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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. 
[recommended-reading id=87909]
<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.
[recommended-reading id=87331]
<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.
[recommended-reading id=82904]
<h3>Testing the impact of MSC stem cell therapy in ALS</h3>
MSCs are stem cells that reside in the bone marrow and fat tissue. These stem cells are able to grow into certain types of connective tissue cells, and they also secrete a wide range of signaling molecules that can modulate the activity of other nearby cells, including nerve cells.
&#8220;We&#8217;ve been studying MSCs &#8230; for ALS for over a decade now,&#8221; Staff said. &#8220;The reason they were selected for a possible therapy is their ability to secrete growth factors, including neourotrophic [nerve-growth-promoting] factors, and modulate the immune system and neuroinflammation.&#8221;
Staff noted that several pharmaceutical companies are already developing potential ALS therapies based on MSCs. The most well-known stem cell therapy for ALS, called <a href="https://alsnewstoday.com/nurown/">NurOwn</a> (debamestrocel), will enter a <a href="https://alsnewstoday.com/news/fda-oks-phase-eb-trial-design-nurown-less-advanced-als/">Phase 3b clinical trial</a> later this year that could be the basis of a new application seeking the treatment&#8217;s approval in the U.S.
At the AAN meeting, Staff presented data from a <a href="https://clinicaltrials.gov/study/NCT03268603">multisite U.S. trial (NCT03268603</a>) that used MSCs collected from participants&#8217; fat tissue in the belly. The treated cells were then expanded to millions before being delivered back into the patients via injections into the spinal canal, known as intrathecal injections.
The study included 57 people with ALS whose symptoms had started no more than two years before enrollment. About two-thirds of the participants were male, almost all were white, and their average age was 56. Nine of these patients had <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>, in which the disease runs in families.
All of the participants were treated with intrathecal MSC injections every three months for a year, for up to four injections. These injections included somewhere between 10 and 100 million cells, based on certain dose modification criteria.
Staff noted that there was &#8220;quite a bit of dropout&#8221; during the year-long study, with nearly half of patients withdrawing before the study&#8217;s end. There were many reasons for quitting the study, though the most common was due to disease progression.
Nearly half of patients experienced side effects from treatment that were judged moderate or severe. Pain was an especially common side effect of this stem cell therapy for ALS, with about 23 patients experiencing moderate to severe back pain, limb pain, or headache.
For most, the side effects went away after a week or two, and Staff said that, overall, the MSC treatment was &#8220;reasonably well tolerated.&#8221; Still, there were some participants who experienced more long-lasting issues that led them to withdraw from the study.
[recommended-reading id=87114]
<h3>Some patients saw slowing of ALSFRS-R scores of at least 25%</h3>
Disease progression was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), in which higher scores represent better functional abilities.
Prior to starting on MSC treatment, ALSFRS-R scores were rapidly decreasing over time, which is typical in ALS. During the year-long study, the rate of worsening was slightly slower compared with before treatment, but the difference failed to reach statistical significance.
However, 21 of the 57 study participants experienced a slowing of ALSFRS-R score of at least 25% after starting on the MSC treatment, Staff noted. This suggests there may be certain patients who respond to MSC therapy, while others derive no benefit from the treatment.
The team will now conduct further analyses from this study, including biomarker assessments, that may help shed further light on which patients do or do not respond to MSC therapy.

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

While the now-discontinued <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) therapy <a href="https://alsnewstoday.com/amx0035">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) failed to show a meaningful effect on disease progression, lung function, or life quality in the Phase 3 PHOENIX clinical trial, ongoing analyses will look at other outcomes such as biomarkers and survival.
That’s according to a presentation from one of the trial’s primary investigators, Leonard H. Van den Berg, MD, PhD, given at the American Academy of Neurology (AAN) 2024 Annual Meeting. The AAN meeting is being held April 13-18, in Denver, and virtually.
“PHOENIX was a well-powered and a well-executed trial,” Van den Berg said in the presentation, titled “Results From a Global Phase 3 Trial Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Amyotrophic Lateral Sclerosis.”
“We will continue to learn from PHOENIX to inform future ALS trials,” Van den Berg said.
Relyvrio&#8217;s developer <a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a> voluntarily <a href="https://alsnewstoday.com/news/relyvrio-withdrawn-from-us-canada-after-phase-3-trial-results/">took the therapy off the market</a> in the U.S. and Canada — where it was marketed as Albrioza — earlier this month after the company first announced that PHOENIX had <a href="https://alsnewstoday.com/news/als-treatment-relyvrio-fails-trial-may-be-withdrawn-market/">failed to meet its main goal</a>.
The medication no longer is available to new patients in either country. However, patients already on Relyvrio as of the April 4 withdrawal date who wish to remain on treatment may be able to transition to a free drug program in consultation with their doctor.
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<h3>PHOENIX trial was intended to confirm positive results from CENTAUR</h3>
Formerly known as AMX0035, Relyvrio is a fixed-dose oral combination of sodium phenylbutyrate and taurursodiol. The two medications are believed to work together to prevent nerve cell death in ALS.
Relyvrio was approved in both the <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">U.S.</a> and <a href="https://alsnewstoday.com/news/amx0035-oral-als-therapy-called-albrioza-approved-canada/">Canada</a> in 2022 based on findings from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">Phase 2 CENTAUR study (NCT03127514)</a>, which involved adults with recently diagnosed and rapidly progressing ALS.
In CENTAUR, the oral medication was associated with <a href="https://alsnewstoday.com/news-posts/2020/09/03/amx0035-safe-effective-in-slowing-als-functional-decline-trial-data-shows/">slower functional declines</a> compared with a placebo, with evidence that it may also <a href="https://alsnewstoday.com/news/amx0035-survival-als-patients-centaur-clinical-trial-analysis-amylyx/">extend survival</a>.
Still, experts were not altogether convinced of the treatment’s efficacy for ALS patients. Indeed, the European Medicines Agency <a href="https://alsnewstoday.com/news/chmp-confirms-initial-recommendation-not-approve-amx0035-eu/">voted against</a> the approval of Relyvrio in the European Union based on data from CENTAUR alone. The treatment’s clearance in Canada also was conditional, meaning regulators wanted to see more clinical trial data before converting to a full approval.
<a href="https://clinicaltrials.gov/ct2/show/NCT05021536">PHOENIX (NCT05021536)</a> was the Phase 3 trial intended to confirm Relyvrio’s safety and effectiveness in a larger group of patients across the U.S. and Europe. A total of 664 people with definite or probable ALS, who were within two years of symptom onset, were enrolled and randomly assigned to receive oral Relyvrio or a placebo for 48 weeks, or about a year.
The primary goal was to confirm the main finding from CENTAUR — that Relyvrio significantly slowed functional declines, as assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), compared with a placebo.
According to Van den Berg’s presentation, the demographic and clinical characteristics of participants in the Relyvrio and placebo groups were well-balanced. In both groups, the average age was about 60, most patients were men (60%-63%), and nearly all (91%-93%) were taking a stable dose of riluzole (sold as <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek</a> among others) upon entering the trial. There also were 3% of patients in each group receiving edaravone, which is approved as <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava or Radicava ORS</a>.
Ultimately, however, the results of the trial&#8217;s primary outcome measure showed that ALSFRS-R scores dropped by an average of 14.98 points in the Relyvrio group and by 15.32 points in the placebo group — a non-significant difference.
Likewise, there was no significant benefit of Relyvrio in pre-specified subgroups, including patients who were not concurrently using edaravone, and patients enrolled only at European sites.
[recommended-reading id=87417]
<h3>Further survival data on Relyvrio likely not available before 2026</h3>
The researchers also looked at a subgroup of “CENTAUR-like” patients, or those who matched the enrollment criteria for the earlier Phase 2 trial. Specifically, those patients had definite ALS and greater than 60% of normal lung function. These individuals also were within 1.5 years of symptom onset.
While those patients did “somewhat better” in terms of disease progression when given Relyvrio, Van den Berg noted that the PHOENIX findings still failed to reach statistical significance in comparison to the placebo in that subgroup.
Secondary goals related to life quality and lung function also were not met.
Overall, despite “promising results” from CENTAUR, “there were no differences between the groups for the primary endpoints and the secondary endpoints in the Phase 3 study,&#8221; Van den Berg concluded.
In terms of survival, the scientist said there&#8217;s still not enough data to adequately evaluate Relyvrio’s effects. An open-label extension phase of the trial is still ongoing, in which participants will receive Relyvrio for up to about two more years. However, Van den Berg said mature survival data may not be available before February 2026.
“We will continue to collect survival data, as survival is an important outcome measure in ALS trials,” Van den Berg said.
[quote=&#8221;center&#8221;]As a community, we all work together to find better treatments for our patients, and we will do that even harder after these results.[/quote]
Other analyses also are still ongoing, including biomarker and subgroup analyses, particularly within the CENTAUR-like population.
Relyvrio was generally well tolerated, with safety findings consistent with the CENTAUR trial. Only diarrhea was more common with Relyvrio versus the placebo.
Van den Berg extended a thank you to PHOENIX participants, investigators, and clinical sites.
“As a community, we all work together to find better treatments for our patients, and we will do that even harder after these results,” the scientist concluded.

Tag: AAN

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

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

AAN 2024: Trial investigator shares details from Relyvrio failure in ALS