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<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.
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<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

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

Tag: NFL

Slower ALS progression evident with lower NfL levels: NurOwn trial

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