Experimental Agent Shows Promise in Slowing Genetic Form of ALS

Damian McNamara

May 02, 2019

PHILADELPHIA — Taking a step closer to translating a genetic discovery in amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease) to the clinical setting, researchers report that the experimental drug BIIB067 or Tofersen (Biogen/Ionis) is well tolerated and may slow progression of this debilitating and fatal disease.

Results of a small phase 2 study show ALS patients who received 100 mg of tofersen experienced a 37% decrease in harmful protein levels in their cerebral spinal fluid (CSF) compared with those who received placebo.

Genetics are responsible for about 10% of ALS cases, and in about 1 in 5 of these instances, ALS is associated with mutations in the superoxide dismutase 1 (SOD1 ) gene.

Tofersen is an antisense oligonucleotide that binds to, and destroys, the RNA responsible for producing the superoxide dismutase (SOD1 )-related protein, interrupting an essential step in production of this mutated protein. Left unchecked, the protein can damage nerve cells that control movement and cause ALS.

Researchers have identified more than 200 SOD1 mutations, many associated with different degrees of ALS progression.

Tofersen "will target all of these, and once we decrease the RNA, then the protein decreases," lead author Timothy M. Miller, MD, PhD, director of the ALS Center and professor of neurology at Washington University School of Medicine in St. Louis, Missouri, told Medscape Medical News.

The study will be presented here at an emerging science session at the American Academy of Neurology (AAN) 2019 Annual Meeting.

Functional Decline Slowed

The dose-ranging study included 50 patients with ALS who had an SOD1 genetic mutation. Researchers randomly assigned participants to receive five doses of either 20, 40, 60, or 100 mg of the experimental drug or placebo through a lumbar puncture over 3 months.

The researchers observed dose-dependent increases in concentrations of tofersen in plasma and CSF, which they said may reflect changes in central nervous system tissue as well.

Safety was the primary outcome of the study. The majority of adverse events were mild or moderate in severity and included headache, pain due to the procedure, and post-lumbar puncture syndrome. "I anticipated this would be safe," Miller said.

The slowing of functional decline was measured using ALS Functional Rating Scale Revised scores. Participants who received the 100 mg dose experienced an average 1.1-point decline compared with an average 5.3-point decline among those in the placebo group. The 100 mg treatment group also performed better on slow vital capacity and muscle strength measures.

The differences were even more pronounced between the 100 mg and placebo groups in participants with SOD1 mutations known to be rapidly progressive, the investigators note.

If approved, tofersen would become the third antisense oligonucleotide (ASO) agent approved for a neurology indication in the United States. In December 2016, nusinersen (Spinraza, Biogen/Ionis) became the first FDA-approved drug to treat adults and children with spinal muscular atrophy (SMA), as reported by Medscape Medical News.

A more recent FDA approval in this class was for inotersen (Tegsedi, Akcea Therapeutics and Ionis Pharmaceuticals), approved in October to treat polyneuropathy in adults with hereditary transthyretin amyloidosis. 

The small number of participants and short time frame (12 weeks) are potential limitations, the researchers note.

"More studies are needed to see if the experimental drug works in larger groups of people and over longer periods of time," said Miller.

Exciting Findings

Commenting on the findings for Medscape Medical News, Stephen Goutman, MD, director of the Multidisciplinary ALS Clinic and associate professor of neurology at the University of Michigan in Ann Arbor, noted that ALS is a heterogeneous disease and ASO therapies are a promising therapeutic option to help personalize treatments for individuals with ALS.

"It is exciting that the authors report that the drug was well-tolerated, that there were reductions in the CSF biomarkers for those individuals receiving the highest dose compared to placebo participants, as well as some indication of disease slowing," added Goutman, who was not involved with the current study.

"I look forward to hearing the full study results and how these findings compare in individuals with varying SOD1 mutations," Goutman said. "Nonetheless, based on this abstract, BIIB067 sounds like a promising therapy and testing of this therapeutic option will hopefully will be moving into the next phase of testing very soon."

Biogen supported the study. Miller is a member of the medical advisory board and receives research support from Biogen. He is also a consultant for Cytokinetics; has a licensing agreement with Ionis Pharmaceuticals and with C2N; and serves as the site principal investigator for clinical trials for Orion and Amylyx. Goutman has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2019 Annual Meeting: Emerging Science Abstract 007. Presented May 7, 2019.

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