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The developer of the add-on treatment <a href="https://alsnewstoday.com/masitinib/">masitinib</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) has been given the go-ahead to ask Health Canada to reconsider its decision from earlier this year against the approval of the oral therapy.
The Canadian regulatory agency granted reconsideration eligibility to <a href="https://www.ab-science.com/">AB Science</a> for masitinib — meaning the company now has 45 days to file a new request seeking the drug&#8217;s approval.
AB Science already has met with Health Canada to discuss the reconsideration process, the company announced in a <a href="https://www.globenewswire.com/news-release/2024/04/03/2857229/0/en/AB-Science-announces-that-Health-Canada-has-granted-eligibility-for-reconsideration-request-for-masitinib-in-ALS.html">press release</a>. As part of the reconsideration, new assessors will re-examine the approval decision based on available data. This could take up to six months.
&#8220;The pivotal argument is on the treatment of missing data,&#8221; AB Science stated in the release, noting that analyses show the therapy was &#8220;successful&#8221; in earlier research.
[recommended-reading id=81693]
<h3>Masitinib tested in nearly 400 ALS patients in Phase 3 trial</h3>
AB first <a href="https://alsnewstoday.com/news/masitinib-under-review-als-add-on-therapy-canada/">asked Health Canada to approve masitinib</a> in 2022. However, the agency <a href="https://alsnewstoday.com/news/health-canada-more-masitinib-data-stops-review/">paused its review</a> after a few months, citing a need for more information. The review was then <a href="https://alsnewstoday.com/news/health-canada-less-than-7-months-decide-approval-masitinib/">resumed in 2023</a> after a revised application was submitted, but the agency decided in February to <a href="https://alsnewstoday.com/news/als-oral-therapy-masitinib-rejected-health-canada/">reject that request</a>.
Less than a month earlier, regulators in the European Union had <a href="https://alsnewstoday.com/news/chmp-delays-opinion-conditional-eu-approval-masitinib-als/">delayed their decision on masitinib</a>, which now is likely by June.
Masitinib is an oral therapy designed to block enzymes that drive inflammation and nerve cell death in ALS. It&#8217;s being investigated as an add-on treatment to riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> among others), the only therapy proven to date to slow disease progression and extend survival in people with the neurodegenerative condition.
&#8220;The recent failure of numerous phase 2 or 3 programs … have dashed the community&#8217;s hopes of benefiting from new therapeutic advances and have effectively set us back with riluzole being the only treatment with a proven modest effect in the overall ALS population,&#8221; said Albert Ludolph, MD, PhD, principal investigator of the Phase 3 trial that tested masitinib, and also medical director of the neurology department at the University of Ulm, in Germany.
&#8220;We should learn from [these] failures,&#8221; Ludolph added.
AB Science&#8217;s applications were supported by data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">AB10015 Phase 3 trial (NCT02588677)</a>, in which 394 ALS patients were randomly assigned one of two doses of masitinib (3 or 4.5 mg/kg) or a placebo, given on top of the standard ALS medication Rilutek.
Data showed that the higher masitinib dose significantly outperformed the placebo at <a href="https://alsnewstoday.com/news-posts/2019/07/10/add-on-masitinib-slows-progression-of-als-final-phase-2-3-trial-results-show/">slowing physical decline</a>, as indicated by a 27% reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) scores after one year.
These benefits were seen in patients with disease progression deemed normal, meaning an ALSFRS-R decrease of less than 1.1 points a month. Slower declines in lung function and quality of life also were found for these patients.
Overall, however, data showed that normal progressors with <a href="https://alsnewstoday.com/news/als-therapy-masitinib-works-best-add-on-moderate-disease-analysis/">mild or moderate ALS</a> achieved the best outcomes, with masitinib slowing the rate of disease progression by 42% and extending survival by 25 months, or just longer than two years.
[recommended-reading id=38613]
<h3>Health Canada had cited 3 issues with data from key AB10015 studt</h3>
Health Canada nevertheless rejected AB&#8217;s application, citing three limitations to the available AB10015 data.
First, the year-long study generated a great deal of missing data. To impute, or represent, these missing values, the researchers used certain statistical tests — but the agency said the resulting data could have biased the results and made masitinib appear more effective than it was.
According to AB, however, sensitivity analyses continued to support masitinib&#8217;s efficacy when the missing data were considered a placebo, a recognized conservative approach to dealing with missing data. Rerandomization, for more precise estimates of causal effects, also was successful.
&#8220;A 48-week study inevitably generates a large number of missing data,&#8221; Ludolph said, who noted that &#8220;this situation is not unique to masitinib.&#8221;
&#8220;Masitinib has published results over a 48-week period, positive when appropriate methodology to treat missing data is applied, and it deserves careful consideration,&#8221; Ludolph said.
Second, after AB10015 was completed, the developer created a new subgroup of study individuals it dubbed &#8220;patients with ALS prior to any loss of function.&#8221;
Among these patients, masitinib significantly extended overall survival versus the placebo. However, the agency said this finding was unreliable because this subgroup wasn&#8217;t part of the study&#8217;s original design.
In its release, AB noted that the subgroup, defined based on masitinib&#8217;s mechanism of action, had a significant median overall survival benefit of more than 22 months, or nearly two years, which was unlikely to be artificial because all patients had access to the same care.
[quote=&#8221;center&#8221;]Masitinib has published results over a 48-week period, positive when appropriate methodology to treat missing data is applied, and it deserves careful consideration.[/quote]
Health Canada&#8217;s third issue was late-in-the-trial changes to the study protocol that were not sufficiently justified, undermining the data&#8217;s reliability. While AB previously acknowledged that the protocol changes were not data-driven, the company said they were typical for such a large clinical trial.
Further, the company also stated that there was a near significant change in the secondary outcome of the Combined Assessment of Function and Survival (CAFS), a composite measure of survival-based outcomes and ALSFRS-R decline. This occurred despite the study not being statically powered for this outcome.
Lastly, progression-free survival, the time from the study&#8217;s start to the earliest date of a functional decline of at least nine ALSFRS-R points, did show significant improvement in favor of masitinib, according to AB Science.

Health Canada agrees to reconsider request for masitinib approval

Health Canada has issued a notice of noncompliance-withdrawal saying it won&#8217;t approve the oral therapy <a href="https://alsnewstoday.com/masitinib/">masitinib</a> as an add-on treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Its developer, <a href="https://www.ab-science.com/">AB Science</a>, can submit a request for reconsideration within the next month, which it plans to do, it announced in a <a href="https://www.globenewswire.com/news-release/2024/02/26/2835372/0/en/AB-Science-announces-that-Health-Canada-has-issued-a-Notice-of-Non-Compliance-Withdrawal-NON-w-for-masitinib-in-ALS.html">press release</a>. As part of a reconsideration, which could take up to six months, new assessors will re-examine the decision based on available data.
AB first sought <a href="https://alsnewstoday.com/news/masitinib-under-review-als-add-on-therapy-canada/">Health Canada&#8217;s approval</a> in 2022, but the <a href="https://alsnewstoday.com/news/health-canada-more-masitinib-data-stops-review/">review was paused</a> after a few months because the regulatory agency said it needed more information from AB. Health Canada <a href="https://alsnewstoday.com/news/health-canada-less-than-7-months-decide-approval-masitinib/">resumed its review</a> in May 2023 after a revised application was submitted.
The rejection comes less than a month after authorities in Europe <a href="https://alsnewstoday.com/news/chmp-delays-opinion-conditional-eu-approval-masitinib-als/">delayed a ruling on masitinib</a>.
The oral therapy is designed to block enzymes that drive inflammation and nerve death in ALS, which is expected to slow disease progression.
[recommended-reading id=81407]
<h3>Outcomes of Phase 2/3 clinical trial</h3>
AB’s applications are based mainly on data from a Phase 2/3 clinical trial called <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">AB10015 (NCT02588677)</a>. The study enrolled 394 people with ALS who were given one of two doses of masitinib (3 or 4.5 mg/kg) or a placebo as an add-on to the approved treatment <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek</a> (riluzole).
After nearly a year, the rate of disease progression — measured by the ALS Functional Rating Scale Revised or ALSFRS-R — was <a href="https://alsnewstoday.com/news-posts/2019/07/10/add-on-masitinib-slows-progression-of-als-final-phase-2-3-trial-results-show/">27% slower</a> in those given the higher masitinib dose over a placebo.
This was observed in the patients with “normal” disease progression, defined as an ALSFRS-R decline of less than 1.1 points a month, who also had significantly slower declines in lung function and quality of life.
The greatest benefits, however, were seen in normal progressors <a href="https://alsnewstoday.com/news/als-therapy-masitinib-works-best-add-on-moderate-disease-analysis/">with mild or moderate ALS</a>. In these patients, masitinib slowed the rate of disease progression by 42% and extended survival by 25 months.
<h3>The basis for rejecting masitinib</h3>
In its notice, Health Canada highlighted three issues with the available data from the AB10015 study. First, the agency said changes in the study protocol were made late in the trial and weren&#8217;t sufficiently justified, leading to uncertainty about how reliable the results are. Second, the agency expressed concern that some statistical tests used to account for missing data could have biased the results, making it seem like masitinib was more effective than it really was.
In its press release, AB acknowledged that changes to the protocol were not data-driven and that they were within the normal range for a large clinical trial. The company also argued that many different statistical tests to account for missing data consistently indicate a clinical effect of masitinib.
The third issue raised by Health Canada is that, as part of its application, AB defined a new subpopulation of ALS patients, namely &#8220;patients with ALS prior to any loss of function.&#8221; In this subpopulation, overall survival was extended with masitinib compared to a placebo, but Health Canada said this finding isn&#8217;t reliable because the subgroup was defined after the study was already over, rather than being considered as part of its original design.
AB said the subpopulation was defined based on guidelines from European regulators and is logical given the push to start treating ALS as soon as possible. The company said improvements in overall survival seen in this subgroup are unlikely to be artificial because all the patients had access to the same supportive care, except that some were given masitinib and others got a placebo.
These counterarguments will form the basis of AB&#8217;s request for reconsideration, the company said.
The company is also conducting a global <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">Phase 3 clinical trial (NCT03127267)</a> to further support masitinib as an add-on treatment to Rilutek. The study will include 495 participants with mild to moderate ALS who were diagnosed less than two years before screening. They will receive daily masitinib (4.5 or 6 mg/kg) or a placebo for nearly a year while continuing Rilutek.

Health Canada rejects masitinib application; reconsideration sought

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

The European Medicines Agency (EMA) is now expected to issue a decision in the first months of 2024 on the conditional approval of <a href="https://alsnewstoday.com/masitinib/">masitinib</a> as an add-on oral therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The deadline extension follows a request, seeking more time, from <a href="https://www.ab-science.com/">AB Science</a>, the therapy&#8217;s developer, to the EMA&#8217;s Committee for Medicinal Products for Human Use, known as CHMP. AB Science had asked for additional time to address a recently implemented EMA guideline regarding product manufacturing.
The CHMP is responsible for evaluating available clinical data and issuing a scientific opinion regarding the approval of medicinal products in Europe; delaying the committee&#8217;s opinion will ultimately delay the agency&#8217;s decision on whether to approve the drug.
&#8220;Based on this updated timetable, the CHMP decision on masitinib marketing authorization in ALS is expected during the first quarter of 2024,&#8221; the company stated in a <a href="https://www.globenewswire.com/news-release/2023/09/18/2745073/0/en/AB-Science-provides-an-update-on-the-EMA-timetable-for-examination-of-the-masitinib-marketing-authorization-application-in-ALS.html">press release</a>.
[recommended-reading id=83944]
<h3>AB Science says its manufacturing process complies with new guidance</h3>
The <a href="https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf">new guidance</a>, implemented by the EMA on July 28, is aimed at all applicants with a marketing authorization application for medications with lab-made or biological active substances. It asks all companies to review their manufacturing processes to identify and reduce the risk of nitrosamine impurities, some of which can lead to cancer.
A conventional stop-clock during a drug review — a period of time that allows applicants to respond to questions from the regulatory authority — is usually 30 days. However, the company noted that such an extension would not be sufficient to evaluate its manufacturing process concerning the risk of nitrosamine formation and make any necessary adjustments to meet the guidelines.
Thus, AB Science had requested an extension, which was accepted during this month&#8217;s CHMP session. So far, according to the company, results from its review have not shown any issues that would derail its application.
&#8220;Based on the current stage of investigations, AB Science is confident that the current manufacturing process of masitinib complies with this new EMA guidance,&#8221; the company wrote.
Masitinib is an oral therapy designed to slow disease progression by reducing the activity of certain immune cells that drive inflammation in ALS.
AB Science&#8217;s application requesting the approval of masitinib is based on data from a <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">Phase 2/3 clinical trial (NCT02588677)</a>, called AB10015. That trial evaluated masitinib as an add-on therapy to <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> (riluzole), an approved ALS treatment, in 394 patients.
Final results from the trial demonstrated that treatment with a 4.5 mg/kg dose of masitinib for nearly one year <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</a> — by 27% — in people with a so-called normal disease progression. Specifically, that means a monthly decline in the ALS Functional Rating Scale-Revised scores of less than 1.1 points.
This higher dose also resulted in slower declines in lung function and quality of life.
While no significant survival differences were observed in the overall population, a significant survival benefit was detected when only people with mild or moderate disease were included in the analysis. In that group, masitinib-treated patients lived more than two years longer than those on Rilutek alone, representing a 44% reduction in the risk of death.
Conditional approval in the EU is granted to medicines that immediately fulfill an unmet medical need — for therapies whose preliminary benefits outweigh their potential risks. If granted, masitinib will be marketed in Europe under the brand name Alsitek.
Still, because a full approval will require confirmatory clinical trials, AB Science already is conducting a global <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">Phase 3 clinical trial (NCT03127267)</a>, called AB19001, to confirm the benefits of adding masitinib to Rilutek.
In that study, about 495 participants will be randomly assigned to take one of two daily doses of masitinib (4.5 or 6 mg/kg), or a placebo, for 48 weeks, or nearly one year. The trial’s main goal is to determine the effect of treatment on disease progression, but its impact on quality of life, lung function, muscle strength, and survival also will be assessed.

Early 2024 eyed for approval decision in EU on masitinib for ALS

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.
[recommended-reading id=21684]
<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.
[recommended-reading id=83581]
<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.

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

<a href="https://alsnewstoday.com/masitinib/">Masitinib</a> as an oral add-on therapy to <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> (riluzole) showed the greatest benefits in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients with mild or moderate disease severity, an analysis of trial data showed.
The findings come from the now-complete <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">AB10015 Phase 2/3 clinical trial (NCT02588677)</a> that excluded people with very severe ALS. Because masitinib is designed to slow disease progression, patients with severe disease were unlikely to benefit from it, <a href="https://www.ab-science.com/">AB Science</a>, the therapy&#8217;s developer, said in a <a href="https://www.globenewswire.com/news-release/2023/04/27/2656847/0/en/AB-Science-Summary-of-the-presentation-on-masitinib-in-ALS-delivered-at-2023-AAN-Annual-Meeting.html">press release</a>.
While the the entire study population showed no survival benefit with masitinib versus a placebo, those with moderate ALS lived significantly longer with masitinib as an add-on treatment. The combined treatment also significantly slowed disease progression and improved lung function and quality of life in those patients without a complete loss of physical function in any activity at the study&#8217;s start.
Details of this new analysis, &#8220;<a href="https://www.ab-science.com/wp-content/uploads/2023/04/AAN2023-Masitinib-VF.pdf">Masitinib Shows Prolonged Survival in Amyotrophic Lateral Sclerosis (ALS) Patients with Mild or Moderate Disease Severity at Baseline</a>,&#8221; were presented at the American Academy of Neurology (AAN) 2023 annual meeting last month.
Masitinib works by blocking the activity of specific tyrosine kinase enzymes that regulate the function of immune cells that cause inflammation. Its intended effect is to slow disease progression and alleviate <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>.
The therapy was evaluated as an add-on treatment to the approved ALS therapy Rilutek in the 48-week AB10015 study and 394 patients were enrolled and assigned to one of two masitinib doses (3 or 4.5 mg/kg) or a placebo given daily for 48 weeks (about 11 months).
Final data showed a daily 4.5 mg/kg dose of masitinib plus Rilutek <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</a> by 27% compared with Rilutek and a placebo. These outcomes occurred in patients with &#8220;normal&#8221; disease progression, defined as a decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores of less than 1.1 points a month.
The combination therapy also led to significantly slower declines in quality of life and lung function in patients progressing normally, but no changes were observed in those progressing faster than normal.
A group analysis suggested initiating masitinib at a less severe stage could result in significant reductions in disease progression in both normal and fast-progressing patients, however.
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<h3>Masitinib with Rilutek slowed disease progression</h3>
The new analysis focused on normally progressing participants with moderate ALS at the start (baseline) — defined as an ALSFRS-R score on every item of at least two points or higher.
In this subgroup, masitinib plus Rilutek significantly slowed progression by 42% versus Rilutek alone. Likewise, moderate patients had a median survival of 69 months with masitinib versus 44 months for placebo-treated patients — a 25-month improvement, representing a 44% reduction in mortality risk.
By comparison, across all trial participants, the median overall survival was 40 months for those given a placebo alone and 46 months with masitinib, a nonsignificant difference.
Researchers also examined the data on ALS patients who hadn&#8217;t yet had a complete loss of physical function, or a zero score on any of the 12 ALSFRS-R components. This analysis included those with normal and fast disease progression, and accounted for about 80% of AB10015 participants.
Using the combined assessment of function and survival (CAFS), a joint measure of survival and disease progression, there was a significant, 18.4% relative benefit in favor of daily 4.5 mg/kg of masitinib than Rilutek alone.
Consistently, ALSFRS-R scores declined 25% less by week 48 in patients receiving masitinib plus Rilutek compared with those given Rilutek alone. A 20.4% reduction was also seen in lung function decline with the combined therapy as well as a 19.8% decline in quality of life measures.
&#8220;Masitinib is most effective in patients with &#8216;moderate ALS&#8217; and prior to any complete loss of function,&#8221; the researchers wrote.
To confirm these findings, AB Science is running the <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">AB19001 Phase 3 clinical trial (NCT03127267)</a>, which expects to enroll up to 495 adults with mild to moderate ALS, diagnosed within the last two years. Participants will be randomly assigned a daily dose of masitinib (4.5 or 6 mg/kg) or a placebo, combined with Rilutek, for 48 weeks.
The trial&#8217;s primary outcome is if masitinib slows disease progression based on ALSFRS-R scores. Secondary measures include changes in lung function, muscle strength, quality of life, CAFS scores, and time to disease progression or death. Top-line results are expected this year.
Masitinib is currently under review for conditional approval in Europe and Canada. A recommendation from Europe&#8217;s Committee for Medicinal Products for Human Use (CHMP) is <a href="https://alsnewstoday.com/news/ema-given-responses-masitinib-conditional-approval-review/">expected in the coming months</a> and the Canadian review <a href="https://alsnewstoday.com/news/health-canada-more-masitinib-data-stops-review/">has been paused</a> after the agency requested more information, which has already been filed by AB Science.

Masitinib works best in moderate ALS, new trial analysis shows

<a href="https://www.ab-science.com/" rel="nofollow">AB Science</a> has submitted its response to the European Medicines Agency (EMA), part of an ongoing review process aiming for the conditional approval of <a href="https://alsnewstoday.com/masitinib/">masitinib</a> as an add-on oral therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The Committee for Medicinal Products for Human Use (CHMP), an arm of the EMA, will assess the answers to questions it had following an initial 120-day review. CHMP then is expected to make a recommendation regarding masitinib&#8217;s conditional approval.
Responses to questions from Health Canada, where the investigative therapy is also under review for conditional approval, will be filed by their April 12 deadline, AB Science said in a <a href="https://www.globenewswire.com/news-release/2023/04/04/2641085/0/en/AB-Science-announces-that-it-has-submitted-its-response-to-the-day-120-questions-in-the-EMA-regulatory-review-of-masitinib-in-amyotrophic-lateral-sclerosis-and-clarifies-the-new-ti.html">company press release</a>. The Canadian regulatory agency <a href="https://alsnewstoday.com/news/health-canada-more-masitinib-data-stops-review/">paused its review of masitinib</a>, asking for more supporting information, late last year.
Conditional approval is given to medicines that fulfill an unmet medical need and whose preliminary benefits outweigh their potential risks. If granted, masitinib will be marketed in Europe under the brand name Alsitek. The therapy&#8217;s full approval requires verification in confirmatory clinical trials.
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<h3>Masitinib tested in combination with Rilutek (riluzole)</h3>
&#8220;The European regulation has provided since 2004 a legislative framework … to support the conditional registration of drugs in incurable diseases when definitive evidence of efficacy is not yet fully met,&#8221; said Sabine Turgeman, executive director of the <a href="https://www.arsla.org/">Association pour la recherche sur la SLA </a>.
&#8220;Conditional registration is the right procedure to accelerate access of new treatments to patients. We urge the EMA to apply maximum regulatory flexibility in the context of ALS, an incurable and fatal degenerative disease,&#8221; Turgeman added.
&#8220;Canadian families living with the devastating disease of ALS and in urgent need of new drug therapies want masitinib to benefit from this conditional registration,&#8221; said Bre Hamilton, executive director of <a href="https://alsactioncanada.org/">ALS Action Canada</a>.
Masitinib is designed to suppress the activity of select tyrosine kinases, enzymes that modulate the function of certain immune cells that drive inflammation in ALS. As such, it is expected to help slow disease progression and ease <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a>.
The therapy was evaluated in the <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">Phase 2/3 clinical trial (NCT02588677)</a>, called AB10015, as an add-on treatment to <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> (riluzole), an approved ALS therapy. Its 394 enrolled patients were randomly assigned to one of two daily masitinib doses (3 or 4.5 mg/kg) or to a placebo, in combination with Rilutek, for about 11 months (48 weeks).
AB10015 met its primary <a href="https://alsnewstoday.com/news/clincal-trial-shows-masitinib-improves-functioning-of-als-patients/">goal of functional gains</a> in masitinib-treated patients, the company reported in 2017. Although the trial did not finish until 2018 and all data was not available for analyses, AB Science asked for masitinib&#8217;s conditional approval in Europe based on interim results.
<a href="https://alsnewstoday.com/news/ema-issues-negative-opinion-masitinib-conditional-marketing-authorization/">CHMP issued a negative opinion</a>, not supporting conditional approval, in 2018, and the company decided <a href="https://alsnewstoday.com/news/ab-science-not-pursuing-ema-reexamination-marketing-approval-masitinib-als-treatment/">not to pursue further</a> an EMA application at that time.
Its recent <a href="https://alsnewstoday.com/news/masitinib-again-under-review-eu-potential-als-treatment/">EMA application for masitinib</a>, accepted in 2022, includes final trial results, demonstrating that Rilutek plus masitinib at its higher dose <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</a> in patients with “normal” disease progression by 27% compared with Rilutek alone, meeting the study&#8217;s main efficacy goal. Reasonable safety also was found.
Normal disease progression was defined as a monthly decline in ALS Functional Rating Scale–Revised (ALSFRS-R) scores of less than 1.1 points. The combination therapy also slowed declines in quality of life and lung function in patients randomized to masitinib at 4.5 mg/kg daily.
<h3>Ongoing Phase 3 trial aims to confirm benefits reported in earlier study</h3>
In the overall trial population, no significant differences were observed in survival. Median overall survival was 37 months for patients on Rilutek alone and 33 months for those also given masitinib.
But after adjusting the analysis to include only patients with mild or moderate disease — those with at least two points or higher on every ALSFRS-R item at the study’s start — researchers found significant survival benefits.
In this group, patients on masitinib lived for a median of 69 months, compared with 44 months for those on a placebo. This resulted in a median survival difference of 25 months, representing a 44% reduction in the risk of death.
AB Science now aims to confirm the combination&#8217;s benefits in AB19001, an ongoing and global <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">Phase 3 clinical trial (NCT03127267)</a>. It is enrolling or has enrolled up to 495 adults diagnosed within the last two years with normal ALS progression and mild to moderate disease.
Participants are randomized to Rilutek in combination with either masitinib, at a daily dose of 4.5 or 6 mg/kg, or a placebo for 48 weeks.
The trial&#8217;s main goal is to determine whether masitinib slows disease progression based on ALSFRS-R score declines over those weeks. Secondary goals include changes in quality of life, lung function, and muscle strength, a combined assessment of function and survival, and time to disease progression or death. Top-line data is expected later this year.
&#8220;Masitinib is one of the most promising drugs in ALS that has just been submitted to the EMA conditional approval process,&#8221; said Olivier Goy, co-founder and president of October, a European finance company. &#8220;I strongly support drugs that are submitted for conditional approval, especially when they have complementary mechanisms of action.&#8221;

EMA receives response for ongoing review of masitinib in treating ALS

<a href="https://alsnewstoday.com/masitinib/">Masitinib</a>, an oral medicine developed by <a href="https://www.ab-science.com/">AB Science</a>, has won orphan drug status for treating <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in Switzerland.
The status is granted by the Swiss Agency for Therapeutic Products (Swissmedic) to therapies that seek to treat life-threatening or chronic diseases affecting no more than five in every 10,000 people in Switzerland.
It provides a range of incentives to accelerate a therapy&#8217;s development, including streamlining the approval process, fee waivers, and a 15-year document protection period compared with the standard 10-year period.
“We are pleased to be granted orphan drug status for masitinib from Swissmedic,” Olivier Hermine, MD, president of the scientific committee of AB Science, said in a <a href="https://www.globenewswire.com/news-release/2022/12/27/2579973/0/en/Masitinib-receives-orphan-drug-status-for-the-treatment-of-amyotrophic-lateral-sclerosis-in-Switzerland.html">company press release</a>. “This represents another important step in our progress and commitment to provide a new treatment option to ALS patients internationally.&#8221;
Hermine is also a professor of hematology at Descartes University and chief of adult hematology at Necker Hospital in Paris, France.
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Masitinib is a small molecule that works by blocking certain tyrosine kinase proteins needed for the activity of microglia and mast cells, two immune cell types thought to contribute to the nerve cell damage that’s behind the <a href="https://alsnewstoday.com/symptoms-of-als-2/">symptoms of ALS</a>.
The therapy has been investigated in a Phase 2/3 clinical trial, called <a href="https://clinicaltrials.gov/ct2/show/NCT02588677">AB10015 (NCT02588677)</a>, as an add-on to the approved ALS treatment <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek (riluzole)</a>. A total of 394 ALS patients were randomly assigned to receive one of two masitinib doses (3.0 or 4.5 mg per kg per day) or a placebo, in addition to Rilutek, for about 11 months.
Results showed the higher dose <a href="https://alsnewstoday.com/news/add-on-masitinib-slows-progression-of-als-final-phase-2-3-trial-results-show/">significantly slowed disease progression by 27%</a> in the patients with normal disease progression, defined as a monthly decline in ALS Functional Rating Scale–Revised (ALSFRS-R) of less than 1.1 points a month. Masitinib also slowed quality of life and lung function declines.
These benefits are now being confirmed in an ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT03127267">Phase 3 clinical trial (NCT03127267)</a> called AB19001. It aims to include up to 495 adults diagnosed in the last two years who will receive a 4.5 or 6 mg/kg daily dose of masitinib, or a placebo, also with Rilutek.
The main goal is to determine whether masitinib slows disease progression over 48 weeks (almost a year) and how safe it is versus a matched placebo.
AB19001 was put on hold for some time due to concerns about a potential risk of heart-related complications as a treatment side effect. After a change in the trial’s protocol to include closer heart health monitoring, AB Science is has been cleared to <a href="https://alsnewstoday.com/news/phase-3-trial-of-masitinib-in-slowing-progression-again-enrolling-in-us/">resume enrollment in the U.S.</a> and <a href="https://alsnewstoday.com/news/als-patient-enrollment-resumes-masitinib-trials-european-sites/">some countries in Europe</a>.
The medicine has already won <a href="https://alsnewstoday.com/news/fda-grants-orphan-drug-status-to-ab-sciences-masitinib-drug-for-als/">orphan drug status in the U.S.</a> and <a href="https://alsnewstoday.com/news/ab-science-potential-als-treatment-masitinib-named-orphan-drug-by-ema/">European Union</a>, where an application for its conditional approval is <a href="https://alsnewstoday.com/news/masitinib-again-under-review-eu-potential-als-treatment/">under review</a>. If approved, the therapy will be marketed in Europe under the name Alsitek.

Tag: masitinib