A SUPER-powered WP Engine Atlas Test Site

Joe&#039;s Atlas Experimentation Site

Note: This story was updated March 6, 2024, to correct the poster was presented by Brainstorm’s executive vice president and chief development officer Bob Dagher.
A pivotal, Phase 3b clinical trial is planned to test the cell-based therapy <a href="https://alsnewstoday.com/nurown/">NurOwn</a> (debamestrocel) in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the treatment&#8217;s developer, <a href="https://brainstorm-cell.com" rel="nofollow">Brainstorm Cell Therapeutics</a>, announced.
The study&#8217;s design, based on positive findings from a previous Phase 3 trial in patients with less advanced disease, is under U.S. Food and Drug Administration (FDA) review.
In that earlier trial, NurOwn was seen to <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">significantly slow disease progression</a> in people with less severe ALS, but it failed at the study&#8217;s main goal of slowing progression across all treated patients. An FDA committee later decided that trial data were <a href="https://alsnewstoday.com/news/fda-advisory-committee-votes-not-enough-efficacy-nurown-als/">insufficient to support NurOwn&#8217;s effectiveness</a> in ALS.
&#8220;We are committed to doing everything we can to make NurOwn available to ALS patients in need,&#8221; Chaim Lebovits, Brainstorm&#8217;s president and CEO, said in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-to-unveil-phase-3b-nurown-trial-design-at-mda-clinical-and-scientific-conference-302072354.html">company press release</a>.
[recommended-reading id=90176]
<h3>NurOwn, a cell therapy, showed potential in people with less advanced ALS</h3>
The company anticipates that the Phase 3b trial will confirm NurOwn&#8217;s benefits in this patient group, potentially supporting a new application requesting the therapy&#8217;s approval for people with mild-to-moderate ALS.
&#8220;The Phase 3b trial takes into account learning from NurOwn’s clinical development program, in addition to the latest insight from the ALS community,&#8221; Stacy Lindborg, co-CEO of Brainstorm, said in a statement to ALS News Today.
&#8220;We’ve simulated the operating characteristics of the trial and are confident this trial is a robust design which will rigorously assess the efficacy and safety of NurOwn,&#8221; she added.
Brainstorm reported <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-submits-special-protocol-assessment-spa-request-to-fda-for-phase-3b-trial-of-nurown-in-als-302069799.html" rel="nofollow">submitting a special protocol assessment (SPA)</a> for the trial to the FDA in late February. An SPA is used to request FDA review of a trial&#8217;s planned design to help ensure that positive results could feasibly support an application for therapy approval.
&#8220;We are grateful for the FDA&#8217;s ongoing engagement and look forward to its feedback and to finalizing the SPA,&#8221; Bob Dagher, MD, Brainstorm&#8217;s executive vice president and chief development officer, said in the release.
Details of the Phase 3b trial will be finalized following the FDA&#8217;s review and response. In the meantime, Dagher presented the planned study design at the Muscular Dystrophy Association&#8217;s 2024 Clinical and Scientific Conference, detailed in the poster &#8220;<a href="https://www.mdaconference.org/abstract-library/design-of-a-phase-3b-trial-of-debamestrocel-in-als/">Design of A Phase 3B Trial of Debamestrocel in ALS</a>.&#8221;
<h3>Planned yearlong trial to enroll 200 people with mild-to-moderate ALS</h3>
This yearlong, two-part study is expected to recruit about 200 adults, ages 18 to 75, with mild-to-moderate disease and <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptom</a> onset less than two years before enrolling. Eligible participants also need to meet certain criteria surrounding physical function and breathing ability, and patients using approved <a href="https://alsnewstoday.com/als-treatment/">ALS treatments</a> must be on a stable dose before a screening for the trial.
In its planned first part, patients will be randomly assigned to NurOwn treatment or a placebo for about six months (24 weeks) while remaining on standard care. In a second part, all enrolled will be treated with NurOwn for another six months. Both placebo and NurOwn will be given by injection into the spine canal (intrathecal injection) every eight weeks.
The planned study&#8217;s main goal will be determining if NurOwn slows patients&#8217; loss of functional abilities, as measured by changes from the trial&#8217;s start in Revised ALS Functional Rating Scale (ALSFRS-R) scores. It also plans to assess changes in measures of muscle strength and breathing ability, as well as survival outcomes.
Patients will be asked to complete a questionnaire on their health status and life quality, and interviews will be conducted with caregivers of participants.
&#8220;The planned study will enroll patients earlier in their disease course, as we believe that this is the appropriate patient population in which the course of the disease can be accurately measured using ALSFRS-R,&#8221; Dagher said.
NurOwn treatment involves collecting mesenchymal stem cells from a patient&#8217;s bone marrow and engineering them in a lab to secrete high levels of neurotrophic factors, signaling molecules that promote nerve health. The modified stem cells then are injected into the patient&#8217;s spinal canal, with the goal of slowing the progressive nerve damage that <a href="https://alsnewstoday.com/causes-of-als/">causes ALS</a>.
The earlier <a href="https://clinicaltrials.gov/study/NCT03280056">Phase 3 trial (NCT03280056)</a>, which ended in 2020, tested NurOwn against a placebo in 189 adults with rapidly progressing ALS, most of whom had advanced disease. Although <a href="https://alsnewstoday.com/news/nurown-continues-show-benefit-rapidly-advancing-als/">some promising trends</a> were seen in patients with less severe disease, the study overall <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed to show</a> a statistically significant difference in disease progression rates between patients on NurOwn and those given a placebo.
<h3>FDA, advisory group found efficacy data lacking in previous approval requests</h3>
Brainstorm <a href="https://alsnewstoday.com/news/brainstorm-plans-filing-nurown-approval-us-corrected-data/">applied to the FDA for NurOwn&#8217;s approval</a> in 2022, hoping that analyses showing beneficial Phase 3 trends would be enough to support treatment efficacy. The FDA initially <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused to consider the application</a>, citing insufficient data.
Brainstorm then used a procedure called <a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">file over protest</a> to seek a review from an FDA advisory committee. But that committee also decided that available data were not enough to support therapy effectiveness, and Brainstorm <a href="https://alsnewstoday.com/news/brainstorm-drops-application-nurown-als-regroup/">withdrew its application</a> in October.
Since then, the company has been <a href="https://alsnewstoday.com/news/brainstorm-fda-map-out-next-steps-nurown-phase-3b-testing/">working with the FDA</a> on the design of a confirmatory Phase 3b trial — planned to enroll patients at sites across the U.S. — that it hopes will provide the evidence needed for NurOwn&#8217;s approval.
&#8220;We have given careful consideration to a Phase 3b trial that will conclusively demonstrate the efficacy and safety of NurOwn and support a new [application seeking FDA approval],&#8221; Dagher said.
&#8220;Our previous studies have provided us with valuable insight into the NurOwn treatment effect,&#8221; he added. &#8220;We believe that by incorporating these learnings into the design of a confirmatory study we can maximize the prospects of a successful outcome.&#8221;

MDA 2024: Planned Phase 3b trial aims to support NurOwn’s approval

<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.
[recommended-reading id=81407]
<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.

Tag: Mild-to-Moderate ALS

MDA 2024: Planned Phase 3b trial aims to support NurOwn’s approval

Masitinib works best in moderate ALS, new trial analysis shows