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Resurrecting ALS Mesenchymal Cell Therapy for Regulatory Approval

Merit Cudkowicz, MD, discussed corrected data from a phase 3 trial of NurOwn that BrainStorm believes supports a BLA submission.

In an unexpected turnaround, BrainStorm Cell Therapeutics is submitting a biologics license application (BLA) against previous FDA advice after announcing a corrected statistical analysis of a phase 3 clinical trial (NCT03280056) of the mesenchymal cell therapy NurOwn that revealed statistically significant improvements in participants with early-stage amyotrophic lateral sclerosis (ALS).1,2

The trial was originally published in Muscle and Nerve in 2021 and did not meet its primary endpoint of responder rates on ALSFRS-R scores in all stages of disease progression. Based on the findings, the FDA recommended against BLA subimssion.2 However, the newly published erratum revealed statistically significant improvements (= .050) of more than 2 points on ALSFRS-R scores in in the pre-specified efficacy subgroup of participants with a baseline score of at least 35.

The original analyses used an efficacy model that unintentionally deviated from the prespecified statistical analysis plan and the correction employed the correct model. In conclusion, the correction demonstrated that all subgroups with ALSFRS-R baseline scores of at least 26 to 35 showed a statistically significant benefit following treatment with NurOwn (≤.050).

CGTLive spoke with Merit Cudkowicz, MD, chief, neurology, and director, Sean M. Healey & AMG Center for ALS, and Julieanne Dorn Professor of Neurology, Harvard Medical School, to learn more about the corrected data and its implications for ALS.

CGTLive: How could NurOwn potentially address unmet needs in ALS?

Merit Cudkowicz, MD: ALS is a really serious illness, 1 of the most serious in neurology and we have few approved drugs. There are 3 in particular, but 2 of them only slow down the illness a little bit and 1 treats symptoms. So there's a huge unmet need of treatments to really slow this down, and eventually, we want treatments that stop it.

NurOwn is able to use a different mechanism of action as the drugs that are on the market right now, It targets neuro inflammation. In theory, it could be additive to the existing treatments, which are riluzole and edaravone. It's administered intrathecally and that was well tolerated. We're seeing that more and more with gene therapies for central nervous system disorders and it’s becoming very feasible.

This phase 3 trial did not meet its primary endpoint. But what we published in the erratum was one of the pre-specified secondary outcome measures. And there are data that suggest that people who were earlier in the illness or had milder illness might have a benefit with NurOwn treatment.

Can you discuss the phase 3 trial and its findings?

People were randomized 1:1 to active treatment versus placebo, each received 3 treatments of the mesenchymal stem cells and were followed for 20 weeks after a pre-run-in phase. Some participants are now in a expanded access program, but the challenge there is gathering data in the same rigor that you do for a clinical trial. So, it's a great program to have, but I don't know that it'll give us that much more information to help with a decision about approval or not.

For the primary endpoint, we used a responder analysis comparing people's real rate of change of their illness before they started treatment to after treatment. That's a new outcome measure in ALS scales, it's more typical of what we see in oncology trials. Unfortunately, we didn't see a positive effect there. We think that part of it could be related to the scale that we used. Because some of the people that came into the trial were more advanced in their illness, they were on the part of the scale that starts to become a little flat. So, it’s hard to determine a responder effect in that lower end of the scale. That's why I think the secondary outcome measure is important because that's looking at the rate of change, independent of where you are before, and we were able to show again, a difference between treatment and placebo in higher functioning participants.

The ALSFRS-R scale is the best measure we have right now in ALS. It covers a range of functions, like function of the upper extremity, lower extremity breathing, swelling, and speaking. In most trials, it progresses kind of linearly. But when you get to the lower end of the scale like I mentioned, it's less reliable, we think. But it's still a pretty good scale and tells us about people's disease and how they're functioning.

Why is this good news for the community?

ALS is such a serious illness that you don't want to discard a treatment that might be potentially helpful. I mean, that's one of the worst things you could do. Maybe 10 years from now or 5years from now, we might have so many treatments that we wouldn’t need to pursue this, but I think we're still at the stage where anything that might help we want to keep pursuing.

This transcript has been edited for clarity.

REFERENCES
1. BrainStorm Cell Therapeutics announces second quarter 2022 financial results and provides a corporate update. News release. BrainStorm Cell Therapeutics. August 15, 2022. https://ir.brainstorm-cell.com/2022-08-15-BrainStorm-Cell-Therapeutics-Announces-Second-Quarter-2022-Financial-Results-and-Provides-a-Corporate-Update
2. BrainStorm Announces High-Level FDA Feedback on NurOwn® ALS Clinical Development Program. News release. BrainStorm Cell Therapeutics. News release. February 22, 2021. https://ir.brainstorm-cell.com/2021-02-22-BrainStorm-Announces-High-Level-FDA-Feedback-on-NurOwn-R-ALS-Clinical-Development-Program