Background
The BrainStorm treatment regimen consists of a person’s own stem cells (called autologous) being removed from bone marrow and then grown outside of the body in the presence of a chemical owned by the company, called NurOwn, which aims to increase the stem cells’ ability to make and secrete protective substances called growth factors. The stem cells are then injected into the fluid that bathes the brain and spinal cord (called cerebrospinal fluid or CSF) with a needle (called intrathecal or IT injection) at multiple intervals. The hope is that these treated stem cells will be able to slow the progression of motor neuron degeneration and hence, the progression of ALS symptoms.
In 2016, the first peer reviewed publication appeared, demonstrating preliminary, positive safety data in combination with BrainStorm completing a phase 2 clinical trial at three renowned US clinical sites.
The phase 2 trial data involved 48 ALS patients (36 treated and 12 placebo) and was published in December 2019 in the journal Neurology, titled “A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy.”
A phase 3 clinical trial testing multiple doses of NurOwn at six sites in the United States was started in 2017. The trial was double-blinded, meaning neither researchers nor participants knew if they were on active treatment or placebo. The primary measurements were to examine safety of repeated intrathecal injections of NurOwn and the ability of NurOwn to slow progression of ALS/MND using a scale called the ALSFRS-R. To determine if NurOwn-treated stem cells were providing the intended biological effect, the CSF was measured for biomarkers including neurotrophic factors (aiming for increased levels) and neurodegenerative/neuroinflammatory factors (aiming for reduced levels).
On November 17, 2020, a press release was issued describing the initial data from the phase 3 clinical trial. The trial did not meet statistical significance in any of the reported data, notably in the primary measurement of disease progression using the ALSFRS-R. A pre-specified subgroup of those with early disease was highlighted in the press release as showing clinically meaningful slowing of ALS progression, however these results were also not statistically significant. Further, it was reported that that NurOwn treatment resulted in an increase of neurotrophic biomarkers and reduction in neurodegenerative and neuroinflammatory biomarkers when compared to the placebo group, which is aligned with what the trial hoped to achieve. Follow up analysis will investigate whether these biomarker results, in addition to further analysis of the pre-specified subgroup of those with early disease, can reveal any additional information. As of January 2021, this recommendation is based also on additional data presented at the International ALS/MND Symposium on December 9, 2020.
On December 10, 2021, the NurOwn phase 3 data was published in the journal Muscle & Nerve, titled “A Randomized Placebo-Controlled Phase 3 Study of Mesenchymal stem cells induced to secrete high levels of neurotrophic factors in Amyotrophic Lateral Sclerosis.”As summarized at the beginning of the discussion “The primary and secondary efficacy endpoints of this Phase 3, placebo-controlled, randomized trial were not statistically significant, however the study provided significant information about the study design and potential biomarkers of treatment response for use in future clinical trials.”
In brief, none of the pre-specificed analyses demonstrated a significant benefit of NurOwn over placebo. The most commonly discussed comparison from this data amongst the ALS community, regarding a measurement of responders in a pre-specificed subgroup of indiviuals >35 ALSFRS-R score at baseline, demonstrated that 9 of 26 individuals met responder criteria on NurOwn, while 5 of 32 individuals responded to placebo. While this trends towards benefit of NurOwn, the comparison is not statistically significant (p=0.29) and a difference of only four individuals, indicating that there is no way to know if the response of the NurOwn group is due to treatment, or the same effects as experienced by the five individuals in the placebo group. Of note, this pre-specified subgroup does not appear to be specified in the study protocol published online here.
Post hoc analyses reveal trends to indicate NurOwn could have some level of efficacy that could suggest a follow-up clinical trial, using the learnings from this study, may be of value. These types of post hoc analyses, particularly where “no adjustments were made for multiple comparisons in testing exploratory efficacy endpoints”, are generally not used as evidence of benefit, but to inform further study. This is a practice accepted widely in industry for good clinical development, as conclusions drawn from post hoc analyses can be misleading.
NurOwn did demonstrate the anticipated significant increase in neurotrophic factors, such as VEGF and decrease in neuroinflammatory markers like MCP-1, but did not significantly alter NfL levels. These biomarker results tell us that NurOwn achieved the desired biological effect, to some extent. None of these biomarkers are as yet validated or accepted as indicative of clinical effect and the marker closest to a wider acceptance as indication of neuronal health, NfL, was not significantly decreased by NurOwn over placebo. A trend towards decrease in NfL provides some supporting evidence for the value of another trial.
Finally, a number of individuals who participated in the phase 3 clinical trial have publicly shared their positive experiences. In the absence of convincing point data indicating a clear number of individuals treated with NurOwn, rather than placebo, who had a radical change in trajectory of disease progression, it is impossible for anyone to know if this can be attributed to an effect of NurOwn. Furthermore, a published secondary endpoint of individuals demonstrating >100% improvement in ALSFRS-R slope, revealed 13 individuals in both the NurOwn- and placebo-treated groups, including 7 of the 9 individuals on NurOwn in the >35 baseline ALSFRS-R group and 5 of the 5 individuals on placebo.
It is also not possible to determine the contribution of NurOwn to any experiences in Expanded Access or Hospital Exemption programs, though once collected, data from these may be valuable in helping BrainStorm to determine a path forward for any future trial.
BrainStorm filed a BLA for NurOwn on September 9, 2022, and received a Refusal to File (RTF) letter from FDA on November 8, 2022. Following a Type A meeting and subsequent discussions with the FDA BrainStorm requested that CBER utilize the FDA’s “File Over Protest” procedure. An Advisory Committee (AdComm) meeting was scheduled for September 27, 2023 and a subsequent PDUFA data for decision by December 8, 2023.
During the AdComm, the committee overwhelmingly voted negatively, with 17 members voting no and 1 member voting yes to the question: “Do the data presented demonstrate substantial evidence of effectiveness for treatment of mild to moderate ALS?” One member abstained. Following the meeting, on October 18th, Brainstorm announced they were withdrawing the Biologics License Application (BLA) for NurOwn. The decision to withdraw the BLA was coordinated with FDA and is viewed by FDA as a withdrawal without prejudice.
On October 24th, Brainstorm announced a strategic realignment to enable accelerated development of NurOwn® for the treatment of amyotrophic lateral sclerosis (ALS). This realignment is designed to 1) support the company plans to conduct a double-blind, placebo-controlled Phase 3b U.S. clinical trial for NurOwn inALS with an open-label extension and 2) continue to publish data from NurOwn’s Phase 3 clinical trial on: biomarkers, long-term safety and survival, and the Expanded Access Program, providing transparency around NurOwn data and progressing ALS drug development. In preparation for the trial design and subsequent meeting with FDA, BrainStorm is consulting with the NurOwn Principal Investigators, who are most familiar with NurOwn, an additional panel of independent ALS experts, and a patient advisory group.
Summary
The Scientific Advisory Council (SAC) notes that there is insufficient evidence at this time to conclude that NurOwn provides any benefit to people with ALS/MND.
The SAC supports the need for a further definitive Phase 3 trial for NurOwn to demonstrate clinical benefit for people with ALS/MND.
International Alliance of ALS/MND Associations
October 2023
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.