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Treatment with <a href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) significantly reduced blood levels of neuroinflammatory biomarkers in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) as early as three months, according to a post hoc analysis of the CENTAUR trial.
Data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">Phase 2 study (NCT03127514)</a> demonstrated that reductions in two biomarkers — C-reactive protein (CRP) and YKL-40, or chitinase-3-like protein 1 — correlated with slowing disease progression.
“Neuroinflammatory biomarkers are important for assessing disease progression and therapeutic response in ALS with chitinases and CRP emerging as potential treatment response biomarkers,” Robert Bowser, PhD, chief scientific officer of Barrow Neurological Institute, in Arizona, said in a <a href="https://www.businesswire.com/news/home/20231117036343/en/Amylyx-Pharmaceuticals-Announces-Publication-of-Data-Showing-the-Effect-of-AMX0035-on-Plasma-Neuroinflammatory-Biomarkers-in-ALS">press release</a>. “The learnings from these analyses are an important step linking the biological impact of [Relyvrio] with potential key biomarkers for ALS.&#8221;
The CENTAUR biomarker findings were published in the <a href="https://jnnp.bmj.com/">Journal of Neurology, Neurosurgery and Psychiatry</a>, in the study, “<a href="https://jnnp.bmj.com/content/early/2023/12/02/jnnp-2023-332106">Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial</a>.”
Relyvrio (previously, AMX0035) is an oral therapy developed by <a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a> that contains two molecules thought to help reduce damage to motor neurons, the nerve cells that control voluntary movements. The medication is <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">approved for ALS patients in the U.S.</a> and <a href="https://alsnewstoday.com/news/amx0035-oral-als-therapy-called-albrioza-approved-canada/">conditionally approved in Canada</a>, under the name Albrioza.
The approvals were supported by data from the CENTAUR trial, which evaluated the treatment against a placebo in 137 adults recently <a href="https://alsnewstoday.com/als-diagnosis/">diagnosed</a> with rapidly progressing ALS. After six months, Relyvrio met its primary goal of <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1916945">slowing functional decline over a placebo</a>, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R).
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<h3>Reductions in two inflammatory biomarkers with Relyvrio</h3>
An analysis done after the trial wrapped up and all the data had been gathered, showed the therapy also significantly <a href="https://alsnewstoday.com/news/relyvrio-extends-survival-10-4-months-rapid-progression-als/">extended the median survival by 10.4 months</a> and lowered the risk of death by 52%, compared with a historical patient control group.
Another post hoc analysis was conducted wherein blood samples regularly collected from 126 CENTAUR participants were assessed for biomarkers associated with neuroinflammation, including YKL-40, CRP, and chitinase 1 (CHIT1).
“Previous studies have shown that levels of YKL-40 in cerebrospinal fluid [the liquid surrounding the brain and spinal cord] correlate with ALS disease progression rate, severity, and survival,” Bowser said.
The mean levels of YKL-40 in the bloodstream dropped by 10% after three months of Relyvrio and by 20% after six months compared with placebo recipients. Mean levels of CRP were reduced by 17% after three months and 30% after six months.
Lower levels of both biomarkers were significantly correlated with functional status, namely with a lower level of disability, as assessed with the ALSFRS-R total score, and with a slowing of disease progression, indicated by a smaller decline in ALSFRS-R scores over time.
“Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS and the findings from these analyses suggest that YKL-40 could be a treatment-sensitive biomarker,” said Machelle Manuel, PhD, head of global medical affairs at Amylyx. “YKL-40 and CRP concentration decreased significantly for the group of participants that received [Relyvrio] compared to placebo and were correlated with disease progression as measured by the ALSFRS-R, further demonstrating the impact of [Relyvrio].&#8221;
Mean CHIT1 blood levels were not significantly different between treatment groups and didn&#8217;t correlate with ALSFRS-R. Researchers also previously showed two biomarkers for nerve damage, phosphorylated neurofilament heavy chain and neurofilament light chain (NfL), were unaffected by treatment.
Further analysis of neuroinflammatory biomarkers is planned in the ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">Phase 3 PHOENIX trial (NCT05021536)</a>, which seeks to confirm Relyvrio’s efficacy in 664 people with early ALS over a year. Top-line data, from sites in the U.S. and Europe, are expected by June 2024.
The Committee for Medicinal Products for Human Use (CHMP), an advisory committee of the European Medicines Agency, <a href="https://alsnewstoday.com/news/chmp-confirms-initial-recommendation-not-approve-amx0035-eu/">recommended not to approve AMX0035</a> for ALS. According to the agency, CENTAUR data didn&#8217;t convincingly show it was effective at slowing ALS progression.

Tag: CENTAUR clinical trial

Relyvrio reduces inflammatory biomarkers in ALS: CENTAUR data