Investigational Therapy Tofersen Can Reduce Toxic SOD1 Protein Levels in Familial ALS Patients, Study Shows

Biogen’s investigational therapy tofersen can significantly reduce toxic levels of SOD1 protein and may slow disability progression in people with familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations, interim study results show.

The positive data from a Phase 1/2 clinical trial support advancing the experimental compound into Phase 3 studies to further confirm its efficacy and safety, the company said in a press release.

The latest trial findings will be discussed May 7 at the Emerging Science session of the 2019 American Academy of Neurology (AAN) Annual Meeting, to be held in Philadelphia.

The oral presentation, “Safety, PK, PD, and exploratory efficacy in single and multiple dose study of a SOD1 antisense oligonucleotide (BIIB067) administered to participants with ALS,” will be given by Timothy M. Miller, MD, PhD, director of the ALS Center at Washington University in St. Louis and author of the study.

Tofersen, previously known as IONIS-SOD1Rx and BIIB067, is an experimental antisense oligonucleotide (ASO) or antisense therapy for people with SOD1-associated familial ALS. It is designed to bind to the SOD1 mRNA — a blueprint of the gene read by the cell machinery to make SOD1 protein — preventing production of the SOD1 protein. It is administered as an injection directly into the spinal fluid, also known as an intrathecal injection.

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The therapy gained orphan drug designation from the European Medicines Agency (EMA) in 2017.

Biogen, who acquired full rights to develop and potentially commercialize tofersen from Ionis Pharmaceuticals in December 2018, hopes the compound will decrease the toxicity of mutant SOD1 and slow disease progression, improving patient function and survival.

Previous studies in animal models of ALS showed that treatment with tofersen could effectively improve muscle function and expand the animals’ life span.

The therapy’s safety is now being assessed in Phase 1/2 clinical trial (NCT02623699) in ALS patients with SOD1 mutations. The study also was designed to evaluate tofersen’s early efficacy, pharmacokinetics (the fate of the drug inside the body), and pharmacodynamics (the drug’s effects and stability on the body).

Researchers are evaluating the impact of single and multiple ascending doses of tofersen in patients with confirmed SOD1-associated ALS.

In the multiple-ascending part of the study, 50 patients were randomly selected to receive tofersen (20, 40, 60, or 100 mg) or a placebo for 12 weeks.

Preliminary data show the highest-tested dose yielded a significant reduction in SOD1 protein in the cerebrospinal fluid (CSF) — the clear, colorless liquid found in the brain and spinal cord — compared with placebo-treated patients. This suggests the experimental treatment may effectively lower the levels of toxic SOD1 in the central nervous system.

Those treated with tofersen also showed a tendency toward slower clinical decline, as judged by their modest reduction in ALS Functional Rating Scale (ALSFRS-R) values — a validated tool to measure motor disability progression. These patients also showed slower decline of their respiratory function and muscle strength.

Participants were found to benefit most from the 100 mg dose, showing greater differences across the various clinical measures compared with the placebo group.

The therapy was found to be safe and well-tolerated, with most reported adverse events being mild or moderate in severity.

“This first report of BIIB067 in SOD1-ALS demonstrates reduction of SOD1 in CSF and strongly supports further investigation of BIIB067 efficacy in people with SOD1-ALS,” the researchers said.

Prompted by the positive results, Biogen recently launched a Phase 3 part of the trial (NCT02623699, named VALOR), with the first patient being dosed in March. The trial is currently recruiting participants. Find more information here. 

This portion of the study will assess the efficacy and safety of tofersen versus placebo. Researchers will measure its impact on patients’ speed of clinical decline by examining changes in ALSFRS-R values from the study’s start.

“The interim results of this study, which achieved proof-of-biology and proof-of-concept, support the initiation of a Phase 3 clinical trial to confirm the efficacy and safety of tofersen in SOD1-ALS patients and further demonstrate the potential of ASOs to target the genetic driver of disease,” said Michael Ehlers, MD, PhD, executive vice president of research and development at Biogen.

“We are committed to bringing a potential breakthrough therapy to patients with ALS and we are expediting our efforts with the aim of addressing this urgent unmet need,” he added.