Tofersen Reduces SOD1 CSF Concentrations in Patients With ALS


In the phase 1/2 study, the Biogen agent showed a favorable reduction of SOD1 concentrations compared to placebo, particularly with the 100-mg dose, and is being assessed in an ongoing phase 3 study, VALOR.

Dr Toby Ferguson

Toby Ferguson, MD, PhD, vice president, and head, Neuromuscular Development Unit, Biogen

Toby Ferguson, MD, PhD

The results of a phase 1/2 trial of tofersen (NCT02623699) suggest that the Biogen antisense oligonucleotide reduces the concentration of superoxide dismutase 1 (SOD1) in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.1

Over a period of 12 weeks, the difference in the change from baseline in CSF SOD1 concentration favored those administered intrathecal tofersen, which was assessed in a number of doses—20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), and 100 mg (n = 10)—compared to placebo across doses (n = 12). As for safety, CSF pleocytosis occurred in some participants receiving tofersen, and lumbar puncture-related adverse events (AEs) were observed in most participants.

“By evaluating genetically validated targets such as SOD1 in defined populations, we believe we can more quickly identify how to treat this devastating disease,” said Toby Ferguson, MD, PhD, vice president, and head, Neuromuscular Development Unit, Biogen, in a statement.2 “Biogen is committed to furthering ALS research in an effort to potentially bring a therapy to people living with this rapidly progressing neurological condition.”

The SOD1 gene mutation is believed to be a genetic driver of ALS in approximately 2% of all cases. As tofersen is a gene therapy, Ferguson told NeurologyLive that the particularly notable component to these data are supportive of the drug’s mechanism of action. “We're really trying to knock down that that mutated SOD1 protein, and one of the key outcomes in this study is that the molecule got in and we saw at the highest dose—100 milligrams—reduction of SOD1,” he said.

All told, at Day 85, differences between the tofersen groups and placebo were 2 percentage points (95% 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. Respectively, the geometric mean ratios of the SOD1 protein concentrations among participants who received tofersen decreased overall by 1%, 27%, 21%, and 36%. Among those who received placebo, the ratio decreased by 3%.

The geometric mean SOD1 concentration at baseline among those who received tofersen was 79.9 ng/mL in the 20-mg dose group, 140.9 ng/mL in the 40-mg dose group, 102.5 ng/mL in the 60-mg dose group, and 139.8 ng/mL in the 100-mg dose group. Comparatively, for placebo, the mean concentration was 84.6 ng/mL.

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With regard to safety findings, the most commonly reported AEs in people who received ≥1 dose of tofersen (n = 38) were headache (n = 16; 42.1%), procedural pain (n = 16; 42.1%), post-lumbar puncture syndrome (n = 13; 34.2%), and falls (n = 13; 34.2%). These were comparable with the placebo rates for headache (n = 7; 58%), procedural pain (n = 5; 42%), post-lumbar puncture syndrome (n = 3; 25%), and falls (n = 3; 25%). Serious AEs were reported by 5 tofersen- and 2 placebo-treated people. One death occurred in the placebo group during the trial due to respiratory failure secondary to ALS, and 2 deaths occurred in the tofersen group during a follow up period due to pulmonary embolism and respiratory failure (20 mg and 60 mg group, respectively).

“The data published in TheNew England Journal of Medicine are an important step in understanding the potential of tofersen and genetic disease drivers as targets for ALS,” said Timothy Miller, MD, PhD, co-principal investigator, and director, ALS Center, Washington University School of Medicine at St. Louis, in a statement. “We are encouraged by these study results and will continue to evaluate the efficacy and safety of tofersen as a potential treatment for SOD1-ALS.”

Additionally, the exploratory measures assessed showed a numerical trend towards the slowing of clinical decline, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), as well as slow vital capacity and muscle strength measured by handheld dynamometer (HHD) in favor of 100-mg tofersen.

The mean change in ALSFRS-R score from baseline to Day 85 was -1.19 in the tofersen group compared to -5.63 in the placebo group on a 48-point scale. Slow vital capacity measures showed the least-squares mean percent at Day 85 changed from baseline by −7.08 percentage points (95% CI, −14.69 to 0.54), as compared with −14.46 percentage points (95% CI, −21.79 to −7.12) in the overall placebo group. For HHD, the mean change at Day 92 was −0.03 ±0.18 in the 100-mg dose group compared with −0.26 ±0.42 in the overall placebo group.

Ferguson additionally highlighted another piece of chemical data from the study results—the reduction of neurofilament that was observed. “[This] also suggests that the molecule is doing something important. Neurofilament is a general marker of axon integrity, and it's known to be increased in a number of different neurodegenerative diseases including ALS,” he told NeurologyLive.

The concentrations of phosphorylated neurofilament heavy chains and neurofilament light chains in plasma and CSF were largely unchanged during the intervention period among the placebo group, whereas the 100-mg group saw concentrations decrease from baseline to Day 85.

A phase 3 study, VALOR (NCT02623699), is currently ongoing and will assess the efficacy and safety of tofersen versus placebo in adults with SOD1-ALS.


1. Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1—2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020; 383:109-119. doi: 10.1056/NEJMoa2003715

2. The New England Journal of Medicine Publishes Final Results from Phase 1/2 Study of Tofersen for a Genetic Form of ALS [press release]. Cambridge, MA. Biogen. Published July 8, 2020. Accessed July 9, 2020.

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