Name: Tofersen
Synonyms: BIIB067, Ionis-SOD1Rx, ASO1
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 3)
Company: Biogen, IONIS Pharmaceuticals


BIIB067 is a second-generation antisense oligonucleotide (ASO) targeting the mRNA for superoxide dismutase 1. It mediates mRNA degradation to prevent SOD1 protein synthesis and reduce levels of SOD1 protein. BIIB067 is being developed for ALS caused by SOD1 mutations, which account for about 20 percent of all familial ALS and 2 percent of all ALS cases. Although the exact pathological mechanism remains unknown, mutant SOD1 is believed to exert a toxic action on motor neurons, and reducing its levels may be beneficial.

In 2013, Ionis tested a first-generation SOD1 ASO, which proved safe in people, but lacked potency (May 2013 news). The company then screened 2,000 SOD1 ASOs and identified two targeting the mRNA 3' untranslated region that were most effective at lowering SOD1 mRNA and protein levels in cells. Injection of ASO1 into the brain or spinal cord of mice or rats expressing mutant SOD1 reduced spinal-cord levels of SOD1 mRNA and protein. A single injection delayed disease onset, improved motor function, and increased survival in the animals. ASO1 treatment preserved neuromuscular innervation and stemmed the rise of phosphorylated neurofilament heavy chain in blood, a prognostic biomarker for ALS. In nonhuman primates, ASO1 lowered SOD mRNA in the CNS after spinal-cord injection (Jul 2018 news on McCampbell et al., 2018).

Biogen licensed ASO1 from Ionis, and is leading its clinical development.


In January 2016, Biogen and Ionis began a Phase 1/2 safety trial in SOD1-ALS. The study enrolled 84 people who received single or multiple ascending doses by intrathecal injection into their lumbar spinal cord. In the multiple-dosing phase, 48 participants in four cohorts were randomized 3:1 to receive 20, 40, 60, or 100 mg BIIB067 or placebo five times over 12 weeks. Primary outcomes were adverse events and PK; the secondary outcome was levels of SOD1 protein in cerebrospinal fluid after the last dose. The study took place at 18 sites in the U.S., Canada, and Western Europe. 

The multiple-dosing phase of the trial was completed in January 2019. According to results presented at the May 2019 American Academy of Neurology conference, and later published, ASO treatment was safe and reduced mutant SOD1 protein (May 2019 conference news; Miller et al., 2020). Most adverse events were mild to moderate; the most common were headache, procedural pain, and postlumbar syndrome related to the spinal taps. Falls were also common. Seven participants had serious adverse events. Three died. One person in the treatment group and one on placebo died of respiratory failure; one person in the treatment group died from a lung embolism. SOD1 protein levels in cerebrospinal fluid dropped by 3 percent in the low-dose group, and 36 percent in the high-dose group, compared with placebo.

Approximately 10 percent of people receiving BIIB067 showed elevated CSF white cell counts, and a similar number had elevated protein in their CSF. No one developed myelitis, an inflammation of the spinal cord accompanied by sensory and motor deficits, but the investigators noted this condition was seen in some people dosed with BIIB067 in an ongoing Phase 3 and long-term extension (see below).

The small trial was not designed to measure efficacy, but exploratory outcomes included change from baseline in the ALS functional Rating Scale-Revised (ALSFRS-R), lung vital capacity and muscle strength, and blood and CSF neurofilament concentrations. The highest-dose group appeared to decline more slowly on the ALSFRS-R, showing a loss of 1.19 points at week 12, compared with 5.63 in the placebo group. Concentrations of neurofilament heavy and light chains in CSF and blood decreased from baseline to 12 weeks in the highest-dose group.

In March 2019, Biogen added a Phase 3 efficacy arm to the same trial. Called VALOR, the study will enroll an additional 99 people with SOD1-ALS, who will receive an undisclosed, fixed dose of BIIB067 or placebo for 28 weeks. The primary outcome is change from baseline in the ALSFRS-R at week 28. Secondary outcomes are other clinical measures such as time to needing a ventilator, muscle strength, survival, and CSF levels of phosphorylated neurofilament heavy chain. The trial is to be conducted at 31 sites in North America, Europe, Australia, and Japan, and finish in July 2021. An ongoing, open-label safety extension will run through June 2023, with treatment offered for up to five years. 

In December 2018, a research study began to evaluate the distribution of BIIB067 in the central nervous system by SPECT/CT imaging after co-administration of a microdose of radiolabeled BIIB067 and high- or low-dose BIIB067 in 20 healthy volunteers. The trial was scheduled to complete in January 2020, but in May 2020, recruitment was suspended and the end date adjusted to December 2020, due to the Covid-19 pandemic.

For details on BIIB067 trials, see

Last Updated: 10 Jul 2020


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News Citations

  1. Antisense Oligonucleotides: Can They Take on ALS, SMA, Prions?
  2. Paper Alert: Antisense Oligonucleotide Therapy Safe for ALS?
  3. Next-Gen Antisense and Small Protein-Protein Disruptors Benefit SOD1 Models

Paper Citations

  1. . Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. PubMed.
  2. . Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018 Aug 1;128(8):3558-3567. Epub 2018 Jul 16 PubMed.

External Citations


Further Reading

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