A SUPER-powered WP Engine Atlas Test Site

Joe&#039;s Atlas Experimentation Site

In a nearly unanimous vote, an advisory committee to the U.S. Food and Drug Administration (FDA) said there&#8217;s not enough evidence to support the efficacy of the experimental stem cell therapy <a href="https://alsnewstoday.com/nurown/">NurOwn</a> as a treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The committee voted on a single question in its meeting: &#8220;Do the data presented demonstrate substantial evidence of effectiveness for treatment of mild to moderate ALS?&#8221;
In all, 17 of the 19 committee members voted no. There was one yes vote and one abstention.
An <a href="https://alsnewstoday.com/news/fda-final-approval-decision-brainstorms-nurown-als-due-december/">official decision from the FDA</a> on NurOwn is set to be handed down in December. The regulatory agency is not obligated to abide by the committee&#8217;s vote, but it usually does.
&#8220;The discussion in today&#8217;s advisory committee meeting, and the heartrending testimony of those living with ALS and their loved ones, underscores not only the need for regulatory flexibility but also for continuing research in the field,&#8221; Chaim Lebovits, president and CEO of <a href="https://brainstorm-cell.com/" rel="nofollow">BrainStorm Cell Therapeutics</a>, NurOwn&#8217;s developer, said in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-provides-update-on-fda-advisory-committee-meeting-to-review-nurown-for-the-treatment-of-als-301941169.html">company press release</a>, adding, &#8220;The people of BrainStorm will do everything in our power to fulfill the obligation we deeply feel we owe to the ALS community, and in the coming weeks we will explore all options available to us.&#8221;
[recommended-reading id=85498]
<h3>FDA found no evidence of so-called floor effect in trial</h3>
NurOwn is a cell-based therapy that involves harvesting stem cells from a patient&#8217;s bone marrow, engineering them in a laboratory so they secrete molecules that promote nerve health, and then infusing the cells back into the patient&#8217;s spine.
Following a decade of testing, BrainStorm submitted an application to the FDA last year seeking approval of NurOwn in the U.S. The agency initially <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused to review</a> the application, saying there was not enough evidence to support an approval.
However, but BrainStorm forced a new review and an advisory committee meeting using the <a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">FDA’s “file over protest” procedure</a>.
BrainStorm&#8217;s application includes data from several clinical trials, including a large <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 study (NCT03280056)</a> that tested NurOwn against a placebo in 189 people with rapidly-progressing ALS.
The study aimed to show that NurOwn could slow the progression of the disease, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), a standardized measure that assesses a person&#8217;s ability to perform activities of daily living. But final results showed <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">no difference in progression</a> between patients given NurOwn or a placebo.
The company argued that this might be due to a so-called <a href="https://alsnewstoday.com/news/mda-2023-issues-als-scale-noted-nurown-trial-failure-analysis/">floor effect</a> —  where some patients had ALSFRS-R scores so low that they couldn&#8217;t meaningfully get lower.
In post hoc analyses done once the study was over, the company analyzed only subsets of patients expected not to have a floor effect. Those results <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">generally suggested</a> slower disease progression with NurOwn compared with a placebo.
In briefing documents put out before the committee meeting, the FDA said it <a href="https://alsnewstoday.com/news/fda-questions-nurown-efficacy-quality-ahead-advisory-panel/">did not find evidence</a> of a floor effect in the patients that BrainStorm had flagged. The agency also cautioned that post hoc analyses are heavily prone to false-positive results, and, overall, reiterated its stance that there are not enough data to support an approval of NurOwn.
[quote=&#8221;center&#8221;]The committee&#8217;s vote was a sad outcome for the ALS community, who have too few options to help manage this merciless and deadly disease.[/quote]
The advisory committee has now strongly voted that the available data are not enough to demonstrate that NurOwn is effective in ALS — a decision that further supports a potential rejection by the FDA.
&#8220;The committee&#8217;s vote was a sad outcome for the ALS community, who have too few options to help manage this merciless and deadly disease,&#8221; said Stacy Lindborg, PhD, co-CEO of BrainStorm.
&#8220;We firmly believe that the totality of data presented for NurOwn today provide a compelling case for approval, with clinical evidence in those with less advanced disease supported by strong and consistent biomarker data that are predictive of clinical response,&#8221; Lindborg said.
Lindborg suggested that too little time was given during the meeting for BrainStorm to answer all of the committee&#8217;s questions.
&#8220;We truly did our best to make the NurOwn data clear to the FDA advisory committee. Unfortunately, had more time and opportunity been allowed, many remaining questions posed by advisory committee members could have been sufficiently addressed,&#8221; Lindborg said.

FDA advisory committee votes against NurOwn approval for ALS

The U.S. Food and Drug Administration (FDA) has shared its major concerns with data available for <a href="https://alsnewstoday.com/nurown/">NurOwn</a>, <a href="https://brainstorm-cell.com/" rel="nofollow">BrainStorm Cell Therapeutics</a>‘ experimental stem cell therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
According to a new <a href="https://www.fda.gov/media/172403/download">briefing document</a> put out by the FDA, the agency believes that currently available clinical data do not provide substantial evidence to support NurOwn&#8217;s effectiveness in people with ALS. It also raised concerns about whether BrainStorm can reliably manufacture the therapy.
The document was released in advance of an FDA advisory committee meeting on NurOwn&#8217;s efficacy, set to take place today, Sept. 27.
[recommended-reading id=86692]
<h3>BrainStorm: &#8216;Floor effect&#8217; reason for NurOwn failure in Phase 3 ALS trial</h3>
NurOwn treatment involves harvesting mesenchymal stem cells (MSCs) from a patient’s bone marrow. The stem cells are engineered in a laboratory so that they secrete high levels of signaling molecules that promote nerve cell growth. Then, the cells are returned to the patient through injections into the spinal canal.
Late last year, the FDA <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused to consider BrainStorm&#8217;s application</a> seeking approval of NurOwn as a <a href="https://alsnewstoday.com/approved-treatments-for-als/">treatment for ALS.</a>
The company then used the <a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">FDA&#8217;s &#8220;file over protest&#8221; procedure</a> to ask the agency to review the application anyway, and a final agency decision on <a href="https://alsnewstoday.com/news/fda-final-approval-decision-brainstorms-nurown-als-due-december/">NurOwn is expected in December</a>.
At the advisory committee meeting, a panel of experts will review available data on NurOwn and offer a recommendation to the FDA. The panel has two questions to address: Do data submitted in support of NurOwn amount to &#8220;substantial evidence of effectiveness meeting the approval standard&#8221;? If not, discuss &#8220;potential designs&#8221; needed in a future trial to produce such evidence.
The FDA isn&#8217;t bound to abide by advisory committee opinions, but it usually follows them.
In its briefing document, the FDA reiterated a major concern it had voiced when it originally refused to consider BrainStorm&#8217;s application for NurOwn: Currently available clinical trial data don&#8217;t show the therapy works to slow ALS progression as intended.
BrainStorm sponsored a <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 clinical trial (NCT03280056)</a> that compared NurOwn against a placebo in 189 people with rapidly progressing ALS.
The trial hoped to show that NurOwn slowed disease progression, as measured by changes over time in a measure of disease severity called the ALS Functional Rating Scale-Revised (ALSFRS-R).
However, the <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">study failed to show a significant difference</a> between patients given NurOwn or a placebo. Other measures of disease progression also generally did not show differences between the two groups.
BrainStorm has argued that the trial&#8217;s negative results might be explained by a <a href="https://alsnewstoday.com/news/mda-2023-issues-als-scale-noted-nurown-trial-failure-analysis/">&#8220;floor effect&#8221;</a> associated with the ALSFRS-R scale. Some patients with more advanced disease, it argued, may have had ALSFRS-R scores so low that they couldn&#8217;t meaningfully get lower, so statistical analyses were unable to accurately capture disease progression in these patients.
The company conducted post hoc analyses — statistical tests designed and run after the trial ends and all data have been collected — where researchers either excluded patients with the potential for a floor effect or included only those with less advanced disease. These analyses were generally positive, suggesting that <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">NurOwn slowed disease progression</a> compared with a placebo.
<h3>FDA questions &#8216;floor effect&#8217; and other findings meant to show NurOwn efficacy</h3>
According to the FDA, however, these analyses aren&#8217;t enough to show the therapy is effective. For one thing, the agency notes that post hoc analyses like these &#8220;in general have high risk of finding false positive results,&#8221; because the tests are being done on data that are already available.
&#8220;Such exploratory analyses provide little confidence on which to base regulatory decisions, and though they may serve to generate hypotheses for testing in future trials, cannot compensate for negative results in a well-controlled study,&#8221; the FDA wrote.
Moreover, the agency says that in its analysis of the data, it did not find evidence of a &#8220;floor effect.&#8221; If such an effect were present, it would be expected that ALSFRS-R scores would plateau when they couldn&#8217;t get lower.
In the FDA&#8217;s analysis, these scores tended to continuously change over the course of the trial, even for patients who BrainStorm flagged as having a &#8220;floor effect.&#8221; In fact, data suggest that ALSFRS-R scores tended to worsen slightly more quickly for patients given NurOwn than a placebo, and the overall change in scores was comparable between the two groups.
Collectively, these data show &#8220;the lack of efficacy of [NurOwn] over placebo cannot be explained by a floor effect,&#8221; the FDA document states.
The agency also noted that, over the course of the six-month trial, 10 patients given NurOwn died, as compared with three given a placebo. While the trial was not designed to assess survival, the agency said this finding &#8220;suggests the lack of efficacy of [NurOwn] on survival of patients with ALS.&#8221;
<h3>FDA concerns about manufacturing consistency and quality for NurOwn</h3>
In addition to concerns about NurOwn&#8217;s efficacy, the FDA also raised concerns about BrainStorm&#8217;s ability to consistently manufacture the therapy. According to the FDA, BrainStorm has failed to demonstrate that it can consistently produce the modified stem cells used for NurOwn, noting that the number of cells produced, as well as the amount of signaling molecules the cells make, has varied across lots for reasons that aren&#8217;t clear.
&#8220;FDA has concerns about the consistency of the manufacturing process and potential sources of product variability,&#8221; the agency wrote.
The briefing document notes that an evaluation of BrainStorm&#8217;s manufacturing and quality control data still is ongoing, and the upcoming advisory committee meeting will focus mainly on questions about the therapy&#8217;s demonstrated efficacy in clinical trials.
<div class="page" title="Page 7">
<div class="layoutArea">
<div class="column">
&#8220;FDA recognizes the urgent unmet need for additional effective treatments for ALS. At the same time, the critical statutory requirements for approval of drugs and biologics include substantial evidence of effectiveness and evidence of safety, and demonstration of adequate product quality,&#8221; it writes.
&#8220;At this advisory committee meeting FDA is seeking to obtain input from the committee as to whether the available data can be considered to constitute substantial evidence of effectiveness to support regulatory approval of [NurOwn] for treatment of ALS.&#8221;
</div>
</div>
</div>

FDA questions NurOwn’s efficacy, quality ahead of today’s hearing

The U.S. Food and Drug Administration (FDA) will hold an advisory committee meeting to discuss <a href="https://brainstorm-cell.com/">BrainStorm Cell Therapeutics</a>&#8216; application to approve <a href="https://alsnewstoday.com/nurown/">NurOwn</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Such a meeting, called an ADCOM, is normally for when a therapy is under regulatory review so experts can discuss its potential merits. The meeting is an independent review and the regulatory agency may or may not follow the committee&#8217;s recommendation.
While BrainStorm filed a biologics license application (BLA) in September for NurOwn&#8217;s approval, the FDA <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused</a> to review it due to insufficient evidence of its benefits.
With the BLA seemingly shut down, it wasn&#8217;t clear if an ADCOM would be scheduled. BrainStorm has utilized a &#8220;file over protest&#8221; procedure, however, meaning it will proceed with the application over the FDA&#8217;s objection, making an ADCOM attainable.
The application, which the company says has been amended to address most of the agency&#8217;s concerns, will be before the FDA&#8217;s Center for Biologics Evaluation and Research.
&#8220;The FDA provided us with more than one path to an ADCOM for NurOwn,&#8221; Chaim Lebovits, president and CEO of BrainStorm, said in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-fda-advisory-committee-meeting-to-review-biologics-license-application-for-nurown-for-the-treatment-of-als-301781735.html">company press release</a>. &#8220;Our goal has always been to make NurOwn available to people living with ALS as quickly as possible, therefore we chose the File Over Protest pathway since this offered the fastest path to an ADCOM and regulatory decision relative to other pathways provided by the FDA &#8230; we firmly believe our data support regulatory approval of NurOwn.&#8221;
The stem cell-based therapy was evaluated in a <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 trial (NCT03280056)</a> of 189 adults with rapidly progressing ALS, but it <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed</a> to meet its main efficacy goal of slowing disease progression relative to a placebo.
At that time, the FDA said there <a href="https://alsnewstoday.com/news/nurown-showed-no-benefit-over-placebo-in-als-clinical-trial-fda-states/">wasn&#8217;t enough data</a> to support a regulatory application.
[recommended-reading id=81517]
<h3>Brainstorm: Efficacy results skewed by advanced disease patients</h3>
BrainStorm later argued the trial contained a large number of patients with advanced disease, which may have obscured NurOwn&#8217;s benefits.
These advanced patients often had some of the lowest possible scores on subscales of the ALS Functional Rating Scale-Revised (ALSFRS-R) when they enrolled, meaning there was no room to detect meaningful disease progression changes.
That assertion was supported by <a href="https://alsnewstoday.com/news/nurown-continues-show-benefit-rapidly-advancing-als/">additional analyses</a> that showed NurOwn could meaningfully and significantly <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">slow disease progression</a> when the severely affected participants were excluded.
With that data in hand, BrainStorm filed a new application, but the FDA declined to review it, citing a lack of “substantial evidence” of efficacy, in addition to <a href="https://alsnewstoday.com/news/fda-grants-jan-11-meeting-discuss-nurown-future-als-brainstorm/">concerns related to chemistry, manufacturing and quality control</a>.
BrainStorm then <a href="https://alsnewstoday.com/news/brainstorm-files-fda-meeting-new-bid-nurown-approval/">requested</a> a Type A meeting with the FDA, with a main goal of securing an ADCOM as quickly as possible. That meeting was held in January.
&#8220;Securing an ADCOM represents an important step towards our goal of making NurOwn broadly available to individuals living with ALS who are in urgent need of new, effective therapies,&#8221; said Stacy Lindborg, PhD, Brainstorm&#8217;s co-CEO.
The ADCOM meeting would serve as &#8220;an open forum for BrainStorm and the FDA, together with medical experts, statisticians, and the ALS community, to thoughtfully review all available evidence supporting NurOwn,&#8221; Lindborg said.
The FDA&#8217;s resistance to reviewing NurOwn was criticized by the ALS community, with two separate patient groups <a href="https://alsnewstoday.com/news/veterans-als-seek-fda-meeting-discuss-nurown-therapy-benefits/">calling</a> for an ADCOM within weeks of the FDA&#8217;s refusal to file.
&#8220;It is critical for all ALS treatments that they be given the chance to proceed to an ADCOM,&#8221; said Brian Wallach, a patient advocate and founder of nonprofit <a href="https://iamals.org/">I AM ALS</a>. &#8220;The ALS community has waited years for this ADCOM. It is time to let the science have a full, fair, and transparent hearing so that we can get this treatment to people who are living with and dying from ALS as soon as possible.&#8221;
A date for the ADCOM has not been set.

Tag: FDA advisory committee

FDA advisory committee votes against NurOwn approval for ALS

FDA questions NurOwn’s efficacy, quality ahead of today’s hearing

BrainStorm nets NurOwn ADCOM meeting over FDA objections