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

NurOwn (MSC-NTF cells) is an innovative patient-bone marrow-derived, (autologous), mesenchymal stem cell therapy. The cells are adapted in the lab to boost their production of multiple neurotrophic factors, which are known to help support and protect neurons, the cells destroyed by Amyotrophic Lateral Sclerosis (ALS), including Brain Derived Growth Factor (BDNF), Glial cell Derived Growth Factor (GDNF), Vascular Endothelial Growth Factor (VEGF) and Hepatocyte Growth Factor (HGF), as well as several immunomodulatory cytokines. The cells are then returned to the patients’ target area of damage. Direct and repeated intrathecal administration of MSC-NTF cells may result in immunomodulatory and neuroprotective effects within the (ALS) disease microenvironment, improved neuronal survival and stabilized neural function. MSC-NTF cells have received Orphan Drug designation status from the U.S. FDA and the European Medicines Agency (EMA) for the treatment of ALS as well as FDA Fast Track Status. We evaluated repeat intrathecal administration of MSC-NTF cells in a randomized, double-blind, placebo-controlled phase 3 clinical trial (NCT03280056) for people with ALS. Study participants received three treatments of MSC-NTF cells or placebo intrathecally. Cerebrospinal fluid was collected throughout the study at 7 timepoints for biomarker analysis. The study was conducted at 6 ALS US medical centers of excellence (University of California, Irvine; Cedars-Sinai Medical Center; California Pacific Medical Center; Massachusetts General Hospital; University of Massachusetts Medical School; and Mayo Clinic). Cell manufacturing for this clinical trial was performed at the City of Hope and Dana Farber Cancer Institute cell-culture facilities. The clinical trial was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0984). A grant was also received from ALSA and IAMALS to support phase 3 biomarker analyses. The primary endpoint evaluated efficacy of MSC-NTF cells through a responder analysis (a change in disease progression post-treatment of ≥1.25 points/month and safety. Secondary endpoints included ALSFRS-R change from baseline, and vital capacity in addition to a detailed biomarker analysis. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. 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 weeks (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. In a pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58), we observed a clinical response rate at 28 weeks of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Furthermore, in the secondary endpoint ALSFRS-R change from baseline in this subgroup, we observed a LS mean difference of 2.09 in the average change from baseline to week 28 (p=0.05). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF cells, with placebo unchanged. In summary, the study did not reach statistical significance on the primary endpoint. However, results observed in a pre-specified subgroup with baseline ALSFRS-R score  ≥ 35 suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Study results have been published in Muscle and Nerve.