BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the 
degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 
protein synthesis. Intrathecal administration of tofersen is being studied for 
the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.
METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in 
adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 
mg), participants were randomly assigned in a 3:1 ratio to receive five doses of 
tofersen or placebo, administered intrathecally for 12 weeks. The primary 
outcomes were safety and pharmacokinetics. The secondary outcome was the change 
from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. 
Clinical function and vital capacity were measured.
RESULTS: A total of 50 participants underwent randomization and were included in 
the analyses; 48 participants received all five planned doses. Lumbar 
puncture-related adverse events were observed in most participants. Elevations 
in CSF white-cell count and protein were reported as adverse events in 4 and 5 
participants, respectively, who received tofersen. Among participants who 
received tofersen, one died from pulmonary embolus on day 137, and one from 
respiratory failure on day 152; one participant in the placebo group died from 
respiratory failure on day 52. The difference at day 85 in the change from 
baseline in the CSF SOD1 concentration between the tofersen groups and the 
placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) 
for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg 
dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 
percentage points (95% CI, -47 to -16) for the 100-mg dose.
CONCLUSIONS: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations 
decreased at the highest concentration of tofersen administered intrathecally 
over a period of 12 weeks. CSF pleocytosis occurred in some participants 
receiving tofersen. Lumbar puncture-related adverse events were observed in most 
participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT 
number, 2015-004098-33.).