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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>.
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<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

Health Canada has resumed its review of <a href="https://www.ab-science.com/">AB Science</a>’s application seeking approval of <a href="https://alsnewstoday.com/masitinib/">masitinib</a>, an oral add-on therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), after the agency halted its review late last year.
In 2022, the agency <a href="https://alsnewstoday.com/news/masitinib-under-review-als-add-on-therapy-canada/">agreed to review</a> the application under the notice of compliance with conditions (NOC/c) policy, which would allow the therapy to receive conditional approval and gain early market access.
However, the <a href="https://alsnewstoday.com/news/health-canada-more-masitinib-data-stops-review/">review was discontinued</a> a few months later when Health Canada issued a notice of deficiency for the application, meaning more information on the therapy was needed from the company within 90 days.
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<h3>AB Science submitted revised application in April</h3>
In April, AB Science submitted its revised application, which was screened and found acceptable for the review process to continue. Under the NOC/c policy, Health Canada now has no more than 200 days, or about seven months, to decide whether to approve masitinib.
&#8220;There is an urgent need expressed by ALS patients and their families in Canada to access masitinib treatment under NOC/c status and we will continue to work diligently with Health Canada to respond to this need,&#8221; Alain Moussy, AB Science&#8217;s co-founder and CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/05/09/2664790/0/en/AB-Science-announces-that-Health-Canada-has-resumed-its-review-of-the-New-Drug-Submission-for-masitinib-in-amyotrophic-lateral-sclerosis-following-issuance-of-a-screening-acceptanc.html">company press release</a>.
Masitinib is also undergoing review for conditional approval in Europe, with a recommendation from Europe&#8217;s Committee for Medicinal Products for Human Use <a href="https://alsnewstoday.com/news/ema-given-responses-masitinib-conditional-approval-review/">expected in the next few months</a>.
In people with ALS, the nerve cells that control voluntary movements, called motor neurons, progressively die, leading to <a href="https://alsnewstoday.com/als-symptoms/">symptoms</a> such as muscle atrophy and wasting. Motor neuron loss is known to be driven by inflammation caused by the activity of certain immune cells, including macrophages, neutrophils, and mast cells.
Masitinib is designed to suppress the activity of tyrosine kinase, an enzyme essential for the function of these immune cells, with the goal of slowing disease progression in ALS and other neurodegenerative diseases.
[quote=&#8221;center&#8221;]There is an urgent need expressed by ALS patients and their families in Canada to access masitinib treatment under NOC/c [notice of compliance with conditions] status and we will continue to work diligently with Health Canada to respond to this need.[/quote]
<h3>Phase 2/3 trial shows slower disease progression in patients on masitinib</h3>
Approval applications were supported by final data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">AB10015 Phase 2/3 clinical trial (NCT02588677)</a>, which evaluated masitinib as an add-on to the approved ALS therapy <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek</a> (riluzole) in 394 ALS patients. Participants were assigned to one of two masitinib doses (3 or 4.5 mg/kg) or a placebo.
After 48 weeks (about 11 months) of daily therapy, <a href="https://alsnewstoday.com/news-posts/2019/07/10/add-on-masitinib-slows-progression-of-als-final-phase-2-3-trial-results-show/">disease progression was significantly slowed by 27%</a> in patients taking the 4.5 mg/kg dose of masitinib plus Rilutek compared with Rilutek and a placebo.
AB Science&#8217;s revised application contained a new examination of AB10015 data showing that patients with mild or moderate disease severity <a href="https://alsnewstoday.com/news/als-therapy-masitinib-works-best-add-on-moderate-disease-analysis/">benefited the most from masitinib</a>.
This analysis focused on patients who had yet to experience a complete loss of any physical function, defined as a zero score on any of the 12 items on the ALS Functional Rating Scale-Revised (ALSFRS-R). This subgroup accounted for about 80% of participants in AB10015.
According to the new data, there was a significant 18.4% improvement in the combined assessment of function and survival (CAFS) in people receiving daily 4.5 mg/kg masitinib compared with those given a placebo alone.
CAFS is a composite outcome that ranks patients&#8217; clinical outcomes based on survival time and rate of ALSFRS-R decline. It is now recommended by Health Canada and the U.S. Food and Drug Administration as a primary measure to assess efficacy in ALS trials.
Masitinib also significantly slowed overall disease progression, based on ALSFRS-R scores, and the decline in lung function and quality of life.
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<h3>Ongoing AB19001 Phase 3 trial testing if masitinib can slow ALSFRS-R declines</h3>
AB Science is now confirming the findings in the ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">AB19001 Phase 3 clinical trial (NCT03127267)</a>, which aims to enroll up to 495 adults with mild to moderate ALS who were diagnosed in the prior two years.
Like the AB10015 study, participants will be assigned to one of two masitinib daily doses (4.5 or 6 mg/kg) or a placebo, given in combination with Rilutek, for 48 weeks.
Whether masitinib can slow ALSFRS-R declines is AB19001&#8217;s main goal. CAFS scores, and changes in muscle strength, lung function, quality of life, as well as time to disease progression or death, will also be assessed. The company expects to report top-line data this year.
Masitinib has been granted orphan drug status in the U.S., the European Union, and, more recently, <a href="https://alsnewstoday.com/news/als-therapy-masitinib-gains-orphan-drug-status-switzerland/">Switzerland</a>, a designation given to potential treatments for life-threatening or chronic rare diseases.

Tag: add-on therapy

CHMP delays opinion on masitinib, up for conditional EU approval

Health Canada resumes its review of add-on ALS therapy masitinib