Relationship of ALS Genes and Single-Nucleotide Polymorphisms with Clinical Outcomes in NurOwn Phase 3 ALS Clinical Trial


Clinical Trials

Poster Number: 29


Sidney Spector, MD, PhD, Brainstorm Cell Therapeutics, Robert Brown, MD, University of Massachusetts School of Medicine, Stacy Lindborg, PhD, Brainstorm Cell Therapeutics, Ralph Kern, MD, Brainstorm Cell Therapeutics, Jenny Li, PhD, Brainstorm Cell Therapeutics, Sidney Spector, MD, PhD, Brainstorm Cell Therapeutics, Kim Thacker, MD, Brainstorm Cell Therapeutics, Merit Cudkowicz, MD, Neurological Clinical Research Institute at Mass General Hospital, James Berry, MD, Harvard Medical School, Anthony Windebank, MD, Mayo Clinic College of Medicine, Nathan Staff, MD, PhD, Mayo Clinic College of Medicine, Namita Goyol, MD, University of California, Irvine, Robert Miller, MD, California Pacific Medical Center, Jonathan Katz, MD, California Pacific Medical Center, Matthew Burford, MD, Cedar Sinai Medical Center, Munish Mehra, MD, Tigermed , Yael Gothelf, PhD, Brainstorm Cell Therapeutics, Chaim Leibovitz, Esq, Brainstorm Cell Therapeutics, Revital Aricha, PhDBrainstorm Cell Therapeutics

Background: Genetic variations in ALS may influence the rate of disease progression, survival, and serve as pharmacogenomic biomarkers. We evaluated the relationship of ALS-linked genes and single nucleotide polymorphism (SNP) genetic variants known to influence ALS phenotype and clinical outcomes in a Phase III randomized, placebo-controlled study (NCT03280056).
Objective: ALS participants (n=189) were randomized to receive intrathecal NurOwn or placebo at baseline, Week 8 and Week 16 and followed through 28 weeks of treatment. 124 of 189 reconsented participants (63 NurOwn; 61 placebo) were re-evaluated via NGS PGxome, PCR and Sanger sequencing. Responders were pre-specified (≥1.25 points/month improvement in pre- to post-treatment ALSFRS-R slope). Baseline differences by treatment group and genotype are summarized, and pre-specified baseline disease characteristics from the primary efficacy model are used in statistical analysis of response rates by genotype.
Results: The overall response rate of participants in the sub-study was 41% NurOwn and 26% Placebo (p=0.2). Eight of 124 (6.5%) participants expressed seven different ALS gene mutations (SOD1, TARDBP, PSEN2, FUS, TBK1, OPTN, C9orf72). Four SNPs (UNC13A, CAMTA1, MOBP, ZNF512B) for which there were sufficient representations were analyzed. The UNC13A C allele (rs12608932 SNP) is a risk locus for ALS associated with shorter survival. In participants with one or two copies of UNC13A (CC and AC), we observed a 53% responder rate on NurOwn vs. 27% on placebo (p=.016). Responder rates in UNC13A non-carriers were similar between treatments (NurOwn 29%, Placebo 25%). Differences in responder rates between NurOwn vs. placebo for CAMTA1, MOBP, ZNf512B were not statistically significant.
Conclusion: UNC13A rs12608932 SNP risk allele potentiates the deleterious effects of TDP-43 cellular mislocalization in ALS. Our results suggest that NurOwn treatment may influence disease progression in ALS patients who possess this risk allele and provides a basis for further genetic characterization in clinical trials.