NurOwn targets multiple disease pathways in ALS Phase 3 Trial

BACKGROUND: MSC‐NTF cells (NurOwn®) are autologous bone marrow derived mesenchymal stem cells that have been shown to favorably modify neuroprotective and neuroinflammatory cerebrospinal fluid (CSF) biomarkers following single intrathecal administration. We conducted a phase 3, randomized, placebo‐controlled, clinical trial to evaluate the efficacy and safety of repeated administration of MSC‐NTF cells in ALS patients. We have separately reported on the clinical effects of MSC‐NTF cells from this trial. The goal of this analysis was to evaluate treatment effects on CSF biomarkers and their relationship to clinical outcomes. METHODS: MSC‐NTF cells were administered intrathecally on 3 occasions, 2‐months apart. CSF samples were obtained prior to the first treatment and at 6 additional times. CSF biomarkers were analyzed using validated multiplex or singleplex assays (Simoa, Procaratplex, and Proximity Extension). Bioinformatic tools were applied to investigate relationships between CSF biomarkers and clinical outcomes. Principal component analyses (PCA) were performed on neuroinflammation, neurodegeneration, and neuroprotection pathways, identified by their contribution to clinical data models to efficiently assess the treatment effects on each pathway separately. A pre‐specified stepwise regression model was used to select biomarkers that that were predictive of the primary efficacy endpoint, from all biomarkers measured, and assess the treatment effect in a combined model. RESULTS: Robust and statistically significant CSF biomarker changes from baseline were observed with MSC‐NTF treatment compared to Placebo in biomarkers related to neuroinflammation, neurodegeneration, and neuroprotection, consistent with earlier trials. For example, there were statistically significant treatment differences in VEGF‐A and MCP‐1 at all post‐treatment time points (p<0.05), with MSC‐NTF increasing VEGF‐A two‐fold following treatment (p<0.0001) and MCP‐1 decreased by 74% compared to Placebo post treatment (p<0.0001). NfL values on MSC‐NTF were 82% relative to Placebo following treatment. PCA analyses retains most of the information provided across all biomarkers collected with 5 PCA components. PCA confirmed the conclusions across biomarkers that MSC‐NTF increased neuroprotection and decreased neuroinflammation and neurodegeneration relative to Placebo. A statistical model demonstrated that MCP‐1, Fetuin‐A, VEGF‐A, MSR1, and NfL were all important predictors of treatment response (all p<0.05), as defined by the primary efficacy endpoint of the trial. The Receiver Operating Curve highlights strong model performance with 82.5% accuracy. Analysis of the primary clinical efficacy endpoint leveraging this model reveals a significant treatment response (p=0.003), with more MSC‐NTF participants meeting the clinical response definition than Placebo participants. DISCUSSION: The significant post‐treatment CSF biomarker changes observed in this study and their relevance to clinical response suggest MSC‐NTF cells have important effects on multiple ALS disease pathways. The data also suggests that simultaneously targeting multiple ALS disease pathways may be necessary to achieve meaningful clinical outcomes.