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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>.
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<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

<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;

Tag: EMA

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

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