Long-term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

• Type of Material: Article
• Authors: Stephen A. Goutman, University of Michigan; Morton B. Brown, University of Michigan; Jonathan D Glass, Emory University; Nicholas Boulis, Emory University; Karl Johe, Neuralstem; Tom Hazel, Neuralstem; Merit Cudkowicz, Harvard Medical School; Nazem Atassi, Harvard Medical School; Lawrence Borges, Harvard Medical School; Parag G. Patil, University of Michigan; Stacey A. Sakowski, University of Michigan; Eva L. Feldman, University of Michigan
• Language: English
• Date: 2018-06-01
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial No Derivatives
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/acn3.567
• Title of Journal or Parent Work: Annals of Clinical and Translational Neurology
• ISSN: 2328-9503
• Volume: 5
• Issue: 6
• Start Page: 730
• End Page: 740
• Grant/Funding Information: Funding was provided by the National Institute of Neurological Disorders and Stroke 1R01NS077982, the ALS Association, Neuralstem, Inc., the A. Alfred Taubman Medical Research Institute, and philanthropic sources.
• Keywords: SOD1 TRANSGENIC RATS; SAFETY OUTCOMES; AMYOTROPHIC-LATERAL-SCLEROSIS; Neurosciences & Neurology; Neurosciences; GRAFTS; I TRIAL; MOTOR-NEURON DISEASE; Life Sciences & Biomedicine; SPINAL-CORD; Science & Technology; REPRODUCIBILITY; Clinical Neurology
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Biostatistics

Abstract

Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Objective: Intraspinal human spinal cord-derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb-onset ALS participants in Phase 1 and 2 (Ph1/2) open-label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs. Methods: Survival, ALSFRS-R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS-R) functional status were assessed for matched participant subsets: PRO-ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20. Results: Survival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO-ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS-R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO-ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO-ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS-Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO-ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study. Interpretation: Comparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO-ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery-controlled efficacy study.