US Food & Drug Administration (FDA) reviewers have expressed misgivings about the investigational amyotrophic lateral sclerosis (ALS) treatment debamestrocel from BrainStorm Cell Therapeutics, before an advisory committee meeting that was to be held this week.
ALS, or Lou Gehrig’s, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord, reports MedPage Today.
When the FDA first received the drug’s application for approval, it determined that the submission was “scientifically incomplete to demonstrate substantial evidence of effectiveness”, and that the manufacturing information was “grossly deficient to ensure adequate product quality”, the agency said in briefing documents prepared before the Wednesday meeting.
The application had missing or incomplete validation of methods and a lack of data demonstrating manufacturing consistency, the FDA reviewers had written.
The agency refused to file the submission and detailed these deficiencies in a letter to BrainStorm, which filed the application over protest. The company subsequently provided additional retrospective analyses and biomarker results.
Yesterday, the FDA’s Cellular, Tissue, and Gene Therapy Advisory Committee was to meet to discuss whether BrainStorm’s data meet the agency’s standard of substantial evidence of effectiveness for approval.
Mesenchymal stromal cells secreting neurotrophic factors, also known as MSC-NTF, or NurOwn – is an autologous cell-based therapy intended to secrete NTFs, which are important for nerve survival and function. The FDA maintains that the drug’s mechanism is unclear, but BrainStorm hypothesises that by secreting NTFs, its therapy could slow disease progression in patients with ALS.
Treatment requires initial bone marrow aspiration from the patient to obtain the cells to produce the product, followed by repeated intrathecal administration.
The MSC-NTF clinical development programme consisted of four studies – two single-arm, open-label, early-phase studies; a phase II trial where ALS patients received a one-time administration of a single intrathecal injection and 24 intramuscular injections; and a phase III randomised, double-blind, placebo-controlled study in which patients received a total of three intrathecal injections, one every eight weeks.
The pivotal phase III trial, the only one to evaluate MSC-NTF using both its intended route and dose interval, did not meet its primary endpoint, with 33% of patients in the MSC-NTF group and 28% in the placebo group meeting clinical response criteria at 28 weeks (P=0.45).
The phase III study randomised 98 ALS patients to MSC-NTF and 98 to placebo. Survival was worse at study completion for people who received MSC-NTF (10 deaths vs three deaths for the placebo group), the FDA noted.
Some biomarker data suggested benefit, but “there was a large amount of missing data for all biomarkers at week 20 (~50%), the last time point for biomarker sample collection and the focused time point for biomarker analyses”, the agency said.
Analysis of a pre-specified subgroup suggested that MSC-NTF participants with less severe disease may have retained more function compared with placebo, but the findings were not statistically significant.
Nonetheless, BrainStorm maintained in its pre-meeting briefing documents, “The totality of evidence shows that NurOwn has a consistent and clinically meaningful treatment effect across a broad range of patients with ALS, further supported by significant results across multiple biomarkers.”
The ALS Association, which often takes a supportive position on new ALS treatments, noted the “amazing testimonials we have seen online do not align with the data that BrainStorm have shared with us or been published in peer-reviewed publications”.
“We have an obligation to the community … to be vigilant and data-driven, and our approach has served the ALS community well in recent FDA reviews,” the group added. “Until we have the opportunity to conduct an independent review, we cannot take a position for or against approval of NurOwn.”
BrainStorm was to make its case yesterday (Wednesday) before a panel of FDA advisors, who were to spend the day reviewing the MSC-NTF data.
The meeting planned to focus on clinical, statistical, and biomarker data only, not the product manufacturing and control processes since those issues aren’t resolved.
The FDA said it would not issue a final determination about MSC-NTF until input from the advisory committee process had been considered and all reviews finalised.
The agency doesn’t have to follow the advice of the committee, but it often does.
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