.
Over more than 500 years of collective exposure to CNM-Au8 across ALS, <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a> clinical trials and expanded access programs, no safety signals or serious adverse events from the experimental therapy have been observed.
“I am also happy to see how helpful a shared open-source dataset such as PRO-ACT is to the field to analyze data from the [open-label extension] portions of clinical trials,&#8221; Cudkowicz said.
&#8220;We encourage all companies working in ALS to contribute their data to PRO-ACT once their trial is complete. I want to also thank all the people with ALS who are part of clinical trials and are helping the community find new treatments,” she added.

Long-term ALS survival benefit with CNM-Au8 seen in trial analyses

Difficulties in measuring the progression of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) among patients with advanced disease can cause complications in clinical trials, according to a new analysis that highlights how such problems may have affected the failed <a href="https://alsnewstoday.com/nurown/">NurOwn</a> study.
The work was led by scientists at <a href="https://brainstorm-cell.com/" rel="nofollow">BrainStorm Cell Therapeutics</a>, which is developing the cell therapy NurOwn as a potential treatment for ALS.
Late last year, the U.S. Food and Drug Administration (FDA) <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">declined to consider</a> an application from BrainStorm seeking NurOwn&#8217;s approval. The company now is working to identify the <a href="https://alsnewstoday.com/news/fda-grants-jan-11-meeting-discuss-nurown-future-als-brainstorm/">next steps</a> for the experimental therapy.
The findings of the new analysis were shared at the recent Muscular Dystrophy Association&#8217;s MDA Clinical &amp; Scientific Conference, in a poster titled &#8220;<a href="https://www.mdaconference.org/abstract-library/measuring-the-rate-of-impairment-in-als-patients-using-the-revised-als-functional-rating-scale-key-insights-into-the-floor-effect-of-the-scale/">Measuring the rate of impairment in ALS patients using the Revised-ALS Functional Rating Scale: Key Insights into the Floor Effect of the Scale</a>.&#8221;
&#8220;While widely used, the [current] scale is hampered by its ability to measure function in those with low functional status,&#8221; such as individuals with advanced disease, the researchers wrote.
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<h3>More than 20% of patients in NurOwn trial had low ALSFRS-R scores</h3>
NurOwn is a cell-based therapy in which mesenchymal stem cells — cells with the capacity to transform into a variety of cell types — are isolated from the bone marrow and matured in the lab to produce large amounts of signaling molecules that promote nerve cell survival and growth.
As part of the treatment&#8217;s development, BrainStorm had conducted a <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 clinical trial (NCT03280056)</a> to test NurOwn against a placebo in people with fast-progressing ALS. Completed in 2020, that trial involved 189 patients, ages 18-60. Its main goal was to test whether the treatment could slow the progression of ALS symptoms.
The trial, however, <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed to meet this goal</a>: the rate of progression was not significantly different between patients given NurOwn or a placebo.
Like many ALS trials, that Phase 3 study of NurOwn used a measure of disease progression called the ALS Functional Rating Scale-Revised (ALSFRS-R).
This scale assigns numeric scores to a patient&#8217;s ability to function across several categories, from swallowing to turning in bed, which are then added to calculate the total score. Higher scores reflect a better ability to function, and scores tend to decrease as ALS progresses and patients lose functional abilities.
In the MDA poster, researchers highlighted that the ALSFRS-R is subject to a so-called floor effect: once a particular measure has reached zero, it can&#8217;t go any lower, even if the patient is continuing to lose functionality. As a result, ALSFRS-R scores can plateau or stabilize in patients with advanced disease, failing to reflect the progression that the patient is actually experiencing.
Through statistical analyses, the researchers showed that more than 1 in 5 patients (22.3%) given a placebo in the Phase 3 trial exhibited a floor effect — ALSFRS-R scores specifically tended to plateau around 27 points.
[quote align=&#8221;center&#8221;]For future trials, these data suggest requiring ALSFRS-R items be at least 2 or seeking a more suitable measure for patients with advanced ALS.[/quote]
Analyses of data for nearly 4,000 ALS patients from a large database called PRO-ACT showed that nearly 5% of patients exhibited a similar floor effect, usually around 25 points on the ALSFRS-R, suggesting that this issue is not unique to the NurOwn trial.
Floor effects were most common among patients who started off with lower ALSFRS-R scores. The researchers noted that the average starting ALSFRS-R score in the NurOwn trial was less than 32 points, which is markedly lower than for other modern ALS trials, where average scores have been 36 or higher.
The researchers then re-analyzed data from the NurOwn trial, but assessing only data for the 106 patients who did not show any signs of a floor effect at the start of the study. Results showed that, over the course of the six-month Phase 3 study, the average decline in ALSFRS-R scores was 2.68 for patients given NurOwn and 4.99 for patients given a placebo.
&#8220;Analyses conducted on those not impacted by the floor &#8230; reveal statistically significant, clinically meaningful treatment effects with NurOwn,&#8221; the researchers wrote.
To prevent issues with the floor effect in future trials that use the ALSFRS-R, the researchers suggested that it may be beneficial to limit studies to only patients who have a score of at least 2 on all parts of the ALSFRS-R.
&#8220;For future trials, these data suggest requiring ALSFRS-R items be at least 2 or seeking a more suitable measure for patients with advanced ALS,&#8221; the team wrote.

MDA 2023: Issues with ALS scale scores noted in NurOwn trial failure

Significant delays in the diagnosis of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) were revealed by a new large-scale analysis of real-world patient records using artificial intelligence (AI).
In fact, the median time from the first symptom to an ALS diagnosis was 11 months for these patients.
Similar delays were seen regardless of the location of symptom onset — either the limbs or the bulbar region that&#8217;s involved in speech and swallowing. But researchers noted that having shortness of breath, called dyspnea, as the first reported symptom led to further delays in diagnosis and neurologist referral.
&#8220;Dyspnea was fairly common and when it was present, a longer delay until visiting the specialist (neurologist) and until diagnosis were observed,&#8221; the team wrote, adding, &#8220;We cannot exclude that this symptom, so common in other [diseases], could have gone unnoticed or could have been attributed to other causes when appearing in very early stages of the disease.&#8221;
The study, “<a href="https://www.nature.com/articles/s41598-023-27863-2">Symptoms timeline and outcomes in amyotrophic lateral sclerosis using artificial intelligence</a>,” was published in the journal <a href="https://www.nature.com/srep/">Scientific Reports</a>.
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<h3>Delayed diagnosis found for ALS patients in real world</h3>
Real-world data describing ALS clinical characteristics, disease management, outcomes, and treatment responses can be found in patient electronic health records, called EHRs for short.
In recent years, computer-based AI and machine learning tools have been applied to EHRs stored in patient registries to extract and analyze real-world clinical information on large numbers of patients. This strategy can be especially helpful for rare diseases such as ALS, according to researchers.
“From a clinical standpoint, diseases with low prevalence are best understood using population-based registries with available follow-up information across large numbers of patients,” the investigators wrote.
To that end, a team based at the University Hospital of Albacete, in Spain, applied AI tools to describe the clinical profile, symptom onset, diagnosis, and relevant outcomes of ALS patients in that country. They used EHR data held in the Spanish SESCAM Healthcare Network registry.
The AI tool — called natural language processing or NLP — enabled computers to understand written text in medical records, then extract the relevant information.
Over the five-year study period, 250 patients were diagnosed with ALS, of whom 61.6% were male. The patients had a mean age of 64.7.
Among them, 159 (64%) had spinal ALS, which first affects the limbs, and 91 (36%) had bulbar ALS, marked by initial symptoms of speaking and swallowing difficulties. The most common co-existing medical conditions were high blood pressure and an imbalance of blood fats.
Data spanning at least one year before the <a href="https://alsnewstoday.com/als-diagnosis/">ALS diagnosis</a> was available for 208 patients. The most visited healthcare services before diagnosis were primary care, for 88.4%, and treatment in an emergency room, for 38.4%. Neurology was the most visited specialist service (38.8%).
The most common symptom up until diagnosis was weakness, followed by shortness of breath, speaking difficulties, swallowing problems, and muscle twitches.
Overall, the median diagnostic delay, or the time from the onset of symptoms to an ALS diagnosis, was 11 months. Similar delays were seen in both spinal and bulbar ALS subgroups.
[quote align=&#8221;center&#8221;]Our results point to &#8230; an overall diagnostic delay of 11 months before the first mention of ALS in patients’ [health records].[/quote]
Additionally, data showed that people who experienced shortness of breath as their first symptom had longer diagnostic delays, of a median of 12 months. Likewise, with shortness of breath as the first symptom, there was a longer delay in neurologist referral and subsequent diagnosis.
&#8220;The patient journey seems to play a role in [diagnostic] delay, with early referral to a neurologist linked to shorter timing to diagnosis,&#8221; the researchers wrote, noting that &#8220;ALS patients are frequently referred to other hospital departments before the neurologist.&#8221;
Compared with the period prior to a diagnosis, there was a two-to-threefold increase in speech problems (15.6% vs. 31.2%), swallowing difficulties (14.0% vs. 34.0%), and muscle twitches (13.6% vs. 37.2%) at the time of diagnosis.
During the median follow-up of 25 months after diagnosis, 52% of participants underwent a feeding tube insertion, while 64% received non-invasive breathing support and 16.4% had a breathing tube insertion, known as a tracheostomy. These procedures all occurred more frequently in the bulbar ALS group.
A total of 87.6% of patients were treated with riluzole (sold as <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-riluzole-oral-suspension/">Tiglutik</a>, and <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>).
Over a median of 19 months from ALS diagnosis, 87 patients (34.8%) died. When tracheostomy also was considered as a mortality outcome, that number increased to 110 (44.0%). The likelihood of feeding tube insertion and needing non-invasive ventilation was significantly higher for those with bulbar ALS.
These findings “highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes,” the researchers wrote.
&#8220;Our results point to &#8230; an overall diagnostic delay of 11 months before the first mention of ALS in patients’ EHRs,&#8221; the team concluded.

Tag: analysis

Long-term ALS survival benefit with CNM-Au8 seen in trial analyses

MDA 2023: Issues with ALS scale scores noted in NurOwn trial failure

Delayed diagnosis in ALS found in new AI analysis of patient records