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<a href="https://alsnewstoday.com/amx0035">Relyvrio</a> (sodium phenylbutyrate and taurursodiol), an approved treatment for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), has failed to meet its primary goal of slowing disease progression in an ongoing Phase 3 clinical trial designed to confirm its effectiveness.
That&#8217;s according to new data from the trial, dubbed PHOENIX, released today by the therapy&#8217;s developer, <a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a>.
Essentially, the data show that patients who received Relyvrio in addition to their standard ALS medications in PHOENIX experienced a similar rate of disease progression as did those given a standard treatment alone.
Based on the data, Amylyx is voluntarily pausing promotion of Relyvrio, and said it will work with regulatory authorities and the broader ALS community to determine the appropriate next steps for the therapy — which may include voluntarily withdrawing it from the market, according to a <a href="https://www.businesswire.com/news/home/20240308462671/en/Amylyx-Pharmaceuticals-Announces-Topline-Results-From-Global-Phase-3-PHOENIX-Trial-of-AMX0035-in-ALS">company press release</a>.
Until then, the therapy will remain available to ALS patients in the U.S. and in Canada, where it&#8217;s marketed under the brand name Albrioza. The company also will continue running its support programs to help patients on the medication, formerly known as AMX0035 for ALS, which has been <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">approved since 2022</a> in both countries.
[quote=&#8221;center&#8221;]Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX.[/quote]
Justin Klee and Joshua Cohen, co-CEOs of Amylyx, said they were &#8220;surprised and deeply disappointed by the PHOENIX results.&#8221;
&#8220;Our main priority at the moment is sharing the information with people living with ALS and their treating physicians; this is part of our continued commitment to them and our mission. Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX,&#8221; Klee and Cohen said.
The CEOs said their discussions with regulators will be informed by &#8220;two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us.&#8221;
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<h3>Regulators in Europe had recommended against therapy&#8217;s approval</h3>
Relyvrio was approved in the U.S. and Canada based mainly on data from a Phase 2 study called <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR (NCT03127514)</a>. It tested the therapy against a placebo in 137 adults with recently-diagnosed, rapidly progressing ALS.
The results showed that, after six months, patients given Relyvrio had <a href="https://alsnewstoday.com/news-posts/2020/09/03/amx0035-safe-effective-in-slowing-als-functional-decline-trial-data-shows/">significantly less decline in physical function</a> than those on a placebo<a href="https://alsnewstoday.com/news-posts/2020/09/03/amx0035-safe-effective-in-slowing-als-functional-decline-trial-data-shows/">,</a> as measured by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R).
Data from the Phase 2 study even hinted Relyvrio <a href="https://alsnewstoday.com/news/amx0035-survival-als-patients-centaur-clinical-trial-analysis-amylyx/">might extend survival</a> for ALS patients. The robustness of the results were questioned, however, with authorities in Europe recommending against approval based on data from the Phase 2 study alone.
The <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">Phase 3 PHOENIX trial (NCT05021536)</a> was launched with the hope of definitively confirming that Relyvrio was effective as an ALS treatment. The study enrolled <a href="https://alsnewstoday.com/news/phoenix-trial-approved-als-therapy-relyvrio-amx0035-enrolled/">664 people with early ALS</a> who were randomly assigned to take Relyvrio or a placebo for about one year.
Because the Phase 3 trial included more patients and followed them for a longer period of time, it was expected that the results would be statistically more robust than in the smaller, shorter Phase 2 study.
The main goal of the PHOENIX trial was to show that patients given Relyvrio had less decline in ALSFRS-R scores, just as was seen in the Phase 2 CENTAUR study. However, the results showed that the Phase 3 trial failed to meet this goal: Rates of ALSFRS-R decline were not significantly different for patients given the therapy or the placebo.
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<h3>PHOENIX trial tested Relyvrio vs. a placebo in over 650 ALS patients</h3>
According to Amylyx, Relyvrio also failed to outperform the placebo across several secondary endpoints, or trial goals, which included patient-reported quality of life, assessments of lung function, and overall survival.
Still, Relyvrio was generally well tolerated in PHOENIX, and no unexpected safety issues were reported in the trial.
Full results from the Phase 3 trial are expected to be presented at an upcoming meeting and published in detail later this year. The company also is continuing to run an extension to the study in which European participants who completed PHOENIX could continue to receive Relyvrio.
The Amylyx CEOs thanked all those who took part in the therapy&#8217;s development, regardless of this trial&#8217;s outcome.
&#8220;On behalf of the entire Amylyx team, we are grateful to the ALS community and for the dedication of trial participants, investigators, and study site teams,&#8221; Klee and Cohen said.
&#8220;With data collected from 664 participants in PHOENIX, we are certain there will be important learnings that will help inform future ALS research,&#8221; they added.
While the next step for Relyvrio in ALS remain to be determined, the therapy will continue to be developed for other neurological disorders. Amylyx also will continue to advance its experimental ALS treatment <a href="https://alsnewstoday.com/news/als-mnd-2023-clinical-tests-aso-treatment-als-happen-next-year/">AMX0114</a>, which targets the calpain-2 protein.
&#8220;We are steadfast in our commitment to the ALS community and our mission, including with AMX0035 where it has shown potential in neurodegenerative diseases such as Wolfram syndrome and progressive supranuclear palsy, and with AMX0114, our investigational antisense oligonucleotide targeting calpain-2, in ALS,&#8221; Klee and Cohen said.

ALS treatment Relyvrio fails trial, may be withdrawn from market

Treatment with <a href="https://alsnewstoday.com/ultomiris-ravulizumab-cwvz/">Ultomiris</a> (ravulizumab-cwvz) — a therapy approved for several rare diseases that works by blocking activation of part of the immune system called the complement cascade — failed to slow the progression of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a Phase 3 clinical trial that had been launched in 2020, a new study shows.
The study, which details the findings from the full 50-week trial data, supports the decision, made in 2021, to terminate that trial early.
&#8220;This trial rapidly showed that terminal complement &#8230; inhibition with [Ultomiris] did not slow functional decline in participants with ALS,&#8221; the researchers wrote.
<a href="https://alexion.com/">Alexion</a>, the therapy&#8217;s developer, ultimately stopped the trial in October 2021 after a pre-specified interim analysis failed to demonstrate any signs of efficacy from Ultomiris.
Titled &#8220;<a href="https://jamanetwork.com/journals/jamaneurology/fullarticle/2809453">Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial</a>,&#8221; the study was published in <a href="https://jamanetwork.com/journals/jamaneurology">JAMA Neurology</a>. The work was funded by Alexion, a subsidiary of AstraZeneca.
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<h3>CHAMPION-ALS study had enrolled 382 adults</h3>
The complement cascade is composed of a group of immune proteins that can become activated to destroy threats — but in some disorders, such activation can help to drive disease-causing inflammation.
Ultomiris, which works by blocking a complement protein called C5, is approved to treat several diseases that are driven by overactivation of the complement cascade, including <a href="https://myastheniagravisnews.com/ultomiris-ravulizumab-for-myasthenia-gravis/">myasthenia gravis</a> and <a href="https://pnhnews.com/ultomiris-ravulizumab-for-pnh/">paroxysmal nocturnal hemoglobinuria</a>, known as PNH.
Although the causes of ALS aren&#8217;t well understood, abnormal inflammation is thought to play a role, and some studies had suggested that complement activity may be increased in people with ALS.
Thus, Alexion sponsored a Phase 3 clinical trial called <a href="https://clinicaltrials.gov/ct2/show/NCT04248465">CHAMPION-ALS (NCT04248465</a>) to test whether Ultomiris treatment might be beneficial in ALS. The trial enrolled 382 adults with ALS, whose symptoms had started up to three years prior, and who were randomly assigned to receive Ultomiris or a placebo.
After two loading doses given two weeks apart, patients received treatment every eight weeks for up to 50 weeks, or nearly one year. All participants could then enroll in an open-label extension part and receive Ultomiris for up to 106 weeks, or a little more than two years.
The study&#8217;s main goal was to test whether Ultomiris could slow disease progression, measured by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R).
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<h3>Initial preterm analysis had predicted failure of Ultomiris</h3>
In large studies like this, independent data monitoring committees will regularly conduct interim analyses testing for futility. Simply put, this involves looking at the available data to calculate whether there&#8217;s a reasonable likelihood the trial might have positive results.
In an interim analysis conducted after half of participants had completed their 26-week assessment, researchers found that the average ALSFRS-R score had worsened by 14.67 points for patients on Ultomiris — in fact showing slightly more worsening than the average of 13.33 points seen in the placebo group.
Statistical analyses suggested that the odds the trial would show slower progression with Ultomiris compared with the placebo was less than 0.1%, and the trial was ultimately terminated early.
[quote=&#8221;center&#8221;]There was a clear rationale for testing [Ultomiris] as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression. &#8230; However, the CHAMPION-ALS study was terminated when the week 26 interim analysis showed that the futility criterion had been met.[/quote]
The investigators now shared full analyses of all available trial data.
These results continued to show no effect of Ultomiris compared with a placebo on ALSFRS-R scores. There also was no benefit on other endpoints, including a combined assessment of survival and disease progression, changes in lung function, time to needing ventilatory support, and all-cause mortality.
Measures of muscle strength and markers of nerve damage also failed to improve with Ultomiris treatment.
A total of 80% of patients experienced side effects related to the therapy, the most common of which were headaches, falls, and constipation. Safety data showed no unexpected findings related to Ultomiris compared with what&#8217;s been seen with the therapy in people with other diseases.
&#8220;There was a clear rationale for testing [Ultomiris] as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression,&#8221; the researchers wrote.
&#8220;However,&#8221; they noted, &#8220;the CHAMPION-ALS study was terminated when the week 26 interim analysis showed that the futility criterion had been met.&#8221;
The researchers pointed that pharmacological data from the trial showed Ultomiris was blocking C5 as designed.
&#8220;It is unclear why C5 inhibition did not result in clinical benefit in patients with ALS and whether this lack of benefit might extend to other complement components,&#8221; they wrote.
The team concluded that this trial &#8220;highlights the unmet need for highly effective treatments to slow functional decline and extend survival in patients with ALS.&#8221;

Tag: failure

ALS treatment Relyvrio fails trial, may be withdrawn from market

Ultomiris failed to show benefit in ALS in clinical trial, per full data