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

James D Berry, Merit E Cudkowicz, Anthony J Windebank, Nathan P Staff, Margaret Owegi, Katherine Nicholson, Diane McKenna-Yasek, Yossef S Levy, Natalie Abramov, Haggai Kaspi, Munish Mehra, Revital Aricha, Yael Gothelf, Robert H Brown, James D Berry, Merit E Cudkowicz, Anthony J Windebank, Nathan P Staff, Margaret Owegi, Katherine Nicholson, Diane McKenna-Yasek, Yossef S Levy, Natalie Abramov, Haggai Kaspi, Munish Mehra, Revital Aricha, Yael Gothelf, Robert H Brown

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.

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Trial design and CONSORT diagram
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…
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…
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…
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.

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Source: PubMed

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