Tofersen antisense oligonucleotide assay for SOD1 ALS
The intrathecally administered antisense oligonucleotide tofersen reduces protein superoxide dismutase 1 (SOD1) synthesis and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).
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In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over 24 weeks. The primary endpoint was the change from baseline to week 28 in total score on the ALS Functional Rating Scale Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants with faster progression. sickness. Secondary endpoints included changes in total cerebrospinal fluid (CSF) SOD1 protein concentration, plasma neurofilament light chain concentration, slow vital capacity, and handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its 52-week open-label extension compared outcomes in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to drug at week 28. (delayed start cohort).
A total of 72 participants received tofersen (39 predicted faster progression) and 36 received placebo (21 predicted faster progression). Tofersen produced greater reductions in CSF SOD1 concentrations and plasma neurofilament light chains than placebo. In the more rapidly progressing subgroup (primary analysis), the change at week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points 95% confidence interval [CI], -3.2 to 5.5; p=0.97). Results for secondary clinical endpoints did not differ significantly between the two groups. A total of 95 participants (88%) participated in the open label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0. 4 to 6.7); unadjusted differences for multiplicity favoring early onset of tofersen were observed for other parameters. Adverse events related to lumbar puncture were common. Serious neurological adverse events occurred in 7% of tofersen recipients.
In people with SOD1 ALS, tofersen reduced CSF SOD1 and plasma neurofilament light chain concentrations over 28 weeks, but did not improve clinical parameters and were associated with adverse events. The potential effects of early versus delayed initiation of tofersen are being evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.)