Nearly all members of an FDA advisory panel voted against the data presented for an investigational amyotrophic lateral sclerosis (ALS) treatment on Wednesday.
In a 17-1 vote, the FDA's Cellular, Tissue, and Gene Therapy Advisory Committee said the data presented about debamestrocel -- also known as mesenchymal stromal cells secreting neurotrophic factors (MSC-NTF), or NurOwn -- did not demonstrate substantial evidence of effectiveness for treatment of mild to moderate ALS.
The single supporting vote came from the committee's consumer representative, Kathleen O'Sullivan-Fortin, JD, of ALD Connect in Middleton, Massachusetts. One member, Nirali Shah, MD, MHSc, of the National Cancer Institute in Bethesda, Maryland, abstained.
At the heart of the decision was the treatment's failure in a of about 200 ALS patients. On the primary endpoint, 33% in the MSC-NTF group and 28% in the placebo group met clinical response criteria at 28 weeks, which was not statistically significant (P=0.45).
"We have a single study -- the phase III study at the dose and formulation that's been proposed -- and it unfortunately didn't achieve evidence of efficacy for either the primary or the secondary endpoints," said committee member G. Caleb Alexander, MD, MS, of Johns Hopkins University in Baltimore.
MSC-NTF is an autologous cell-based therapy intended to secrete NTFs, which are important for nerve survival and function. The mechanism of action of MSC-NTF is unknown, but developer BrainStorm Cell Therapeutics hypothesizes that by secreting NTFs, the therapy could slow disease progression in patients with ALS. Treatment requires bone marrow aspiration to obtain the cells to produce the product, followed by repeated intrathecal administration.
In briefing documents released before the Wednesday meeting, FDA reviewers raised concerns not only about the drug's clinical trial data, but its manufacturing process. When the agency first received the drug's application for approval, it determined the submission was "scientifically incomplete to demonstrate substantial evidence of effectiveness, and that the manufacturing information was grossly deficient to ensure adequate product quality," FDA reviewers wrote.
In the phase III trial, survival was worse for ALS patients who received MSC-NTF compared with placebo. Some cerebrospinal fluid biomarkers hinted at a benefit with MSC-NTF treatment, but biomarker data were missing for about half of participants at week 20.
Analysis of a prespecified subgroup suggested that MSC-NTF participants with less severe disease may have retained more function compared with placebo, but those findings were not statistically significant.
Brainstorm focused largely on this subgroup in its presentation Wednesday. However, FDA staff members pointed out that even in this population, patterns weren't clear.
"This is not a case where there was a trend toward a treatment effect, but the drug just missed statistical significance. There was no such trend," FDA analyst Gumei Liu, MD, PhD, told the advisory committee.
An additional clinical trial is warranted, the advisory committee maintained. While ALS is a devastating disease and there's an urgent need for effective treatments, "providing false hope can be ethically problematic," observed committee member Lisa Lee, PhD, of Virginia Tech in Blacksburg.
"False hope is provided when the probability of a positive outcome is overestimated, and I think that seems to be the case here," Lee said.
The advocacy group I Am ALS indicated support for MSC-NTF at the Wednesday meeting. However, the ALS Association, which often takes a supportive position on new ALS treatments, that the "amazing testimonials we have seen online do not align with the data that BrainStorm has shared with us or has been published in peer-reviewed publications."
In a statement released after the advisory committee meeting, the ALS Association called on BrainStorm to in the phase III trial, which concluded over 3 years ago.
BrainStorm originally filed a biologics license application for MSC-NTF in September 2022. The FDA refused the submission and detailed reasons why in a letter to the company, which subsequently filed the application over protest.
The agency is expected to decide whether to approve MSC-NTF by December 8. The FDA isn't required to follow the advice of its advisory committees, but often it does.