Background

This drug 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. Tofersen 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 brains or spinal cords 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.

Findings

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, and 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 people 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 white cell counts in their CSF, and a similar number had elevated protein in 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 enrolled 108 people with SOD1-ALS, of whom 72 received eight infusions of 100 mg BIIB067 over 28 weeks; 36 received placebo. The primary outcome was change from baseline in the ALSFRS-R at week 28 in a subgroup of patients defined as faster progressing using trial-specific prognostic criteria. Secondary outcomes were other clinical measures such as time to needing a ventilator, muscle strength, survival, CSF SOD1, and plasma phosphorylated neurofilament heavy chain. The trial was conducted at 32 sites in North America, Europe, Australia, and Japan, and finished in July 2021. An ongoing, open-label safety extension involving 139 patients will run through August 2024, 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. Recruitment was suspended in May 2020, due to the COVID-19 pandemic, and the study was completed in July 2021 with just eight participants.

In May 2021, recruitment began for a Phase 3 study in presymptomatic carriers of an SOD1 mutation. Called ATLAS, this study intends to enroll 150 people, who must also have elevated plasma NfL. After a run-in period to confirm NfL elevation, participants will receive 100 mg tofersen or placebo via intrathecal injection three times in the first month, and then monthly for up to two years. The primary endpoint is the number of participants who develop ALS symptoms within the first year of treatment. Secondary outcomes include the time to emergence of symptoms, ALSFRS-R, lung function, need for ventilation, death, adverse events, and changes in SOD1 and neurofilament light chain (NfL). Participants who become symptomatic during the trial will be eligible for open-label treatment for up to two years. The study will run through August 2027. The protocol is published (Benatar et al., 2022).

On October 17, 2021, Biogen announced that the VALOR trial had missed its primary endpoint of slowing decline on the ALSFRS-R at week 28 (Oct 2021 news). Full trial data was subsequently published (Miller et al., 2022). The efficacy analysis was based on 60 fast progressors, with 39 receiving tofersen, 21 placebo. Treatment was associated with a numerical improvement of ALSFRS and other endpoints, but it fell short of statistical significance. Tofersen reduced mutant CSF SOD1 by 29 percent, compared to a 16 percent increase with placebo. Plasma NfL declined by 60 percent in the treated group, and increased by 20 percent in the placebo group. The groups were unbalanced at baseline, with the treated group starting with about 15 percent higher NfL than those who got placebo. In an open-label extension, patients who switched from placebo to treatment had, by the 12-month time point, decreases in CSF SOD1, NfL, and a slowing in their rate of decline on multiple clinical measures.

In the trial, adverse events were mostly related to spinal infusions or ALS, except that more tofersen recipients reported arm, leg, or back pain. Tofersen caused serious neurological side effects in 7 percent of people, including inflammation around nerves or the spinal cord, nerve pain, and increased intracranial pressure (e.g., see Reilich et al., 2024). More than half of tofersen recipients had at least one instance of elevated white cells in their CSF. Median CSF protein concentration increased in the treated, but not placebo, participants. Separate case reports identified macrophages with numerous cytoplasmic inclusions accounting for more than half of the CSF infiltrating cells, similar to cells previously seen during treatment with the ASO nusinersen in people with spinal muscular atrophy (Sparasci et al., 2023, Vidovic et al., 2024).

On July 26, 2022, Biogen and Ionis announced that the FDA had accepted a new drug application for tofersen, granting it priority review. Biogen sought accelerated approval based on changes in the surrogate biomarker NfL (press release). The FDA set a decision date of January 25, 2023.

On April 26, 2023, the agency granted tofersen accelerated approval for use in people with SOD1-ALS, after an advisory committee unanimously agreed that the drop in NfL in VALOR was likely predictive of a clinical benefit (April 2023 news). Per FDA rules, the company is obliged to show efficacy by way of the ongoing Phase 3 Atlas trial, which will run until 2027. The new drug will be marketed under the name QALSODY™.

In May 2024, QALSODY™ was approved for sale in the European Union (press release).

Several studies are following the experience of patients receiving tofersen in the clinic. In one cohort of 17 patients who were treated for at least a year, progression slowed significantly during treatment compared to before (Sabatelli et al., 2024). Nine stabilized or slightly improved on the ALSFLS-R, while four deteriorated. The rest progressed too slowly to detect significant changes. As in the VALOR trial, most patients markedly reduced their serum NfL. Just over half had increased levels of white blood cells and protein in CSF, and two developed symptomatic nerve inflammation that responded to steroids. A follow-up of German patients confirmed a decline in serum NfL with clinical use of tofersen (Wiesenfarth et al., 2024; Meyer et al., 2023). NfL reductions occurred in patients who were homozygous or heterozygous for the D91A SOD1 mutation, suggesting a causative role for the mutation even in heterozygotes (Weishaupt et al., 2024). Improvements in clinical and patient-reported outcomes led to high patient satisfaction and recommendation of tofersen (Meyer et al., 2024). Tofersen treatment increased levels of CSF selenium, potentially indicating improved CNS redox status (Vinceti et al., 2024).

For details on BIIB067 trials, see clinicaltrials.gov.