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A European Medicines Agency (EMA) committee again has delayed issuing an opinion on whether to grant conditional approval to <a href="https://alsnewstoday.com/masitinib/">masitinib</a>, a potential add-on oral therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
<a href="https://www.ab-science.com/">AB Science</a>, the therapy&#8217;s developer, now expects a recommendation in the second quarter of this year.
The postponement by the Committee for Medicinal Products for Human Use (CHMP) is due to outstanding issues regarding AB Science&#8217;s application requesting masitinib&#8217;s approval.
Responses to CHMP questions at this stage of the review process typically are given as oral explanations, and a meeting was scheduled for Jan. 24. But shortly before that date, the agency asked for written responses, an unusual request, AB Science stated in a <a href="https://www.globenewswire.com/news-release/2024/01/26/2818214/0/en/AB-Science-announces-an-update-in-the-marketing-authorization-application-of-masitinib-in-amyotrophic-lateral-sclerosis-at-the-European-Medicines-Agency.html">company press release</a>.
[recommended-reading id=89315]
<h3>New EMA guidelines were the cause of initial delayed opinion for masitinib</h3>
Written responses, AB Science noted in agreeing to the request, will provide CHMP with more detailed answers than likely would be possible in an oral presentation, and gives CHMP more time to evaluate the responses. A new oral meeting could be scheduled if major objections remain.
In September 2023, the company requested <a href="https://alsnewstoday.com/news/early-2024-likely-masitinib-eu-conditional-approval-decision-als/">more time to review masitinib production processes</a> to ensure they met recently implemented EMA guidelines regarding product manufacturing. CHMP accepted that request, which was expected to push into March a committee opinion on the therapy&#8217;s application, filed in 2022. The guidelines asked that companies review their manufacturing processes to identify and reduce an impurity called nitrosamine, which can increase cancer risk.
Masitinib is designed to block certain enzymes thought to drive inflammation and neurodegeneration in ALS, aiming to slow disease progression and ease <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a>.
AB Science&#8217;s application is supported by the results of the <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">Phase 2/3 </a><a href="https://clinicaltrials.gov/ct2/show/NCT02588677">AB10015</a><a href="https://clinicaltrials.gov/ct2/show/NCT02588677"> clinical trial (NCT02588677)</a>, which tested masitinib as an add-on to the approved ALS therapy <a class="c-link" href="https://alsnewstoday.com/rilutek-riluzole-for-als/" target="_blank" rel="noopener noreferrer" data-stringify-link="https://alsnewstoday.com/rilutek-riluzole-for-als/" data-sk="tooltip_parent">Rilutek</a> (riluzole) in 394 patients.
Findings showed that a 4.5 mg/kg daily dose of masitinib plus riluzole <a href="https://alsnewstoday.com/news-posts/2019/07/10/add-on-masitinib-slows-progression-of-als-final-phase-2-3-trial-results-show/">significantly slowed disease progression by 27%</a> versus riluzole and a placebo after nearly one year of treatment. These outcomes were in patients with so-called normal disease progression, defined as a monthly drop in the ALS Functional Rating Scale-Revised scores of less than 1.1 points.
Slower declines in quality of life and lung function also were observed with the combination therapy, particularly in patients progressing normally. In contrast, no changes were found among those progressing faster than usual.
Across the entire study population, no survival benefits with masitinib over a placebo were seen. Still, a recent analysis of trial data showed that patients with <a href="https://alsnewstoday.com/news/als-therapy-masitinib-works-best-add-on-moderate-disease-analysis/">mild or moderate ALS benefited most from adding masitinib</a>. These patients lived more than two years longer than those on riluzole alone, representing a 44% reduction in mortality risk.
<h3>Phase 3 trial evaluating masitinib as riluzole add-on in nearly 500 patients</h3>
Conditional approval in Europe is granted to medicines whose preliminary benefits outweigh their potential risks and fill an unmet medical need. But confirmatory clinical trials generally are required to support a full approval.
AB Science is sponsoring a global <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">Phase 3 clinical trial (NCT03127267)</a> to confirm the benefits of adding masitinib to riluzole in about 495 patients. Eligible participants are randomly assigned to daily masitinib (4.5 or 6 mg/kg) plus riluzole or a placebo for 48 weeks (nearly one year). Assessed outcomes include changes in disease progression, lung function, muscle strength, quality of life, and survival.
If approved in Europe, masitinib is to be marketed under the brand name Alsitek.

CHMP delays opinion on masitinib, up for conditional EU approval

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>.
[recommended-reading id=86997]
<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.

CHMP confirms its initial position against approving AMX0035 in EU

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>.
[recommended-reading id=85161]
<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.

EMA branch opposes conditional approval of AMX0035 in Europe

A committee of the European Medicines Agency (EMA) is leaning toward not recommending a conditional approval of <a href="https://www.amylyx.com">Amylyx Pharmaceuticals</a>’ AMX0035 for treating <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in the European Union.
The drug is already marketed in the U.S. under the name <a href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) and in Canada as Albrioza, but has faced some hurdles in its <a href="https://alsnewstoday.com/news/amylyxs-amx0035-now-under-review-approval-europe/">regulatory review</a> in the European Union.
Earlier this year, the EMA’s Committee for Medicinal Products for Human Use (CHMP) met with experts to evaluate the drug and provide recommendations for its approval. The committee instead sought <a href="https://alsnewstoday.com/news/european-approval-amx0035-als-faces-new-hurdle-review/">more answers</a> on major objections that remained.
A final opinion on the marketing authorization application is expected June 19-22, when CHMP holds its next meeting. While not binding, the opinion will be considered by the EMA when it makes its decision.
[recommended-reading id=81650]
<h3>What happens next?</h3>
Should CHMP issue a negative opinion, the company plans to seek a formal re-examination based on available data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR trial (NCT03127514)</a>. A re-examination could take about four months.
“We disagree with the current view expressed by the CHMP and remain confident in the data from the CENTAUR trial. Should a negative opinion ultimately be issued, we intend to request a formal re-examination procedure,” Tammy Sarnelli, global head of regulatory affairs and clinical compliance at Amylyx, said in a <a href="https://www.businesswire.com/news/home/20230530005232/en/Amylyx-Pharmaceuticals-Provides-Update-on-Ongoing-Regulatory-Review-of-AMX0035-for-the-Treatment-of-ALS-in-the-European-Union">company press release</a>.
AMX0035 is an oral fixed-dose combination of sodium phenylbutyrate and taurursodiol, two compounds thought to protect nerve cells from cellular stress and help slow the progression of <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a>.
Its approval, first <a href="https://alsnewstoday.com/news/amx0035-albrioza-oral-als-therapy-available-canada/">with conditions in Canada</a> and about a month <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">later in the U.S.</a>, was based on data from CENTAUR, a Phase 2 clinical trial involving 137 adults with rapidly progressing ALS.
The data showed AMX0035 was well tolerated and significantly slowed functional disability progression compared with a placebo. The findings from CENTAUR and its open-label extension also showed a <a href="https://alsnewstoday.com/news/amx0035-survival-als-patients-centaur-clinical-trial-analysis-amylyx/">10-month survival benefit</a> from the therapy.
“There has not been a new product approved in the European Union for ALS in over 25 years,” said Stéphanie Hoffmann-Gendebien, Amylyx’s head and general manager of international markets. “We know from the European ALS community that there is a desperate need for new therapeutic options for this devastating disease, and timely access to safe and effective treatments is especially important.&#8221;

EMA committee leaning toward not recommending AMX0035 approval

<a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a> is facing a new hurdle — a second round of questions from a European Medicines Agency (EMA) committee — in its quest to have <a href="https://alsnewstoday.com/amx0035/">AMX0035</a> approved as a treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in Europe.
The questions, from the Committee for Medicinal Products for Human Use, known as CHMP, come after the company completed a scientific advisory group meeting, in which experts come together to evaluate a specific drug and provide recommendations for approval. However, the committee said there were still certain major objections to AMX0035 that should be addressed.
Amylyx will now respond to the questions, and expects an opinion from the committee by mid-2023. The EMA will consider that opinion in its decision on AMX0035&#8217;s potential approval.
While the company had previously said it was expecting a decision from the regulatory authority <a href="https://alsnewstoday.com/news/phoenix-trial-approved-als-therapy-relyvrio-amx0035-enrolled/">in the first half of 2023</a>, updated timelines now point to &#8220;the third quarter of 2023 at the earliest,&#8221; Amylyx stated in <a href="https://www.businesswire.com/news/home/20230313005731/en/Amylyx-Pharmaceuticals-Reports-Fourth-Quarter-and-Full-Year-2022-Financial-Results">press release</a> announcing its financial results for 2022.
“We continue to engage with the European Medicines Agency as it reviews our marketing authorisation application for AMX0035,&#8221; said Joshua Cohen and Justin Klee, co-CEOs at Amylyx. &#8220;We remain focused on our efforts &#8230; to drive the broadest coverage possible for this important new therapeutic option.”
[recommended-reading id=79299]
<h3>&#8216;Much work remains,&#8217; Amylyx CEOs say</h3>
AMX0035 is an oral fixed-dose combination of two small molecules — tauroursodeoxycholic acid and sodium phenylbutyrate — that protect nerve cells from damage induced by cellular stress.
The treatment is <a href="https://alsnewstoday.com/news/amx0035-albrioza-oral-als-therapy-available-canada/">commercially available</a> to treat people with ALS in Canada, under the name Albrioza. In the U.S., it was <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">approved in September</a> of last year and is marketed as Relyvrio.
“2022 was an exceptionally exciting year for Amylyx, culminating with the approval of Relyvrio in the U.S. following the approval with conditions for Albrioza in Canada, marking an important step toward delivering much-needed advancements in treatment options to the ALS community,” Cohen and Klee said.
Approvals of AMX0035 in North America were supported by data from <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR (NCT03127514)</a>, a Phase 2 trial in which the therapy was found to significantly slow functional decline and extend survival in people with the neurodegenerative disease. That trial involved 137 people with recently diagnosed and rapidly progressing ALS.
Now, the company is conducting the <a href="https://clinicaltrials.gov/ct2/show/NCT05021536">PHOENIX Phase 3 trial (NCT05021536)</a> to test the therapy in a larger group of patients. <a href="https://alsnewstoday.com/news/phoenix-trial-approved-als-therapy-relyvrio-amx0035-enrolled/">Enrollment was completed</a> last month, with a total of 664 participants who will receive the medication or a placebo for 48 weeks (nearly one year).
The trial’s main goals are to assess AMX0035&#8217;s safety and changes in disease progression, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures include changes in lung function, quality of life, and survival.
After completing the trial, patients will be able to join an open-label extension part and continue receiving treatment for two more years.
[quote align=&#8221;center&#8221;]2022 was an exceptionally exciting year for Amylyx, culminating with the approval of Relyvrio in the U.S. following the approval with conditions for Albrioza in Canada, marking an important step toward delivering much-needed advancements in treatment options to the ALS community.[/quote]
Earlier this year, Amylyx entered an <a href="https://alsnewstoday.com/news/amylyx-select-neopharm-market-amx0035-middle-east/">exclusive license and distribution agreement</a> with <a href="https://www.neopharmisrael.co.il/">Neopharm</a>, which, pending its approval, would make the Israel-based company responsible for regulatory submissions and commercialization of AMX0035 in certain Middle East regions. Those regions include Israel, Gaza, the West Bank, and the Palestinian Authority.
“Our commercial launch is off to a strong start, and we are encouraged by the engagement we have seen from physicians, people living with ALS, and payors,” Cohen and Klee said.
“While we are thrilled with this progress, we are also cognizant that much work remains to meet our goal of quick and efficient access for every eligible person living with ALS,” they added.

Tag: CHMP

CHMP delays opinion on masitinib, up for conditional EU approval

CHMP confirms its initial position against approving AMX0035 in EU

EMA branch opposes conditional approval of AMX0035 in Europe

EMA committee leaning toward not recommending AMX0035 approval

European approval of AMX0035 for ALS faces new hurdle in review