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<a href="https://alsnewstoday.com/amx0035">Relyvrio</a> (sodium phenylbutyrate and taurursodiol), an approved treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), was voluntarily removed from the U.S. and Canadian markets.
<a href="https://www.amylyx.eu/">Amylyx Pharmaceuticals</a>, the therapy&#8217;s developer, made the decision after <a href="https://alsnewstoday.com/news/als-treatment-relyvrio-fails-trial-may-be-withdrawn-market/">top-line results</a> from the <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">Phase 3 PHOENIX trial (NCT05021536)</a> showed that patients who received Relyvrio as an add-on to standard ALS medications experienced a similar rate of disease progression as those given a standard treatment alone.
As of April 4, Relyvrio is no longer available for new patients. Patients receiving the therapy in the U.S. and in Canada, where it was marketed under the brand name Albrioza, who want to continue on treatment can transition to a free drug program after consulting with their physicians.
&#8220;While this is a difficult moment for the ALS community, we reached this path forward in partnership with the stakeholders who will be impacted and in line with our steadfast commitment to people living with ALS and other neurodegenerative diseases,&#8221; said Joshua Cohen and Justin Klee, co-CEOs of Amylyx, in a <a href="https://www.businesswire.com/news/home/20240404501040/en/Amylyx-Pharmaceuticals-Announces-Formal-Intention-to-Remove-RELYVRIOALBRIOZA-from-the-Market-Provides-Updates-on-Access-to-Therapy-Pipeline-Corporate-Restructuring-and-Strategy">company press release</a>.
&#8220;The decision to remove Relyvrio/Albrioza from the market and provide therapy free of charge for those who wish to continue was informed by the PHOENIX trial results, engagement with regulatory authorities, and discussions with the ALS community,&#8221; Cohen and Klee said. &#8220;Thank you to each and every person who shared feedback with us and continues to support our commitment to the ALS community.&#8221;
[recommended-reading id=90368]
<h3>Phase 2 results suggested slowing of functional decline</h3>
Relyvrio, formerly known as AMX0035, <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">was approved</a> in the U.S. and Canada in 2022 based on data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">Phase 2 CENTAUR study (NCT03127514)</a>. The study enrolled 137 adults with recently diagnosed, rapidly progressing ALS.
After six months, there was <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>, as assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), among adults given Relyvrio than those on a placebo. Data also suggested the therapy may <a href="https://alsnewstoday.com/news/amx0035-survival-als-patients-centaur-clinical-trial-analysis-amylyx/">extend survival</a>.
Still, an advisory committee with the U.S. Food and Drug Administration <a href="https://alsnewstoday.com/news/fda-committee-votes-against-recommending-als-therapy-amx0035/">initially voted</a> there was not enough substantial evidence to support Relyvrio’s efficacy, and European authorities also <a href="http://recommended">recommended against approval</a> based on these data alone.
Although the treatment was ultimately approved in the U.S. based on the early data, the company said it would consider withdrawing the marketing application if Relyvrio failed to prove beneficial in a confirmatory Phase 3 trial.
The PHOENIX trial was launched to confirm Relyvrio&#8217;s effectiveness over one year, enrolling 664 people with early ALS. However, top-line data showed the trial failed to meet its primary goal of slowing the decline in ALSFRS-R scores compared with a placebo. These results were a key factor in the decision to remove Relyvrio from the market.
Top-line PHOENIX data will be presented at the American Academy of Neurology (AAN) annual meeting this month and will be available on <a href="https://www.amylyx.com/publications">Amylyx&#8217;s website</a> following the presentation.
[recommended-reading id=90100]
<h3>PHOENIX results to inform future research</h3>
The company will evaluate and share PHOENIX&#8217;s findings to help inform future ALS research and collect survival data at the encouragement of ALS specialists. The <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05619783">PHOENIX open-label extension study (NCT05619783)</a> in Europe is ongoing.
Relyvrio also is being evaluated as a potential treatment for other neurodegenerative conditions, including Wolfram syndrome and progressive supranuclear palsy.
Amylyx will continue to advance its experimental ALS treatment AMX0114, which targets calpain-2, a protein involved in nerve fiber degeneration. In preclinical studies, AMX0114 achieved a dose-dependent reduction of calpain-2 protein levels in human motor neurons, the nerve cells affected in ALS. The company <a href="https://alsnewstoday.com/news/als-mnd-2023-clinical-tests-aso-treatment-als-happen-next-year/">expects to launch a clinical trial</a> to test AMX0114 in ALS later this year.
&#8220;We also remain focused on ALS and believe AMX0114 has strong potential for the treatment of ALS and other diseases,&#8221; said Camille L. Bedrosian, MD, chief medical officer of Amylyx. &#8220;Calpain-2 is considered an essential protein in the process of axonal degeneration.&#8221;
&#8220;In our preclinical studies of AMX0114 and in multiple independent published studies, inhibition of calpain-2 has reduced cell death and degeneration,&#8221; Bedrosian said. &#8220;We expect to initiate a clinical trial studying AMX0114 in ALS in the second half of this year.&#8221;

Relyvrio withdrawn from US, Canada after Phase 3 trial results

An advisory committee of the European Medicines Agency has maintained its recommendation not to approve <a href="https://alsnewstoday.com/amx0035/">AMX0035</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
In its <a href="https://alsnewstoday.com/news/chmp-opposes-approval-amx0035s-als-treatment-europe/">initial assessment issued in June</a>, the Committee for Medicinal Products for Human Use (CHMP) said data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR Phase 2 trial (NCT03127514)</a>, which formed the basis for the application, did not convincingly show that AMX0035 was effective at slowing ALS progression.
<a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a>, the company developing the treatment, then requested a formal re-examination, in which available clinical data were evaluated by a different set of examiners, but this second review process has confirmed the initial opinion.
An official decision on AMX0035 from the European Medicines Agency is now set to be handed down by year&#8217;s end. The regulatory agency is not obligated to abide by the committee’s opinion, but it usually does.
“We are disappointed to learn of this outcome, as it is a further setback for the more than 30,000 people <a href="https://alsnewstoday.com/living-with-als-2/">living with ALS</a> and their loved ones in Europe who have not seen therapeutic progress for this devastating disease in over 25 years,” the patients and carers board of the <a href="https://als.eu/">European Organization for Professionals and Patients with ALS</a> said in a <a href="https://www.businesswire.com/news/home/20231012969323/en/Amylyx-Pharmaceuticals-Receives-Negative-CHMP-Opinion-on-its-Marketing-Authorisation-Application-for-AMX0035-for-the-Treatment-of-ALS-in-the-European-Union-Following-Re-Examination-Process">press release</a>.
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<h3>Other paths to AMX0035&#8217;s approval in Europe being explored</h3>
Meanwhile, the company says it will continue to explore other paths to AMX0035&#8217;s approval in Europe.
The treatment is being evaluated in a larger Phase 3 trial called <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">PHOENIX (NCT05021536)</a>, whose data was not included in the initial application. Pending positive results, Amylyx is planning to submit an application to the European agency as soon as possible.
AMX0035, a fixed-dose combination of tauroursodeoxycholic acid and sodium phenylbutyrate, is already available in the U.S. under the brand name Relyvrio. It has also gained <a href="https://alsnewstoday.com/news/amx0035-oral-als-therapy-called-albrioza-approved-canada/">conditional approval in Canada</a>, where it is sold as Albrioza — that brand name will also be used in Europe if it&#8217;s approved.
“We share the frustration felt by the European ALS community, who has no time to wait for new, safe, and effective treatment options,” said Stéphanie Hoffmann-Gendebien, general manager and head of Europe, the Middle East, and Africa at Amylyx.
“We remain committed to exploring all potential paths forward in support of the company’s goal of getting AMX0035 to people living with ALS in the EU as quickly as possible,” she added.
The safety and effectiveness of AMX0035 was initially assessed in the CENTAUR trial, which enrolled 137 adults with early and rapidly progressing ALS. Data showed Relyvrio significantly <a href="https://alsnewstoday.com/news-posts/2020/09/03/amx0035-safe-effective-in-slowing-als-functional-decline-trial-data-shows/">slowed functional decline</a> and <a href="https://alsnewstoday.com/news-posts/2020/10/19/amylyxs-amx0035-significantly-extends-als-patients-lives-long-term-trial-data-show-also-slows-functional-decline/">extended survival</a>, compared with a placebo.
“AMX0035 is the first and only drug to show an effect on both function and survival in the same trial. Since the medication’s approval with conditions in Canada and full approval in the U.S., thousands of people have been prescribed AMX0035 in North America,&#8221; said Joshua Cohen and Justin Klee, co-CEOs of Amylyx.
[quote=&#8221;center&#8221;]We are disappointed to learn of this outcome, as it is a further setback for the more than 30,000 people living with ALS and their loved ones in Europe who have not seen therapeutic progress for this devastating disease in over 25 years.[/quote]
<h3>Phase 3 PHOENIX trial fully enrolled with 664 participants in US, Europe</h3>
The PHOENIX trial was then launched to confirm the benefits seen in CENTAUR in a larger group of ALS patients. The trial is <a href="https://alsnewstoday.com/news/phoenix-trial-approved-als-therapy-relyvrio-amx0035-enrolled/">fully enrolled</a>, with 664 participants recruited across 69 clinical sites in the U.S. and Europe.
Participants were randomly assigned to Relyvrio or a placebo, given daily for 48 weeks, or nearly one year. They will then be given the option to join an open-label extension part, where all will the receive the medication for two years.
The trial&#8217;s main goal is to determine if AMX0035 can slow disease progression, as assessed by changes in the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures include changes in lung function and quality of life, and an extension in survival time.
Top-line data are expected by June 2024.
&#8220;ALS has no geographical boundaries, and we are working with urgency toward providing timely, broad, and sustainable access to AMX0035 for eligible people living with ALS who may benefit,” Cohen and Klee added.

Tag: Phase 3 PHOENIX trial

Relyvrio withdrawn from US, Canada after Phase 3 trial results

CHMP confirms its initial position against approving AMX0035 in EU