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The U.S. Food and Drug Administration (FDA) has agreed on the design of a Phase 3b trial that will test the investigational cell-based therapy <a href="https://alsnewstoday.com/nurown/">NurOwn</a> (debamestrocel) in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients with less advanced disease.
The developer, <a href="https://brainstorm-cell.com/">BrainS</a><a href="https://brainstorm-cell.com/">torm Cell Therapeutics</a>, plans to launch the trial this year, and should the data be positive, it will back an application seeking regulatory approval of the therapy.
The FDA reviewed the clinical trial protocol and statistical analyses under what’s known as a Special Protocol Assessment (SPA). Developers can request these evaluations to make sure the agency believes a trial’s design is generally adequate to support a future regulatory application. Still, the SPA agreement is not a guarantee of the FDA’s approval of all aspects of the trial or the therapy’s potential clearance.
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“We are pleased to have reached an agreement with the FDA on key elements of the Phase 3b trial design that provides a potential path forward towards obtaining regulatory approval,&#8221; Chaim Lebovits, president and CEO of BrainStorm, said in a <a href="https://ir.brainstorm-cell.com/2024-04-09-BrainStorm-Cell-Therapeutics-Announces-Agreement-with-FDA-on-a-Special-Protocol-Assessment-SPA-for-Phase-3b-Trial-in-ALS">company press release</a>.
“BrainStorm&#8217;s ultimate goal is to provide a new treatment option that can help patients afflicted with ALS, and we believe that the SPA potentially brings us one step closer to this goal,” Lebovits added.
<h3>BrainStorm&#8217;s new effort</h3>
The Phase 3b trial has <a href="https://alsnewstoday.com/news/brainstorm-making-cuts-support-new-trial-nurown-als/">been in the works since last year</a>, when U.S. regulators indicated that evidence from completed clinical trials was insufficient to back NurOwn’s approval.
“We have worked with leading neurologists, scientists, and members of the ALS community to create a robust study designed to evaluate the effectiveness and safety of NurOwn,” said Stacy Lindborg, PhD and co-CEO of BrainStorm. “Over the past year, we&#8217;ve assembled an excellent team in clinical development that is highly qualified to execute this trial with excellence.”
NurOwn involves collecting a patient’s own mesenchymal stem cells (MSCs) from the bone marrow and engineering them in a lab to secrete large amounts of signaling molecules that promote nerve cell health.
The modified cells are then expanded and returned to the patient via injections into the spinal canal, where they’re expected to help protect the motor nerve cells that are characteristically lost in ALS, thereby slowing disease progression.
An earlier <a href="https://clinicaltrials.gov/study/NCT03280056">Phase 3 trial (NCT03280056)</a> tested the therapy in adults with rapidly progressing ALS, most of whom had advanced disease. The trial <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 slowing of disease progression with NurOwn when compared with a placebo.
Still, additional analyses indicated that <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">disease progression was slowed</a> among the subgroup of patients with less severe disease. BrainStorm applied for approval of NurOwn in 2022 on the basis of those promising data, but the FDA <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">declined to consider the application</a>, citing that the data were insufficient.
The company later used a special process called “<a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">file over protest</a>” to proceed with its application anyway, but the company later <a href="https://alsnewstoday.com/news/brainstorm-drops-application-nurown-als-regroup/">withdrew its application</a> after an FDA advisory committee <a href="https://alsnewstoday.com/news/fda-advisory-committee-votes-not-enough-efficacy-nurown-als/">echoed</a> the FDA’s earlier sentiment.
BrainStorm has been communicating with FDA regulators since then, planning for the launch of the Phase 3b trial, which it hopes will provide the agency with the evidence needed to approve NurOwn.
<h3>2-part study planned</h3>
The multicenter Phase 3b trial, called BCT-006-US, will be a <a href="https://alsnewstoday.com/news/mda-2024-phase-3b-trial-aims-support-nurown-efficacy-als/">two-part study</a> designed to evaluate NurOwn’s safety and efficacy in early ALS patients whose symptoms emerged within the last two years.
“This trial builds on valuable insights from our earlier studies and will enroll people living with ALS who are earlier in the course of their disease,” Lindborg noted.
Around 200 adult participants will be enrolled and randomly assigned to receive three injections of NurOwn or a placebo, given once every eight weeks for about six months. All participants will then receive another three injections of NurOwn in the study&#8217;s second part, which will also last six months.
Participants will also be allowed to continue treatment with approved standard-of-care <a href="https://alsnewstoday.com/als-treatment/">ALS therapies</a> throughout the study.
The trial’s main goal is to evaluate whether NurOwn slows disease progression compared with a placebo, as assessed by changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) over the first 24 weeks.
Final conclusions on whether this goal was met will rely on a combined assessment of functional changes and survival, to take into account any deaths observed during the study.
Samples of blood and cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — will be collected during the trial to evaluate biomarkers of neuroinflammation, neurodegeneration, and neuroprotection.
Safety will be monitored by an independent Data Monitoring Committee throughout the study, according to the company.
“Based on the evidence generated on NurOwn to date, we have a trial that we&#8217;re optimistic will be positive,” Lindborg said. “We&#8217;ve been parallel processing to enable us to deliver the first dose in the trial in 2024, and we&#8217;re anxious to get started.&#8221;

FDA OKs Phase 3b trial design for NurOwn in less advanced ALS

Early data from Phase 2 programs showing that <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a>, an oral therapy candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), induced significant reductions in a nerve damage biomarker but did not meet the criteria for accelerated approval at this time, the U.S. Food and Drug Administration (FDA) concluded.
Despite the FDA’s decision at a recent meeting, <a href="https://clene.com/">Clene Nanomedicine</a>, the therapy’s developer, <a href="https://www.globenewswire.com/news-release/2023/12/21/2799888/0/en/Clene-Reports-Reduction-in-Biomarker-Plasma-Neurofilament-Light-NfL-Levels-and-Improved-Survival-With-CNM-Au8-Treatment-From-HEALEY-ALS-Platform-Trial-Long-Term-Open-Label-Extensio.html">released promising new data</a> from the long-term extension study of the <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS platform trial (NCT04297683)</a>.
Results showed CNM-Au8 significantly reduced the blood levels of the nerve damage biomarker neurofilament light chain (NfL) by 16% after about 18 months, decreased the risk of long-term all-cause mortality by 60%, and reduced the risk of clinical worsening in the highest-risk participants.
Clene plans to provide the FDA with supplemental data in the first half of 2024. The data package will include additional long-term clinical evidence and biomarker results, data on CNM-Au8’s mechanism of action and its connection to NfL reduction, as well as the association between lower NfL and improved clinical outcomes, including prolonged survival.
“As we continue to analyze the data from our Phase 2 clinical program, we believe the evidence supports that CNM-Au8 treatment improved survival in people living with ALS,” Benjamin Greenberg, MD, Clene’s head of medical, said in a <a href="https://www.globenewswire.com/news-release/2023/12/21/2799889/0/en/Clene-Provides-Update-on-ALS-Clinical-Development-Meeting-With-FDA.html">company press release</a>. “We are also encouraged that the recently disclosed long-term NfL biomarker decreases are consistent with delayed clinical time-to-event outcomes.”
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<h3>Candidate therapy aims to support health of motor neurons</h3>
CNM-Au8 is an oral liquid suspension of gold nanocrystals that aims to support the health of motor neurons, nerve cells that control voluntary muscle movement which <a href="https://alsnewstoday.com/causes-of-als/">progressively die in people with ALS</a>.
The therapy has been granted orphan drug status by the FDA for ALS, a designation that provides incentives to accelerate CNM-Au8’s clinical development and regulatory review.
In addition to an arm of the HEALEY trial, which simultaneously tested several ALS treatment candidates against a shared placebo group, the therapy is being evaluated in the <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">Phase 2 RESCUE-ALS trial (NCT04098406)</a> and its <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension (OLE) study (NCT05299658)</a>. So far, study data show that CNM-Au8 is safe, <a href="https://alsnewstoday.com/news/cnm-au8-seen-to-extend-survival-by-more-than-1-5-years-in-als-trial/">slows ALS progression</a>, and <a href="https://alsnewstoday.com/news/long-term-survival-benefit-seen-cnm-au8-healey-als-analyses-trial/">extends patient survival</a>.
During the initial six months of treatment in the HEALEY trial, CNM-Au8 was associated with a 10% relative reduction in NfL compared with a placebo.
Newly released data from HEALEY’s 12-month OLE study showed the 30 mg dose of CNM-Au8 reduced NfL levels by 16% after 76 weeks, or about 18 months, relative to those initially assigned to a placebo. Similar results were found when data was combined from both doses tested (30 mg and 60 mg).
A long-term survival analysis of HEALEY OLE data compared patients originally assigned CNM-Au8 in the main study compared with those given a placebo. While those on a placebo eventually switched to CNM-Au8 in the OLE, the researchers employed a statistical model that estimated their survival had they remained on a placebo during the OLE period. The data showed a 60% reduction in the risk of all-cause mortality in patients given CNM-Au8 for the entire period.
<h3>Studying relationship between NfL, worsening ALS</h3>
To investigate the relationship between NfL and the incidence of ALS worsening, Clene pooled data from the HEALEY ALS platform and the RESCUE-ALS trials. Participants were classified based on NfL levels before receiving CNM-Au8 (baseline). ALS worsening events included death, needing a breathing or feeding tube, or the initiation of permanent assisted ventilation.
Analyses showed CNM-Au8 significantly delayed these worsening events in the group of patients with the highest baseline NfL levels, indicating greatest nerve cell damage. In these patients, the risk of such events was reduced by 75%.
At the same time, there also were significant extensions in the time to death or the initiation of permanent assisted ventilation, and a reduction in all-cause mortality.
The company plans to launch a Phase 3 study to confirm these findings in 2024.
Meanwhile, the National Institutes of Health (NIH) has recently <a href="https://alsnewstoday.com/news/new-eap-makes-cnm-au8-available-als-patients-outside-trials/">awarded about $45.1 million toward an expanded access program</a> (EAP) of CNM-Au8. Referred to as compassionate use, this program will join two other CNM-Au8 EAP programs to provide CNM-Au8 to U.S. patients who are not eligible for these clinical trials.
“Clene is committed to people living with ALS,” said Rob Etherington, CEO of Clene. “We presently support two ongoing CNM-Au8 compassionate use (expanded access) programs and are shortly commencing a third compassionate use program that is supported by a $45.1M grant from the National Institutes of Health.
“In addition, we anticipate launching the Phase 3 ALS confirmatory study in 2024. Importantly, we also plan to submit new information to the FDA for further discussions on the totality of evidence in order to advance the accelerated development of CNM-Au8 for the treatment of ALS.”
Clene also is testing CNM-Au8 for the treatment of <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s disease</a>, two other neurodegenerative disorders.

Biomarker data insufficient to support CNM-Au8’s approval: FDA

<a href="https://brainstorm-cell.com/" rel="nofollow">BrainStorm Cell Therapeutics</a> is making strategic adjustments — including cuts in its workforce — to accelerate the clinical development of <a href="https://alsnewstoday.com/nurown/">NurOwn</a> as an <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) treatment.
The decision follows the recent <a href="https://alsnewstoday.com/news/brainstorm-drops-application-nurown-als-regroup/">withdrawal of its regulatory application</a> with the U.S. Food and Drug Administration (FDA) seeking the therapy&#8217;s approval, after an FDA advisory committee overwhelmingly decided that available data from a <a href="https://clinicaltrials.gov/study/NCT03280056">Phase 3 clinical trial (NCT03280056)</a> were <a href="https://alsnewstoday.com/news/fda-advisory-committee-votes-not-enough-efficacy-nurown-als/">insufficient to support NurOwn&#8217;s efficacy</a> in ALS.
The FDA since has offered a face-to-face meeting with company officials, and BrainStorm is continuing to collect NurOwn data to support a future regulatory application. This includes additional biomarker and long-term safety and survival data from the completed Phase 3 trial, as well as a planned Phase 3b trial in the U.S. with an open-label extension.
That new clinical study, a focus of the upcoming FDA meeting, likely will be in ALS patients with less advanced disease.
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<h3>&#8216;Steadfast in our goal to make NurOwn available to the ALS community&#8217;</h3>
To support these goals, BrainStorm is exploring options for raising capital and will reduce and refocus existing resources. These efforts include a targeted, roughly 30% reduction in its workforce, with employees crucial for the new clinical trial and future regulatory submissions being retained, it announced in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-strategic-realignment-prioritizing-nurown-for-the-treatment-of-als-301965642.html">company press release</a>.
NurOwn&#8217;s executive vice president and chief medical officer — reported to be largely in charge of global medical affairs and broader launch activities — is among those stepping down. Overall, the company expects to cut by half the company&#8217;s total resource consumption.
“We remain steadfast in our goal to make NurOwn available to the ALS community as quickly as possible, and we believe that this strategic realignment offers our best chance for success,” said Chaim Lebovits, president and CEO of NurOwn. “While remaining open to partnership opportunities that could accelerate growth, the steps we are taking now reflect our unwavering commitment to those battling this horrific disease and our firm belief in the potential value of NurOwn.”
BrainStorm also is consulting with principal investigators from its NurOwn trials, independent ALS experts, and a patient advisory group to prepare the Phase 3b trial&#8217;s design and for the upcoming FDA meeting.
A cell-based therapy, NurOwn involves collecting a person&#8217;s stem cells and engineering them in the lab to produce high amounts of a signaling molecule thought to promote nerve cell health and growth. When returned to the patient via an injection directly into the spine, the therapy is expected to support nerve cell survival.
The completed Phase 3 trial, which enrolled 189 people with rapidly progressing ALS, <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed to meet its main goal</a> of demonstrating NurOwn was superior to a placebo at slowing disease progression. This was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R), in which lower scores indicate greater disability.
Clinically meaningful responses to NurOwn, however, were seen in a pre-specified group of patients with less-advanced disease, but they did not differ significantly from those of patients given a placebo.
Based on available trial data, the FDA <a href="https://alsnewstoday.com/news/nurown-trial-data-lacking-brainstorm-fda-approval-review/">discouraged a regulatory filing</a>, and later <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused to review the filed application</a>, citing insufficient evidence of the therapy’s benefits.
But Brainstorm <a href="https://alsnewstoday.com/news/als-therapy-maker-brainstorm-secures-adcom-over-fda-objection/">used a ‘filed over protest’ procedure</a> to move its application ahead, allowing for the Sept. 27 advisory committee meeting that, in a 17-1 vote, found insufficient support.
<h3>Possibility of a floor effect masking benefits in earlier Phase 3 trial</h3>
The company has argued that further analyses of NurOwn data indicate the presence of a <a href="https://alsnewstoday.com/news/mda-2023-issues-als-scale-noted-nurown-trial-failure-analysis/">floor effect</a><a href="https://alsnewstoday.com/news/mda-2023-issues-als-scale-noted-nurown-trial-failure-analysis/"> in the ALSFRS-R</a>, the scale used to measure progression in its Phase 3 trial. Given that a large number of participants had advanced disease and some of the lowest possible scores on that measure&#8217;s subscales, there was no room for further meaningful score declines, even if patients — including those in the placebo group — were continuing to lose functionality.
As such, it’s possible that meaningful and significant differences between NurOwn&#8217;s use and a placebo were missed. This hypothesis is supported by the therapy being shown <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">to slow disease progression</a> in trial patients with less severe disease, where the impact of the floor effect isn&#8217;t expected to be as profound.
“While the Phase 3 trial was confounded by the ALSFRS-R scale&#8217;s inability to measure disease progression in participants with advanced ALS, the trial did demonstrate a clinically meaningful response in a pre-specified subgroup of patients with less advanced disease,” said Stacy Lindborg, PhD, co-CEO of BrainStorm. “This finding was further supported by biomarker data.”
The FDA responded by <a href="https://alsnewstoday.com/news/fda-questions-nurown-efficacy-quality-ahead-advisory-panel/">questioning the presence</a> of this floor effect and repeating its chief efficacy concerns shortly before the advisory committee meeting.
“Based on learnings from the Phase 3 trial, we believe in the utility of NurOwn in mild to moderate ALS and that the ALS community deserves every effort we can give to definitively demonstrate its clinical value,” Lindborg said.

BrainStorm making cuts to support new trial, advance NurOwn for ALS

<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

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.
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<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.
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&#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;
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FDA questions NurOwn’s efficacy, quality ahead of today’s hearing

Changes in neurofilament light chain (NfL) levels — a biomarker of nerve cell damage — were deemed by an advisory committee reasonably likely to predict clinical efficacy from <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">tofersen</a> in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by SOD1 gene mutations.
The unanimous vote from the Peripheral and Central Nervous System Drugs Advisory Committee, part of the U.S. Food and Drug Administration (FDA), indicates that NfL levels alone may be considered as a good surrogate marker of the experimental therapy&#8217;s effectiveness.
However, the committee narrowly voted &#8220;no&#8221; when asked if currently available data gives substantial evidence that tofersen is effective in SOD1-ALS patients.
The FDA will consider these recommendations from the committee&#8217;s March 22 meeting in its <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">ongoing review of tofersen</a>, with a decision <a href="https://alsnewstoday.com/news/decision-delayed-proposed-als-therapy-tofersen-until-april-2023/">expected by April 25</a>. The agency usually aligns with the decisions of its expert committees, but is not obligated to do so.
[recommended-reading id=82361]
&#8220;We thank the FDA for convening this important discussion,&#8221; Priya Singhal, MD, executive vice president and head of development, and interim head of research and global safety and regulatory sciences at <a href="https://www.biogen.com/">Biogen</a>, said in a <a href="https://investors.biogen.com/news-releases/news-release-details/biogen-provides-update-fda-advisory-committee-meeting-tofersen">press release</a>.
Biogen is developing tofersen after licensing the therapy from prior developer Ionis Pharmaceuticals.
&#8220;We are encouraged by the outcome of today&#8217;s advisory committee meeting,&#8221; C. Frank Bennett, PhD, executive vice president and chief scientific officer at <a href="https://www.ionispharma.com/">Ionis</a>, said in a <a href="https://www.prnewswire.com/news-releases/ionis-accounces-fda-advisory-committee-voted-unanimously-for-a-potential-accelerated-approval-of-tofersen-for-sod1-als-301779437.html">press release</a> from the company. &#8220;If approved, tofersen would be the first medicine targeting a known cause of familial ALS.&#8221;
Mutations in the <a href="https://alsnewstoday.com/als-and-genetics/">SOD1 gene</a> are found in up to 20% of people with <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a>, and up to 2% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic ALS</a> cases. These mutations lead to the production of an abnormal version of the SOD1 protein that forms clumps in nerve cells, which are thought to be toxic and drive disease progression.
Tofersen is an RNA-based therapy designed to disrupt the production of the SOD1 protein, thereby reducing the formation of these toxic protein clumps. It&#8217;s administered via an injection into the spinal canal, called an intrathecal injection.
<h3>VALOR clinical trial</h3>
Biogen&#8217;s <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">application for accelerated approval</a> of tofersen is supported by data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">Phase 1/2/3 clinical trial VALOR (NCT02623699)</a>. The Phase 1 and 2 portions of the study provided <a href="https://alsnewstoday.com/news/tofersen-safe-appears-to-slow-disease-progression-in-sod1-als-patients-phase-1-2-trial-shows/">proof-of-concept</a> that tofersen could lower SOD1 protein levels as designed, and also indicated the treatment was generally well tolerated.
In the Phase 3 part of VALOR, 108 adults with ALS were assigned randomly to receive eight injections of tofersen (100 mg) or a placebo over the course of 28 weeks, or about six months. The study&#8217;s main goal was to assess the impact of treatment on disease progression, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R).
<a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">Top-line results</a> from VALOR showed it failed to meet that goal; changes in ALSFRS-R scores were not significantly different between patients given tofersen or a placebo.
However, newer data from an <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a>, in which 95 patients from VALOR are being treated with tofersen for up to seven years, indicated that <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">disease progression was slower</a> among patients given tofersen in the initial study, compared with those who got placebo for six months in the original trial.
Data from VALOR and its extension study also indicated that treatment with tofersen markedly reduced levels of NfL, a structural protein in nerve fibers. When nerve cells are injured or die, NfL gets released into bodily fluids, so it often is used as a marker of nerve damage.
Analyses from VALOR suggested that tofersen-treated patients with a sharper NfL reduction in the first months after initiating treatment tended to experience <a href="https://alsnewstoday.com/news/tofersen-clinical-benefits-linked-nfl-levels-trial-data/">slower disease progression</a>.
In its meeting, the FDA voted unanimously &#8220;yes&#8221; in answer to the question, &#8220;Is the available evidence sufficient to conclude that a reduction in plasma neurofilament light chain (NfL) concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen for treatment of patients with SOD1-ALS?&#8221;
<h3> Seeking accelerated approval</h3>
Biogen is seeking approval of tofersen under the FDA&#8217;s accelerated approval pathway, which allows the agency to give conditional marketing authorization for therapies where early biomarker data suggest a likely benefit. Developers of therapies given accelerated approval are mandated to conduct additional testing to confirm a clinical benefit.
According to Biogen and Ionis, the unanimous vote from the committee likely favors accelerated approval.
&#8220;After hearing the moving experiences of the ALS community and reviewing the totality of data, the Committee voted that reductions of neurofilament are reasonably likely to predict clinical benefit of tofersen,&#8221; Singhal said. &#8220;If approved, tofersen would potentially represent a major advance for people living with SOD1-ALS.&#8221;
Considering NfL as a good surrogate biomarker of efficacy may have implications beyond ALS, as NfL is a common marker of nerve damage and is elevated in numerous neurological disorders. However, it still remains to be seen whether the FDA itself will deem the NfL data sufficient to support an accelerated approval.
<h3>The second question</h3>
The committee was mixed, however, in its vote on the question, &#8220;Does the clinical data from the placebo-controlled study and available long-term extension study results, with additional supporting results from the effects on relevant biomarkers (i.e., changes in plasma NfL concentration and/or reductions in SOD1), provide substantial evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS?&#8221;
In answer, five committee members voted no, three voted yes, and one abstained. This represents a narrow vote against a traditional approval of tofersen at this time, according to the therapy&#8217;s developers.
Biogen is running a <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">Phase 3 trial, ATLAS (NCT04856982)</a>, to learn more about the efficacy of tofersen. The study is testing tofersen against placebo in people who have SOD1 mutations and elevated NfL levels, but have not yet developed any <a href="https://alsnewstoday.com/als-symptoms/">symptoms of ALS</a>. The study is <a href="https://clinicaltrials.gov/ct2/show/NCT04856982#contactlocation">recruiting participants</a> at locations worldwide.
&#8220;We are grateful to all the people with SOD1-ALS who participated in our tofersen studies, and their caregivers, families, study investigators and the entire community, without whom this scientific progress could not have been made,&#8221; Singhal said.

FDA panel votes in favor of tofersen biomarker data

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: FDA