The intrathecally administered antisense oligonucleotide Tofersen decreases the synthesis of the protein superoxide dismutase 1 (SOD1) and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 AS).
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In this phase 3 study, we randomly assigned adults SOD1 ALS in a 2:1 ratio to receive eight doses of Tofersen (100 mg) or placebo over a 24-week period. The primary endpoint was the change in total scores on the revised ALS Function Rating Scale (ALSFRS-R; range 0 to 48, with higher scores indicating better function) from baseline to week 28 in those participants predicted to progress faster with the disease . Secondary endpoints included changes in total cerebrospinal fluid (CSF) SOD1 protein concentration, plasma neurofilament light chain concentration, slow vital capacity and hand dynamometry in 16 muscles. A combined analysis of the randomized component of the study and its open-label extension at 52 weeks compared the outcomes of participants who started on Tofersen at study entry (early-start cohort) versus participants who switched from placebo to the drug at week 28 (delayed start cohort).
A total of 72 participants received Tofersen (39 were predicted to progress more quickly) and 36 received placebo (21 were predicted to progress more quickly). Tofersen resulted in greater reductions in CSF SOD1 and plasma neurofilament light chain concentrations than placebo. In the faster progressing subgroup (primary analysis), the change in ALSFRS-R score through week 28 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). The 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 start cohort and -9.5 in the delayed start cohort (difference, 3.5 points; 95% CI, 0.4 to 6 ,7); non-multiplicity-adjusted differences favoring Tofersen with early onset were observed for other endpoints. Side effects associated with lumbar puncture were common. Serious neurological adverse events occurred in 7% of Tofersen recipients.
For people with SOD1 ALS, Tofersen reduced levels of CSF SOD1 and plasma neurofilament light chains over 28 weeks but did not improve clinical endpoints and was associated with adverse events. The potential impact of earlier versus delayed onset of Tofersen will be further 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.)