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Can an antisense oligonucleotide benefit patients with SOD1-ALS?



– In patients with amyotrophic lateral sclerosis (ALS) caused by gain-of-toxic function mutations in the SOD1 gene, treatment with an investigational antisense oligonucleotide leads to dose-dependent reductions of the SOD1 protein in cerebrospinal fluid (CSF), according to phase 1/2 trial results presented at the annual meeting of the American Academy of Neurology. Exploratory analyses suggest that the drug, known as tofersen (also known as BIIB067), may lessen declines in function, respiratory function, and strength. The treatment generally was safe and well tolerated, researchers said.

Most ALS cases are sporadic, but about 10% are genetic, of which approximately 20% are caused by SOD1 mutations. “Although SOD1-ALS disease progression is heterogeneous, the underlying pathophysiology, attributable to mutant SOD1 toxicity, is thought to be consistent across SOD1 mutation types,” said Timothy M. Miller, MD, PhD, of Washington University, St. Louis, and colleagues. “As such, effective reduction of SOD1 protein, irrespective of mutation, has the potential to alter the disease course of people with SOD1-ALS.”

Tofersen is an antisense oligonucleotide ribonuclease H1-mediated inhibitor of SOD1 messenger RNA. To study its safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy in patients with SOD1-ALS, investigators conducted a double-blind study. The investigators randomized 50 patients with ALS with a SOD1 mutation to 20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), or 100 mg (n = 10) of tofersen or placebo (n = 12).

Patients received tofersen by intrathecal bolus over 1-3 minutes. They received a loading regimen on days 1, 15, and 29 and maintenance dosing on days 57 and 85. After the dosing period, patients completed a 12-week follow-up period.

Adverse events

All patients received at least one dose of the study treatment, and 48 received all treatments. Three patients died during the study. One patient in the 20-mg group died of pulmonary embolism, and one patient in both the 60-mg group and placebo group died of respiratory failure. Investigators considered the deaths secondary to ALS or other conditions and not drug related.

Most adverse events were mild or moderate. The most common adverse events among tofersen-treated patients were headache (n = 16), procedural pain (n = 14), and post–lumbar puncture syndrome (n = 13). Five patients who received tofersen and two who received placebo experienced serious adverse events; no serious adverse events occurred in the 100-mg dose group.

“A reduction from baseline in CSF SOD1 concentrations was observed in the tofersen 40-, 60-, and 100-mg cohorts with the maximal reduction observed in the 100 mg–treated group [37% vs. no reduction in the placebo group; P less than 0.002] at day 85,” the investigators reported.

Possible efficacy

In exploratory analyses, the 100-mg dose slowed decline on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ASLFRS-R), compared with placebo. Mean change in ASLFRS-R from baseline to day 85 was –1.1 in patients who received 100 mg of tofersen, compared with –5.3 for patients who received placebo. Declines on measures of respiratory function and muscle strength also slowed. “Across clinical measures, separation from placebo was most apparent in participants with fast progressing disease,” the researchers said.

“Lower concentrations of the protein in the spinal fluid suggest that there were also lower concentrations in the brain and spinal cord,” Dr. Miller said in a news release. “Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this further.”

The study was sponsored by Biogen, which is developing tofersen. Some of the study authors are Biogen employees. Dr. Miller is on Biogen’s medical advisory board and receives clinical research support from Biogen. In addition, he consults, has licensing agreements with, and is a principal investigator for other companies.

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