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<a href="https://brainstorm-cell.com/">BrainStorm Cell Therapeutics</a> is withdrawing the application requesting U.S. approval of its cell-based therapy <a href="https://alsnewstoday.com/nurown/">NurOwn</a> for the treatment of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The decision comes on the heels of a recent U.S. Food and Drug Administration (FDA) advisory committee meeting, in which experts ruled nearly unanimously that available data for the experimental therapy <a href="https://alsnewstoday.com/news/fda-advisory-committee-votes-not-enough-efficacy-nurown-als/">does not provide enough evidence</a> to support its effectiveness in ALS.
While an official decision from the FDA was expected in December, the withdrawal of the biological license application (BLA) means the agency no will longer review the data. BrainStorm has coordinated its decision to withdraw the BLA with the FDA, which regards the move as a withdrawal without prejudice for a future refiling.
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Meanwhile, the regulatory agency invited the company to request an expedited face-to-face meeting to discuss the next steps for NurOwn&#8217;s development. The company intends to use the meeting to explore a number of approaches, including the publication of emerging clinical data and an additional Phase 3b clinical study.
&#8220;After exploring possible options, we have reached this conclusion that the only path forward of NurOwn for ALS is to conduct another trial. Therefore, we&#8217;re withdrawing our BLA,&#8221; Chaim Lebovits, president and CEO of BrainStorm, said in a <a href="https://www.webcaster4.com/Player/Index?webcastId=49296&amp;g=824e82b3-5502-4572-b94f-9050e434ebcc&amp;uid=6296598&amp;sid=">company webcast</a> announcing the decision.
&#8220;We&#8217;re accepting [the] FDA&#8217;s invitation to have a face-to-face discussion on a Phase 3b trial, with the aim to reach an agreed-upon trial design,&#8221; he added. &#8220;We recognize the need to align with the FDA and will do all we can to deliver a valuable treatment option to the ALS community.&#8221;
Based on data from the earlier <a href="https://clinicaltrials.gov/study/NCT03280056">Phase 3 clinical trial (NCT03280056)</a>, the upcoming study &#8220;likely&#8221; will focus on a mild or less advanced patient population, said Stacy Lindborg, PhD, co-CEO of BrainStorm.
<h3>How NurOwn works</h3>
NurOwn is a cell-based therapy that involves collecting a patient’s stem cells from the bone marrow, engineering them in a laboratory so they produce high levels of signaling molecules that promote nerve health and growth, and then returning the modified cells directly to the patient through an injection into the spine.
A completed Phase 3 trial was designed to study the therapy against a placebo in a group of 189 people with rapidly-progressing ALS.
The trial <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed to meet its primary goal</a> of showing that NurOwn could slow disease progression on the ALS Functional Rating Scale-Revised (ALSFRS-R) scale. But additional analyses showed it could slow the decline in that scale in a group of patients with less-advanced disease.
This prompted BrainStorm to submit the data to the FDA back in 2021, at which point the agency, citing lack of clinical evidence, <a href="https://alsnewstoday.com/news/nurown-trial-data-lacking-brainstorm-fda-approval-review/">discouraged the filing</a> of a regulatory application.
Later findings from the company showed that the lack of a significant effect could be attributable to a so-called <a href="https://alsnewstoday.com/news/mda-2023-issues-als-scale-noted-nurown-trial-failure-analysis/">floor effect</a>, where patients in the trial had such advanced disease that scores could not decrease even further as the disease progressed. That meant a slowdown in disease decline would not be detected.
In line with this, an analysis focusing only on patients with less-severe disease, which were not expected to be affected by this floor effect, suggested that NurOwn <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">could slow disease progression</a>, compared with a placebo.
This time, <a href="https://alsnewstoday.com/news/brainstorm-plans-filing-nurown-approval-us-corrected-data/">the company submitted an application</a> in August 2022, which the FDA <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused to consider</a> in November of that year. Still, BrainStorm decided to &#8220;<a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">file over protest</a>,&#8221; which granted it an advisory committee meeting where experts reviewed not only the clinical data, but also reports of patient and clinician experiences with NurOwn.
The committee, however, <a href="https://alsnewstoday.com/news/fda-questions-nurown-efficacy-quality-ahead-advisory-panel/">failed to detect evidence of a floor effect</a> in the trial, and cautioned that the analyses conducted after the trial ended are highly prone to false-positive results. That led to a 17-to-1 vote that the available clinical evidence was not enough to support the benefits of NurOwn in ALS patients.
&#8220;We are confident in the data supporting the value of NurOwn as an addition to the options for treating ALS, and we have every desire to bring it to the ALS community,&#8221; Lebovits said in a company <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-to-meet-with-us-fda-to-discuss-development-plan-for-nurown-as-a-treatment-of-als-301960219.html">press release</a>.
<h3>Pivotal trial in the offing</h3>
&#8220;We look forward to working with the FDA to define the path forward. We understand that an additional pivotal trial will be necessary, and we are doing everything in our power to execute on this as quickly as possible,&#8221; he added.
The withdrawal also enables BrainStorm to finally tell patients who participated in the trial whether they were initially given a placebo or the cell therapy, the company said on the webcast.
&#8220;Information regarding randomization will be provided to the principal investigators at each of the clinical sites, who will provide information directly to participants and their families,&#8221; said Lindborg.

BrainStorm drops FDA application for NurOwn

A final decision by the U.S. Food and Drug Administration (FDA) on whether or not to approve <a href="https://alsnewstoday.com/nurown/">NurOwn</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is now expected no later than Dec. 8.
But before that, on Sept. 27, an FDA advisory committee will meet to review the potential benefits of the <a href="https://brainstorm-cell.com/">BrainStorm Cell Therapeutics</a> experimental cell therapy, according to a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-fda-advisory-committee-meeting-to-review-nurown-biologics-license-application-scheduled-for-september-27-2023-301843416.html">company press release</a>. That ADCOM meeting, to be held by the agency’s Cellular, Tissue and Gene Therapies Advisory Committee, will be available for live streaming.
The committee will provide the FDA with an independent recommendation for its use in considering regulatory approval for the ALS therapy candidate. However, the agency is not required to follow the committee&#8217;s recommendation.
The ADCOM meeting comes after the agency <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused to review</a> a biologics license application (BLA) for NurOwn, filed by BrainStorm in September 2022, due to a lack of strong evidence of the therapy&#8217;s benefits in clinical trials. Brainstorm says that application now has been amended to address most of the FDA’s concerns.
“We remain confident in NurOwn and believe our data support regulatory approval,” said Stacy Lindborg, PhD, co-CEO at BrainStorm, adding, &#8220;As is the case with most ALS research, our clinical program generated complex results, which deserve a thoughtful and holistic review by scientists, ALS experts, FDA reviewers, advocates, and patients.&#8221;
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<h3>ADCOM meeting set for NurOwn after Brainstorm&#8217;s file over protest</h3>
BrainStorm was granted the ADCOM meeting <a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">after its use of the FDA&#8217;s &#8220;file over protest&#8221; procedure</a> following the rejection of the BLA. As its name suggests, the file over protest procedure means that a company proceeds with filing a regulatory application despite the agency’s objection, which makes an advisory committee meeting possible.
Patient groups also <a href="https://alsnewstoday.com/news/als-patients-given-nurown-call-fda-meeting-discuss-refusal/">had called</a> for an ADCOM meeting after the FDA’s refusal to review NurOwn’s BLA. Five individuals with ALS treated in the NurOwn clinical trials and two family members of patients who died from the rare disorder had sent a written letter to the FDA in support of such a meeting.
“We believe this approach honors the needs of those living with ALS and offers the greatest promise for BrainStorm to fulfill our commitment to the ALS community,” Lindborg said of the upcoming meeting.
[quote align=&#8221;center&#8221;]We are encouraged by the regulatory flexibility that the FDA has shown over the last year in ALS broadly, and with respect to NurOwn in particular, and believe an Advisory Committee meeting is good for patients.[/quote]
NurOwn is a cell-based therapy in which mesenchymal stem cells — which can give rise to a variety of cell types — are harvested from a patient’s bone marrow and matured in the lab into cells that produce large amounts of signaling molecules that promote nerve cell health and growth.
The modified cells are then injected into the patient’s spinal canal to promote and support nerve cell repair, which is expected to help slow disease progression.
A <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 clinical trial (NCT03280056)</a>, completed in 2020, had tested NurOwn in patients with rapidly progressing ALS, who were given three injections of either the therapy or a placebo two months apart. The trial involved 189 adults followed for 28 weeks, or about seven months.
The results showed that NurOwn <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">was not significantly more effective than a placebo</a> at slowing disease progression, measured by the ALS functional rating scale (ALSFR-R). But according to BrainStorm, this was likely due to a large proportion of trial participants with advanced ALS — a population that already has the lowest scores in some ALSFR-R subscales.
Brainstorm said that the participants&#8217; advanced disease likely prevented the proper detection of changes in ALS progression.
Subsequent analysis excluding patients with more severe ALS showed <a href="https://alsnewstoday.com/news/nurown-continues-show-benefit-rapidly-advancing-als/">evidence of the therapy&#8217;s effectiveness in slowing ALS progression</a>, with statistically significant differences in ALSFR-R.
NurOwn <a href="https://alsnewstoday.com/news/als-biomarkers-boosted-nurown-regardless-disease-severity/">consistently reduced</a> markers of inflammation and neurodegeneration in the cerebrospinal fluid, the liquid surrounding the brain and the spinal cord, while increasing markers of neuroprotection. The levels of three of these biomarkers could predict clinical response to NurOwn.
“We are encouraged by the regulatory flexibility that the FDA has shown over the last year in ALS broadly, and with respect to NurOwn in particular, and believe an Advisory Committee meeting is good for patients,” said Chaim Lebovits, president and CEO at BrainStorm.
“We are of course deeply committed to the scientific and regulatory process, which includes continuing research to confirm the results of the NurOwn clinical program and are working with ALS experts in designing a rigorous clinical study to answer important questions about this therapy and inform further research on ALS,” Lebovits added.

FDA final approval decision on NurOwn for ALS due by year’s end

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.
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<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.

BrainStorm nets NurOwn ADCOM meeting over FDA objections

The U.S. Food and Drug Administration (FDA) has granted a Type A meeting to BrainStorm Cell Therapeutics to discuss the agency&#8217;s refusal to review <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).
According to the FDA, <a href="https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otat-type-meetings">type A meetings</a> are used for &#8220;an otherwise stalled product development program,&#8221; to talk about and settle differences between regulators and the developer of a potential therapy.
The upcoming meeting has been set for Jan. 11.
&#8220;We look forward to the Type A meeting which will provide an opportunity to discuss the path forward for NurOwn in ALS, including a possible Advisory Committee Meeting,&#8221; Chaim Lebovits, CEO of <a href="https://brainstorm-cell.com/">BrainStorm</a>, said in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-type-a-meeting-with-fda-granted-for-nurown-301710196.html">company press release</a>.
The meeting will focus on the contents of a refusal to file letter issued by the FDA following BrainStorm&#8217;s new Biologics License Application (BLA) for the stem cell-based therapy.
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<h3>BrainStorm seeking new &#8216;path forward&#8217; for NurOwn</h3>
NurOwn is a cell-based therapy that requires first harvesting mesenchymal stem cells from a patient’s bone marrow. This is followed by a period of cell maturation, in which cells are induced to produce large amounts of signaling molecules that promote nerve cell health and growth. The modified cells are then returned to the patient via a spinal canal injection.
BrainStorm carried out a <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 trial (NCT03280056)</a> to test the safety and efficacy of NurOwn in a group of 189 adults with rapidly progressing ALS. Patients received three injections of either NurOwn or a placebo, given every other month, and were then followed for about seven months (28 weeks).
Results showed that NurOwn was not significantly more effective than a placebo at slowing disease progression, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R). This meant that the trial failed to meet its <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">primary goal</a>.
However, Brainstorm argued that the large proportion of patients with advanced disease in the trial may have masked NurOwn’s effects.
Such a population already has the lowest scores in some subscales of the ALSFRS-R, which creates a &#8220;floor effect&#8221; that prevents changes in disease progression from being properly detected, the company said.
Indeed, <a href="https://alsnewstoday.com/news/nurown-continues-show-benefit-rapidly-advancing-als/">subsequent analyses</a> that excluded patients with more severe ALS showed that the therapy has the potential to slow disease progression in a clinically meaningful manner compared with a placebo.
However, the <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">FDA still declined to review</a> the BLA requesting NurOwn’s approval, citing insufficient evidence of effectiveness to support it. Regulators also cited concerns related to chemistry, manufacturing, and control procedures.
Faced with the FDA’s rejection, Brainstorm <a href="https://alsnewstoday.com/news/brainstorm-files-fda-meeting-new-bid-nurown-approval/">submitted a request</a> for the Type A meeting to discuss the situation.
Along with the request, the company provided an extensive briefing package addressing the FDA’s concerns, expressing confidence in “achieving quick alignment with the FDA” on these matters, Lebovits said in the <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-submits-type-a-meeting-request-to-us-food-and-drug-administration-301700042.html">press release</a> concerning the submission.
[quote align=&#8221;center&#8221;]We believe that an advisory committee meeting would serve as an important part of the review process[/quote]
The FDA’s refusal to review NurOwn also prompted a response from the ALS community. Two open letters in favor of NurOwn’s review were published, one from <a href="https://alsnewstoday.com/news/als-patients-given-nurown-call-fda-meeting-discuss-refusal/">a group of ALS patients</a> who received NurOwn during clinical testing, and another authored by U.S. military veterans with ALS.
The letters urged the FDA to hold a public advisory committee meeting to discuss the therapy with patients and ALS experts — including healthcare professionals who followed patients treated with NurOwn — and allow their voices to be heard and considered in the debate.
At the scheduled Type A meeting, Brainstorm will focus on securing an advisory committee meeting as the next step for a potential approval of NurOwn as an ALS therapy.
&#8220;We believe that an advisory committee meeting would serve as an important part of the review process and would provide an open forum for BrainStorm, together with medical experts, statisticians, patients and other members of the ALS community to discuss the body of clinical evidence supporting NurOwn,” Lebovits said.
The company plans to provide further updates after receiving the minutes from the meeting, or “when we have more clarity on the next steps in the approval process,” Lebovits added.

Tag: BrainStorm Cell Therapeutics

BrainStorm drops FDA application for NurOwn

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FDA Grants Jan. 11 Meeting to Discuss Future of NurOwn for ALS