Abstract
Background
The intrathecally administered antisense oligonucleotide tofersen reduces the synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 IF).
Methods:
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In this Phase 3 study, we randomly assigned adults with: SOD1 ALS in a 2:1 ratio to receive eight doses of tofers (100 mg) or placebo over a 24 week period. The primary endpoint was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) in participants expected to progress more quickly. books. disease. Secondary endpoints were changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity and in hand dynamometry in 16 muscles. A combined analysis of the randomized component of the study and its open-label extension beyond 52 weeks compared results in participants who started on tofersen at study start (early start cohort) with those who started placebo at week 28. switched the drug (delayed start cohort).
Results
A total of 72 participants received tofers (39 predicted faster progression) and 36 received placebo (21 predicted faster progression). Tofersen resulted in greater reductions in plasma SOD1 concentrations of SOD1 and neurofilament light chains than placebo. In the faster progressive subgroup (primary analysis), the change at week 28 in 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 ALSFRS-R score was -6.0 in the early-onset cohort and 9.5 in the delayed-onset cohort (difference 3.5 points; 95% CI 0.4 to 6.7 ); non-multiplicity-adjusted differences in favor of early start tofers were seen for other endpoints. Lumbar puncture-related adverse events were common. Neurological serious adverse events occurred in 7% of token recipients.
conclusions
In persons with SOD1 ALS decreased the concentrations of SOD1 in CSF and neurofilament light chains in plasma for 28 weeks, but did not improve the clinical endpoints and was associated with side effects. The possible effects of earlier compared to delayed tofers initiation are further evaluated in the elongation phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.)
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