Critical Importance of FDA AdComm Meeting for ALS Therapy NurOwn

Namita A. Goyal, MD

NurOwn (BrainStorm Cell Therapeutics) is an investigational therapy made up of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF) for the potential treatment of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The submitted biologics license application (BLA) for the agent was based on a phase 3 study (NCT03280056) in which the agent originally failed to meet its primary end point; however, it continued to have significant effects on less severe forms of ALS. In the original analysis, 33% and 28% of patients on NurOwn and placebo respectively, met the primary end point of change in disease progression of at least 1.25 points on ALS Functional Rating Scale (ALSFRS-R).¹

Recently, the company announced the FDA will hold an advisory committee meeting hearing to discuss the NurOwn as a potential treatment for patients with ALS after months of convening.² The company requested that the Center for Biologics Evaluation and Research (CBER) utilize the FDA’s File Over Protest procedure. Previously, in November 2022, the company received a refusal to file a letter from the FDA for the BLA of NurOwn, and following that BrainStorm filed an amendment that responded to most of the outstanding questions the FDA had posed.

Recently, Namita A. Goyal, MD, a principal investigator on the phase 3 NurOwn pivotal trial, sat down with NeurologyLive® to discuss the findings from the trial. Goyal, board-certified neurologist and director at the ALS Clinic at UC Irvine Health, talked about the significance of the results and the importance of the upcoming FDA AdComm meeting and its impact on the ALS community.

NeurologyLive®: What were the results of the clinical trial with NurOwn?

Namita A. Goyal, MD: What we know from the clinical trials is that mesenchymal cells are treated with this product, NurOwn, which is designed to deliver neuroinflammatory protective effects to try to reduce neuroinflammation. Also, it is designed to deliver growth factors in the spinal fluid where the motor neurons lay in the brain and the spinal cord. Results showed that the patients treated with mesenchymal cells with NurOwn appeared to have target engagement. We did see a reduction in inflammation and an increase in neurotrophic markers, which are neuroprotective markers in the spinal fluid. This suggests that there is target engagement, which we did not see in the patients on placebo. I think of the mesenchymal cells as a vehicle that delivers NurOwn to these protective markers to protect the motor neurons from degenerating.

What is the potential impact of NurOwn on mechanisms underlying ALS, and how does it affect pathways related to neuroinflammation?

One of the challenges with ALS is that the mechanism that causes the disease is thought to be multifactorial. It results from complex interaction of multiple different pathways, from the cellular, molecular, and genetic levels. What's interesting about NurOwn is it appears to affect multiple pathways in this complex scene that causes ALS, which we have seen from the CSF biomarkers. The reduction in inflammation and delivery of neuroprotective markers like neurotrophic growth factors are all postulated mechanisms that seem to be affected in ALS.

What were some of the other findings from the trial and their significance?

The phase 3 primary endpoint did not hit statistical significance, but what we did see is that a subset of patients, those with less severe disease, seem to have a better treatment response than patients that received placebo. I think we really need to understand what this means with a full review of this data set.

I think we have two very important findings. We have this subset of patients that had ALSFRS-R baseline score of 35 or higher or at least 35, and they seemed to have a treatment effect. Importantly, we have these anecdotal experiences of our patients telling us that they were able to either regain some mild function. We did see some clinical outliers that appear to have a slowing of progression. In my clinical experience, I would have expected those patients to progress. It didn't happen in all patients, but there was certainly a subset of patients where we saw this based on the data, as well as anecdotally.

What are some potential ways to improve the quality of life and increase the lifespan of patients with ALS?

We know that ALS does not have an effective treatment to stop or reverse the symptoms. At best, we see that some of the FDA approved treatments may be slowing down progression. We hear over and over again, that ALS is a clock ticking and there's only so much time that an ALS patient has [in their life]. I think we can give back patients more time, improve quality of life, and potentially more function those would be remarkable wins in ALS.

Why is it critical for the FDA to hold an AdComm meeting to discuss this data?

I think these findings are important to be explored. I think it's really important that the FDA gives a thoughtful scientific review of the full data set to understand these findings if there is true efficacy, and what the safety is. The second part of the story is the CSF biomarker data. We have data that in the patients treated with NurOwn, neuroinflammation was down, growth factors were up, and neuroprotective markers were increased. We really need to understand what that means clinically. I think that's going to help this trial, as well as all ALS trials. I think a scientific discussion that really caters to understanding these findings will be really important for the ALS community overall.

What are the challenges in understanding how NurOwn affects all patients with ALS, and what factors need to be considered in analyzing the data?

I think the main challenge, and even understanding the data, is understanding how NurOwn affects all patients with ALS. We are seeing a subset of patients that are responders, and is that just because that they have less severe disease? Or are there other ALS clinical factors involved? But I think a review of the status set, getting a perspective from scientists, clinicians, statisticians, and even the patient community, will really give us insight into this data and the challenges that may or may not be applicable to NurOwn with ALS community.

What impact will the AdComm have on the ALS community?

I'm very happy to hear that the FDA is committed to reviewing these findings and having the scientific discussion of the data. There are so many patients that are invested in NurOwn because they participated in the clinical trial as well as those that have been following NurOwn very carefully. They too, want to understand what the status that means. I think it will be very meaningful to the ALS community at large to have a review of these findings. I just think that the patients have invested so much, we owe it to them. These are patients that are on a time clock. We certainly above all owe it to them to really understand what's happening. I'm thrilled the FDA is moving forward.

Transcript edited for clarity.

REFERENCES
1. Cudkowicz ME, Lindborg SR, Goyal NA, et al. A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle & Nerve. Published online December 10, 2021. doi:10.1002/mus.27472
2. BrainStorm Cell Therapeutics announces FDA Advisory Committee meeting to review biologics license application for NurOwn for the treatment of ALS. March 27, 2023. Accessed March 31, 2023. https://ir.brainstorm-cell.com/2023-03-27-BrainStorm-Cell-Therapeutics-Announces-FDA-Advisory-Committee-Meeting-to-Review-Biologics-License-Application-for-NurOwn-R-for-the-Treatment-of-ALS