NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results

Abstract

Objective: To determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial.

Methods: The study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months. CSF was collected before and 2 weeks after transplantation.

Results: The study met its primary safety endpoint. The rate of disease progression (Revised ALS Functional Rating Scale [ALSFRS-R] slope change) in the overall study population was similar in treated and placebo participants. In a prespecified rapid progressor subgroup (n = 21), rate of disease progression was improved at early time points (p < 0.05). To address heterogeneity, a responder analysis showed that a higher proportion of treated participants experienced ≥1.5 points/month ALSFRS-R slope improvement compared to placebo at all time points, and was significant in rapid progressors at 4 and 12 weeks (p = 0.004 and 0.046, respectively). CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants (p < 0.05) post-transplantation. CSF monocyte chemoattractant protein-1 levels correlated with ALSFRS-R slope improvement up to 24 weeks (p < 0.05).

Conclusion: A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS.

Classification of evidence: This phase II study provides Class I evidence.

Figure 1. Trial design and CONSORT diagram

(A) Trial design. (B) CONSORT diagram: participant enrollment, intervention allocation, and follow-up. MSC = mesenchymal stem cell; NTF = neurotrophic factor.

Figure 2. Mean change in Revised ALS Functional Rating Scale (ALSFRS-R) slope over time (top) and responder analyses: ≥1.5-point ALSFRS-R slope improvement over the post-treatment follow-up period (bottom)

(A, B) ALSFRS-R least squares (LS) means of the change in slope (post-treatment minus pretreatment) for each of the post-treatment time points for the total population (A) and rapid progressors (defined as those participants with a pretreatment ALSFRS-R change ≥−2 between screening and baseline) (B). The difference between the treated and placebo groups was statistically significant at the 2 and 4 weeks timepoints (p = 0.021 and 0.033, respectively, indicated by a * for p < 0.05). (C, D) The percentage of participants with a ≥1.5-point improvement in the ALSFRS-R slope at the indicated time points as compared to their pretreatment slope over the ∼12 weeks pretreatment period in the mesenchymal stem cell (MSC)–neurotrophic factor (NTF) cells treated and the placebo group total population (C) and rapid progressors (defined as participants with a pretreatment ALSFRS-R change ≥−2 between screening and baseline) (D). In the overall population, the difference was statistically significant at week 4 (p = 0.033). In rapid progressors, the differences between the treated and placebo groups were statistically significant at the 4 and 12 weeks timepoints (p = 0.004 and 0.046, respectively, indicated by a * for p < 0.05).

Figure 3. CSF analysis pretransplantation (V5) and 2 weeks post-transplantation (V6)

(A) A significant increase in vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) levels is shown in the CSF of the mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells treated group (upper panels) with no detectable change in the placebo group (lower panels). (B) A significant decrease in monocyte chemoattractant protein-1 (MCP-1), stromal cell-derived factor-1a (SDF-1), and chitotriosidase-1 (CHIT-1) levels is shown in the CSF of the MSC-NTF cells treated group (upper panels) with no significant change in the placebo group (lower panels). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 4. Monocyte chemoattractant protein-1 (MCP-1) correlation to vascular endothelial growth factor (VEGF) secretion and to disease progression

(A) A significant correlation between VEGF increase and MCP-1 decrease is shown in the CSF of the mesenchymal stem cell (MSC)–neurotrophic factor (NTF) cells treated group at visit six 2 weeks post-transplantation with no significant change in the placebo group. No correlation was seen between VEGF and MCP-1 levels prior to treatment (V5). (B) A significant correlation between MCP-1 in the CSF at 2 weeks post MSC-NTF cells treatment (visit 6, right panel) and a slower disease progression at 12 weeks post-treatment is shown, with no significant change in the placebo group (left panel). ALSFRS-R = Revised ALS Functional Rating Scale.