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Genetic and clinical factors that can influence how <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) progresses were identified in a recent analysis of data from <a href="https://www.precisionals.ie/">PRECISION-ALS</a>, a large European research project.
Consistent with known risk factors for <a href="https://alsnewstoday.com/stages-of-als/">ALS progression</a>, C9ORF72 genetic mutations, <a href="https://alsnewstoday.com/forms-of-als/#Clinical_onset">bulbar-onset disease</a>, and faster functional declines were linked to a shorter survival time, as was older age at disease onset.
However, differences were seen among the project&#8217;s centers in the time it took for interventions like feeding tube placement (gastrostomy) or noninvasive ventilation to be needed, and the reasons require further study, according to the scientists.
Harry McDonough, a clinical researcher at the University of Sheffield in England, and Alejandro Caravaca Puchades, a clinician at the Hospital of Bellvitge in Spain, discussed findings in the oral presentation &#8220;<a href="https://www.tandfonline.com/doi/pdf/10.1080/21678421.2023.2260189" rel="nofollow">Mapping the natural history of ALS in Europe</a>,&#8221; given at the 34th International Symposium on ALS/MND held last week in Basel, Switzerland, and virtually. It was supported by <a href="https://www.biogen.com/" rel="nofollow">Biogen</a>, which also supports the PRECISION-ALS study.
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<h3>Likely ALS progression via factors like speed of diagnosis, disease type at onset</h3>
PRECISION-ALS, launched last year, is a European collaboration with the broad goal of <a href="https://alsnewstoday.com/news/e10m-european-collaborative-project-hopes-use-ai-als-precision-medicine/">better understanding the natural history of ALS</a> and the factors that influence differences in <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> and progression among patients.
&#8220;We know that ALS is a condition with lots of variation between individuals,&#8221; McDonough said in the presentation. &#8220;By studying the natural history we hope to be able to understand the factors that impact this variation, and hopefully, in turn, that helps us clinically to improve outcomes for our patients &#8230; [and] hopefully directing them towards trials that are most likely to benefit them.&#8221;
Nine clinical sites across eight countries are involved in the project, which brings together clinical researchers, data scientists, and industry partners.
The recent analysis concerned PRECISION-ALS&#8217; extant data study, meaning it was an analysis of previously collected and existing clinical data. All nine sites contributed information from patients in their individual databases, which were combined for a population-based assessment of ALS progression from symptom onset, to diagnosis, clinical interventions, and death.
Data covered 21,571 ALS patients, mostly male (57.2%). Across the entire group, the median age at symptom onset was 63.9, with a delay of about one year between symptom onset and an <a href="https://alsnewstoday.com/als-diagnosis/">ALS diagnosis</a>.
Disease onset tended to be earlier in men, patients with spinal-onset ALS — where symptoms of limb weakness are the first to emerge — and those with mutations in the ALS-associated genes FUS or SOD1.
Individuals with bulbar-onset ALS — where symptoms initially affect muscles in the head and neck needed for speech, swallowing, and breathing — and those with mutations in the C9ORF72 gene experienced a shorter diagnostic delay.
An earlier symptom onset tended to link with a slower functional decline — indicated by a less than 0.3 point monthly decline in a patient&#8217;s ALS Functional Rating Scale-Revised (ALSFRS-R) scores — compared with patients with intermediate or quickly progressing disease. In turn, a faster functional decline, defined as a monthly change in ALSFRS-R scores of more than 1.06, was associated with a shorter diagnostic delay.
<h3>Earlier need for gastrostomy seen with bulbar onset, C9ORF7 mutations</h3>
Overall median survival among these patients was 2.59 years. Bulbar-onset ALS, fast disease progression, older age at onset (ages 70 and older), and FUS and C9ORF7 mutations all were seen as independent predictors of poorer survival in a final analysis. Better lung function and a slower arrival at a definitive ALS diagnosis linked with longer survival times.
The time to reach certain clinical interventions — namely, gastrostomy and noninvasive ventilation — also were influenced by these factors, with bulbar-onset ALS and C9ORF7 mutations linked to an earlier need for a gastrostomy.
In adjusted statistical analyses, the start of noninvasive ventilation was significantly associated with respiratory-onset ALS and male sex, whereas better lung function and a longer diagnostic delay again were seen to protect against a need for such ventilation.
Notably, significant differences among clinical sites were seen in the time from ALS diagnosis to a gastrostomy or noninvasive ventilation, as well as in patients&#8217; average lung function when ventilation started.
Analyses taking these factors into account indicated that centers with less ready use of noninvasive ventilation had poorer survival outcomes, but these differences were not statistically significant.
&#8220;It&#8217;s important to note that given the significant amount of missing data that we have, it is difficult to draw conclusions on this alone,&#8221; McDonough said.
Currently, it&#8217;s not clear whether differences among clinical sites are &#8220;due to differences in clinical practice, differences in the cohorts between these clinical centers, or data collection or a combination of these factors,&#8221; the scientists noted.
PRECISION-ALS is working on a prospective study, where data will be collected across its nine sites using a specific data platform, to help improve uniformity.

ALS/MND 2023: European study spotting factors that affect progression

A Phase 3 clinical trial that&#8217;s testing FNP122, <a href="https://www.ferrer.com/en" rel="nofollow">Ferrer’</a>s oral formulation of edaravone, in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is now rolling participants into its open-label extension study.
The <a href="https://www.clinicaltrials.gov/study/NCT05178810">ADORE trial (NCT05178810)</a> is testing FNP122 against a placebo in about 300 patients across Europe whose symptoms started less than two years earlier. Those who completed the trial&#8217;s 48 weeks now have the opportunity to join an extension study called <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05866926">ADOREXT (NCT05866926)</a>, where all will receive FNP122 for up to three years. The goal is to assess the treatment&#8217;s long-term safety.
“The ADOREXT study allows the company&#8217;s research team to continue in its aim to bring significant and differential value to people suffering from serious diseases such as ALS,” Tatjana Naranda, Ferrer&#8217;s chief research and development officer, said in a <a href="https://www.businesswire.com/news/home/20230621955112/en/Ferrer-Initiates-its-ADOREXT-Extension-Study-in-Amyotrophic-Lateral-Sclerosis-ALS">company press release</a>.
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<h3>Edaravone, as the oral treatment Radicava ORS, is not available in Europe</h3>
Edaravone is an <a href="https://alsnewstoday.com/approved-treatments-for-als/">ALS treatment</a> that works to slow disease progression by reducing oxidative damage to cells. Oxidative stress, an imbalance between the production of potentially harmful free radicals and a cell’s ability to detoxify them, is believed to be a key driver of nerve cell death in the disease.
The medication is currently approved in the U.S. in two distinct formulations: <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a>, which is administered through intravenous (into-the-vein) infusions, and Radicava ORS, which is an oral suspension taken by mouth or via a feeding tube.
Both are given in 28-day cycles. After an initial cycle of treatment for 14 consecutive days, followed by a two-week period without treatment, the therapy is taken daily over 10 of the next 14 days, followed by two weeks of no treatment.
While the two formulation can safely and effectively <a href="https://alsnewstoday.com/news-posts/2020/03/30/radicava-effective-slowing-als-progression-across-1-year-use-patients-trial-data/">slow functional decline</a> in ALS patients, the administration schedule may pose some challenges. These Radicava formulations also are not approved in the European Union, where Ferrer is based.
In a previous Phase 1 trial, FNP122 was reported to be well tolerated and to have a higher bioavailability — a measure of how much of the medication is distributed in the body to reach its target areas — than Radicava.
The ADORE trial is ongoing at more than three dozens of clinical sites across Europe to <a href="https://alsnewstoday.com/news/first-patient-enrolled-phase-3-adore-trial-fnp122-oral-form-edaravone-europe/">assess FNP122&#8217;s safety and efficacy</a> in adults, ages 18 to 80, with ALS. Participants were randomly assigned in a 2-to-1 ratio to the edaravone formulation, a daily oral dose of 100 mg, or to a placebo, for 48 weeks (nearly one year).
Its main goal is changes with treatment in a patient&#8217;s ability to perform daily activities, as measured with the ALS Functional Rating Scale &#8211; Revised (ALSFRS-R). The medication&#8217;s effects on survival also are being determined.
<h3>TRICALS also supporting the long-term ADOREXT study</h3>
All patients completing ADORE&#8217;s 48 weeks, including those who stopped treatment for other than safety reasons but remained on the trial, are invited to join the extension study.
According to Ferrer, enrollment for ADOREXT began in March, and several patients across nine countries — Spain, France, Italy, Belgium, Germany, the Netherlands, Poland, Ireland, and Sweden — are now in the extension. Participants from other European countries are expected to join next.
Both trials are being supported by the <a href="https://www.tricals.org/en/">Treatment Research Initiative to Cure ALS</a> (TRICALS), the largest European research initiative working to find a cure for ALS.
The protocol for the extension study was developed taking into consideration patients’ needs and perspectives, which were collected in an ALS Patient Representatives Advisory Board (PAB), Ferrer reported. Eight patient organizations from Europe and North America participated in the advisory board.

FNP122, edaravone in oral form, enters Phase 3 extension trial

The Committee for Medicinal Products for Human Use (CHMP) has issued an opinion opposing <a href="https://www.amylyx.com/" rel="nofollow">Amylyx Pharmaceuticals</a>’ bid for conditional European Union approval of AMX0035, its oral treatment to slow the progression of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The negative recommendation from the advisory committee, an arm of the European Medicines Agency (EMA), is not binding. But the EMA will consider the opinion when making its final approval decision, while Amylyx intends to request that CHMP reconsider its findings.
According to the EMA, <a href="https://www.ema.europa.eu/en/medicines/human/summaries-opinion/albrioza">the committee had concerns</a> that data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR trial (NCT03127514)</a>, on which the application was based, did not &#8220;convincingly show&#8221; that AMX0035 was effective at <a href="https://alsnewstoday.com/living-with-als-2/">slowing ALS progression</a>.
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<h3>Oral ALS treatment has conditional approval in US and Canada, not Europe</h3>
Survival findings also were &#8220;unreliable,&#8221; the opinion stated, given how these data were collected and analyzed. In support of its decision, <a href="https://alsnewstoday.com/news/european-approval-amx0035-als-faces-new-hurdle-review/">advice from expert groups</a>, including neurology specialists and patient representatives, was considered.
The therapy is approved in the U.S. under the name <a href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) and in Canada as Albrioza — the brand name that will be used in Europe should it be approved.
“We are confident in the strength of our CENTAUR trial data, which we believe meets the criteria for conditional approval. These data were also the basis of the full approval received from the U.S. Food and Drug Administration and the approval with conditions from Health Canada,” Tammy Sarnelli, global head of regulatory affairs and clinical compliance at Amylyx, said in a <a href="https://www.businesswire.com/news/home/20230622200968/en/Amylyx-Pharmaceuticals-Receives-CHMP-Negative-Opinion-on-its-Conditional-Marketing-Authorisation-Application-for-AMX0035-for-the-Treatment-of-ALS-in-the-European-Union">company press release</a>. “We disagree with the CHMP’s opinion and will request a formal re-examination procedure of the current Marketing Authorisation Application (MAA).”
Filing for a formal reconsideration of the application starts a process that takes about four months. Based on an evaluation by a different set of examiners than those of the initial assessment, the process will close with CHMP adopting a final opinion.
“We will continue to engage with CHMP and EMA through the re-examination process with the goal of making Albrioza available in Europe as it is in the United States and Canada,” said Joshua Cohen and Justin Klee, Amylyx’s co-CEOs. “We know how precious time is for people with ALS and their families.”
Although it is not clear how AMX0035 works, its two active ingredients, sodium phenylbutyrate and ursodoxicoltaurine (taurursodiol in the U.S), are thought to reduce the nerve cell damage that <a href="https://alsnewstoday.com/causes-of-als/">causes ALS</a> and slow the progression of <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a>.
<h3>Findings of Phase 3 trial of AMX0035 in ALS patients likely in mid-2024</h3>
Data from CENTAUR, a Phase 2 trial that enrolled 137 adults with rapidly progressing ALS, supported its <a href="https://alsnewstoday.com/news/amx0035-albrioza-oral-als-therapy-available-canada/">conditional approval in Canada</a> and <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">its U.S approval.</a>
Meeting its primary goal, the trial showed that AMX0035 significantly <a href="https://alsnewstoday.com/news-posts/2020/09/03/amx0035-safe-effective-in-slowing-als-functional-decline-trial-data-shows/">slowed disability progression</a> compared with a placebo. Data spanning CENTAUR and its open-label extension study also supported a <a href="https://alsnewstoday.com/news/amx0035-survival-als-patients-centaur-clinical-trial-analysis-amylyx/">10-month survival benefit</a> in people assigned to AMX0035 from the start.
A Phase 3 trial called <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">PHOENIX (NCT05021536)</a> is underway to confirm AMX0035’s safety and efficacy in 664 ALS patients at sites across the U.S. and Europe. The new <a href="https://alsnewstoday.com/news/phoenix-trial-approved-als-therapy-relyvrio-amx0035-enrolled/">trial is fully enrolled</a>, with top-line data expected by June 2o24.
“While our MAA continues to be under review, we will also work towards completing our global Phase 3 PHOENIX study, with topline results anticipated in mid-2024, which will provide important additional data on the efficacy and safety profile of Albrioza,” said Stéphanie Hoffmann-Gendebien, general manager at Amylyx. “There have been no new innovations approved in Europe for this devastating disease in over 25 years, and we recognize the urgent need of the ALS community in Europe to access new treatment options.”
CHMP’s negative opinion will not affect patients currently enrolled in clinical trials of AMX0035, Amylyx stated. It encourages study participants needing further information to speak with their clinical trial physician.

Tag: Europe

ALS/MND 2023: European study spotting factors that affect progression

FNP122, edaravone in oral form, enters Phase 3 extension trial

EMA branch opposes conditional approval of AMX0035 in Europe