Tofersen, a SOD1 Antisense Oligonucleotide in Participants with ALS – Results From a Multiple Dose Study (657)

Objective: To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and neurofilament levels of tofersen in people with amyotrophic lateral sclerosis (ALS) and confirmed SOD1 mutation (SOD1-ALS). Background: ALS is a fatal, neurodegenerative disease characterized by loss or dysfunction of motor neurons. Approximately 2% of ALS cases are linked to superoxide dismutase (SOD1) mutations. Over 200 SOD1 mutations have been identified with variation in rate of disease progression. Toxicity of mutant SOD1 protein is due to gain of function, suggesting SOD1 reduction may be therapeutic. Tofersen, a genetically targeted antisense oligonucleotide that targets SOD1 mRNA and reduces SOD1 protein synthesis, is under development for treatment of SOD1-ALS. Design/Methods: This randomized, placebo-controlled, multiple-ascending dose study randomized 50 participants with confirmed SOD1 mutation to receive 4 doses of tofersen or placebo (3:1) for 12 weeks and followed for an additional ~12 weeks. Final primary, secondary, and exploratory endpoint data will be presented. Results: The majority of adverse events were mild or moderate in severity. Dose-dependent increases in tofersen concentrations in plasma and CSF were observed and a statistically significant reduction of CSF SOD1 (100 mg vs placebo) was also observed. A slowing of functional decline as measured by ALS Functional Rating Scale-Revised scores, slow vital capacity, and muscle strength was observed (100 mg vs placebo), with a greater difference observed between the 100 mg and placebo groups in participants with fast progressing SOD1 mutations. Baseline CSF and plasma phosphorylated neurofilament heavy and neurofilament light were generally highest in faster progressing participants. Treatment with tofersen was associated with a decline in neurofilament over time in contrast to apparent stabilization or increase observed in placebo-treated patients. Conclusions: These data support further investigation of tofersen in people with SOD1-ALS, and highlight the potential role of neurofilament as a biomarker of disease activity and treatment response in ALS. Disclosure: Dr. Cudkowicz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with takeda, biogen, cytokinetics, sunovian, immunitypharm, avexis.Dr. Miller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Cytokinetics, and Disarm Therapeutics. Dr. Miller has received royalty, license fees, or contractual rights payments from Ionis Pharmaceuticals and C2N. Dr. Miller has received research support from Biogen and Ionis Pharmaceuticals.Dr. Shaw has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultancy for serving on Scientific Advisory Board for Biogen and for speaking, symposium organisation for Cytokinetics. Dr. Shaw has received research support from Research support from Pfizer for investigation of molecular mechanisms of neuronal injury in C9orf72 ALS.. Dr. Bennett has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Ionis. Dr. Bennett has received compensation for serving on the Board of Directors of Ionis, compensation includes salary and stock options.. Dr. Bennett holds stock and/or stock options in Ionis, compensation includes salary and stock options that exceed $10,000 in value which sponsored research in which Dr. Bennett was involved as an investigator. Dr. Bennett holds stock and/or stock options in Ionis, compensation includes salary and stock options that exceed $10,000 in value. Dr. Lane has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Ionis. Dr. Lane has received compensation for serving on the Board of Directors of Ionis, compensation includes salary and stock options.. Dr. Lane holds stock and/or stock options in Ionis, compensation includes salary and stock options that exceed $10,000 in value which sponsored research in which Dr. Lane was involved as an investigator. Dr. Lane holds stock and/or stock options in Ionis, compensation includes salary and stock options that exceed $10,000 in value. Dr. Chang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Chang holds stock and/or stock options in Biogen, stock greater than 10K which sponsored research in which Dr. Chang was involved as an investigator. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Chen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Nestorov has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Graham has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Graham has received compensation for serving on the Board of Directors of Biogen. Dr. Graham holds stock and/or stock options in Biogen which sponsored research in which Dr. Graham was involved as an investigator. Dr. Fanning has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Fanning holds stock and/or stock options in Biogen, stock greater than 10K which sponsored research in which Dr. Fanning was involved as an investigator. Dr. McNeill has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Fradette has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Ionis. Dr. Fradette has received compensation for serving on the Board of Directors of Biogen, compensation includes stock. Dr. Fradette holds stock and/or stock options in Biogen, stock greater than 10K which sponsored research in which Dr. Fradette was involved as an investigator. Dr. Ferguson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Ferguson has received compensation for serving on the Board of Directors of Biogen, compensation includes stock. Dr. Ferguson holds stock and/or stock options in Biogen, stock greater than 10K which sponsored research in which Dr. Ferguson was involved as an investigator.