TY - JOUR
T1 - NurOwn, phase 2, randomized, clinical trial in patients with ALS
T2 - Safety, clinical, and biomarker results
AU - Berry, James D.
AU - Cudkowicz, Merit E.
AU - Windebank, Anthony J.
AU - Staff, Nathan P.
AU - Owegi, Margaret
AU - Nicholson, Katherine
AU - McKenna-Yasek, Diane
AU - Levy, Yossef S.
AU - Abramov, Natalie
AU - Kaspi, Haggai
AU - Mehra, Munish
AU - Aricha, Revital
AU - Gothelf, Yael
AU - Brown, Robert H.
N1 - Funding Information:
J. Berry has no financial conflicts; has acted as a consultant for an advisory panel for Denali Therapeutics; and has research funding and/or acts as an investigator for studies funded by MT Pharma, Brainstorm Cell Therapeutics, Amylyx Pharmaceuticals, Genentech, Anelixis Pharmaceuticals, ALS Association, Muscular Dystrophy Association, ALS Finding a Cure, and ALS One. M. Cudkowicz is a consultant for Biohaven, Takeda, MT pharma, Aclipse and Avexis; was on a DSMB for Lilly; and receives grant support from NINDS, ALSFAC, and the ALS Association. A. Windeank is a consultant for the Federal Trade Commission on stem cell issues (those consulting fees go to his research budget at Mayo Clinic); and serves on the external advisory boards of 2 research institutes in Europe: CURAM in Ireland and SCI-TReCS in Austria (he derives no compensation for these positions other than for travel and accommodation). N. Staff has no financial conflicts; has research funding and/or acts as an investigator for studies funded by Orion Pharmaceuticals, Cytokinetics, Regenerative Medicine Minnesota, and Brainstorm Therapeutics; and has research funding from the NIH (R01 CA 211887). M. Owegi has no financial conflicts with Brainstorm and no relevant financial interests/disclosures. K. Nicholson has no financial conflicts with the Brainstorm Study; has acted as a consultant for an advisory panel for Avanir Pharmaceuticals; and has research funding and/or acts as an investigator for studies funded by Brainstorm Cell Therapeutics, Amylyx Pharmaceuticals, ALS Association, Muscular Dystrophy Association, ALS Finding a Cure, Target ALS, and the Salah Foundation. D. McKenna-Yasek has no conflict of interests regarding the Brainstorm Therapeutics clinical trial. Y.S. Levy is a Brainstorm employee. N. Abramov is a Brainstorm employee. H. Kaspi is a Brainstorm employee. M. Mehra received consulting fees for the analyses from Brainstorm Cell Therapeutics. R. Aricha is a Brainstorm employee. Y. Gothelf is a Brainstorm employee. R. Brown has no financial conflicts with the Brainstorm study; is a scientific founder of Apic-Bio and holds equity in Amlyx and Imstar; and has research funding and/or acts as an investigator without personal financial compensation for studies funded by Brainstorm Cell Therapeutics, the Angel Fund, ALS Association, Muscular Dystrophy Association, ALS Finding a Cure, Project ALS, Target ALS, and ALS One. Go to Neurology.org/N for full disclosures.
PY - 2019/12/10
Y1 - 2019/12/10
N2 - ObjectiveTo 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.MethodsThe 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.ResultsThe 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).ConclusionA 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 evidenceThis phase II study provides Class I evidence.
AB - ObjectiveTo 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.MethodsThe 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.ResultsThe 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).ConclusionA 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 evidenceThis phase II study provides Class I evidence.
UR - http://www.scopus.com/inward/record.url?scp=85076329841&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076329841&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000008620
DO - 10.1212/WNL.0000000000008620
M3 - Article
C2 - 31740545
AN - SCOPUS:85076329841
VL - 93
SP - E2294-E2305
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 24
ER -