A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis

• Main Authors: Aricha, R. (Author), Baloh, R.H (Author), Berry, D.A (Author), Berry, J.D (Author), Brown, R.H., Jr (Author), Burford, M.J (Author), Cudkowicz, M.E (Author), Gothelf, Y. (Author), Goyal, N.A (Author), Jenkins, L.J (Author), Katz, J.S (Author), Kern, R.Z (Author), Levy, Y.S (Author), Lewis, R.A (Author), Lindborg, S.R (Author), Miller, R.G (Author), Mozaffar, T. (Author), Nicholson, K.A (Author), Owegi, M.A (Author), Staff, N.P (Author), Windebank, A.J (Author)
• Format: Article
• Language: English
• Published: John Wiley and Sons Inc 2022
• Subjects: adult; ALSFRS-R; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; Article; autotransplantation; biological marker; biomarker; clinical effectiveness; clinical trial; controlled study; double blind procedure; Double-Blind Method; female; human; human cell; Humans; major clinical study; male; mesenchymal stem cell; mesenchymal stem cell transplantation; Mesenchymal Stem Cells; metabolism; multicenter study; nerve growth factor; Nerve Growth Factors; neurotrophic factor; pain; parallel design; patient safety; phase 3 clinical trial; placebo; randomized controlled trial; riluzole; stem cells; Transplantation, Autologous; treatment response
• Online Access: View Fulltext in Publisher

 Introduction/Aims: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. Methods: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. Results: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P =.45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P =.29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. Discussion: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation. © 2021 BrainStorm Cell Therapeutics. Muscle & Nerve published by Wiley Periodicals LLC.