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Tofersen for ALS Clears Phase 1/2 Trial, Now in Phase 3

Key findings

  • Tofersen, an antisense oligonucleotide, is being investigated in patients with amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene
  • In this phase 1/2 trial, 48 participants with ALS received five intrathecal doses of placebo or tofersen over 12 weeks and were followed for 12 weeks
  • The most common adverse events in the tofersen groups were headache, procedural pain, post–lumbar puncture syndrome and falls
  • This study shows that tofersen lowered SOD1 protein levels and neurofilament levels (a measure of diseased motor neurons), and helped identify the dose for a global phase 3 trial
  • Now underway: A phase 3, randomized, double-blind, placebo-controlled trial of tofersen in ALS and its long-term extension study

More than 180 different mutations in the gene encoding superoxide dismutase 1 (SOD1) have been identified in amyotrophic lateral sclerosis (ALS). Antisense oligonucleotides, a class of drugs that inhibit messenger RNA (mRNA) translation, have prolonged survival and improved motor performance in rodent models of ALS by targeting SOD1 messenger RNA.

Tofersen, an investigational antisense oligonucleotide, is designed to facilitate degradation of SOD1 mRNA and thereby reduce the synthesis of the SOD1 protein. Researchers at Massachusetts General Hospital are participating in a three-part trial of tofersen and previously observed promising results with a single ascending dose.

Now, Merit E. Cudkowicz, MD, MSc, chief of the Department Neurology and director of the Sean M. Healey & AMG Center for ALS at Mass General, Timothy Miller, MD, PhD, of Washington University School of Medicine, and colleagues have concluded the second part of the trial, which evaluated multiple ascending doses. They report the safety results in The New England Journal of Medicine.

Study Details

The phase 1/2, randomized, double-blind placebo-controlled trial was conducted at 18 sites in the U.S., Canada and Western Europe beginning in January 2016. In groups of 12, patients with ALS were randomly assigned to placebo or one of four tofersen dose cohorts (20, 40, 60 or 100 mg), which were initiated and assessed sequentially.

The study lasted 31 weeks: up to seven weeks for screening, five intrathecal doses of placebo or tofersen over 12 weeks and 12 weeks of follow-up.


50 patients were included in the analyses, of whom 48 received all five planned doses of placebo or tofersen and 38 received one or more tofersen doses:

  • Placebo (n=12)
  • Tofersen 20 mg (n=10)
  • Tofersen 40 mg (n=9)
  • Tofersen 60 mg (n=9)
  • Tofersen 100 mg (n=10)

Adverse Events

  • The most common adverse events in the tofersen groups were headache (n=16 patients), procedural pain (n=16), post–lumbar puncture syndrome (n=13) and falls (n=13)
  • One serious event judged to be related to tofersen occurred in the 60 mg group
  • Three deaths occurred: one in the placebo group (ALS-related respiratory failure), one in the 20 mg dose group during follow-up (pulmonary embolism) and one in the 60 mg dose group during follow-up (ALS-related respiratory failure)
  • Elevated protein concentration in cerebrospinal fluid was pronounced enough to be considered an adverse event in 8% of patients in the combined placebo groups vs. 54% in the combined tofersen groups
  • CSF pleocytosis (at least one CSF white-cell count >10 cells/cm3) was considered an adverse event in 0% vs. 44%

SOD1 Reduction in CSF

The study was not powered to test the effect of tofersen on clinical or biologic measures, except for the reduction of SOD1 protein in CSF from baseline to day 85 (end of the intervention period). They found:

  • Placebo—3% reduction
  • Tofersen 20 mg—1%
  • Tofersen 40 mg—27%
  • Tofersen 60 mg—21%
  • Tofersen 100 mg—36%

Research Continues

The safety and efficacy of tofersen in ALS are now being evaluated in a phase 3, randomized, double-blind placebo-controlled trial and its long-term extension study. Changes in CSF variables and any manifestations of central nervous system inflammation will continue to be monitored.

Learn more about the Sean M. Healey & AMG Center for ALS

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