Timothy M. Miller, MD, PhDTimothy M. Miller, MD, PhD
Tofersen, an investigational antisense oligonucleotide, is promising as a treatment for patients with amyotrophic lateral sclerosis (ALS) with superoxide dismutase 1 (SOD1) gene mutation, according to interim study results presented at the 2019 American Academy of Neurology Annual Meeting, May 4-10 in Philadelphia.

Investigators led by Timothy M. Miller, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, reported both proof of biology and proof of concept data that supports the recent initiation of a phase 3 clinical trial to further confirm safety and efficacy.  

“We are encouraged by the positive results of this phase 1/2 study of tofersen in patients with SOD1-ALS and are excited to advance this clinical program to a phase 3 trial to further investigate its therapeutic potential,” Merit Cudkowicz, MD, co-principal investigator and director of the Healey Center at Massachusetts General Hospital, said in a statement.2

Approximately 2% of ALS cases are associated with SOD1 mutations, of which there are more than 200 identified – all of which are associated with different rates of disease progression. The toxicity of mutant SOD1 suggests that SOD1 reduction may be therapeutic.

The multiple ascending dose portion of the randomized, placebo-controlled study included 50 patients with confirmed SOD1-ALS who were randomly assigned to receive the study drug (20, 40, 60, or 100 mg) or placebo for 12 weeks.

Overall, adverse events were mild to moderate in severity. Investigators reported a statistically significant reduction of SOD1 in cerebrospinal fluid in patients who received the 100-mg dose (n=10) compared with placebo (n=12; P =.002).

“Lower concentrations of the protein in the spinal fluid suggest that there were also lower concentrations in the brain and spinal cord,” Miller said in a statement.3 “Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this further.”

Slowing of functional decline as measured by the ALS Functional Rating Scale Revised score, slow vital capacity, and muscle strength was also observed in the 100-mg cohort versus placebo.

Notably, for participants with rapidly progressive SOD1 mutations, more significant changes in these measures were observed in participants in the 100-mg cohort compared with placebo.

As of March 2019, the first patient in the phase 3 VALOR study of tofersen has been dosed. The trial will evaluate the safety and efficacy of the study drug versus placebo, with a primary endpoint of change in ALS Functional Rating Scale Revised score, signifying disability progression.2

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REFERENCES
1. Miller TM, Cudkowicz ME, Shaw PJ, et al. Safety, PK, PD, and exploratory efficacy in single and multiple dose study of a SOD1 antisense oligonucleotide (BIIB067) administered to participants with ALS. Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.
2. Biogen to Present New Interim Data from Its Phase 1/2 Clinical Study of Tofersen (BIIB067) for the Potential Treatment of a Subtype of Familial Amyotrophic Lateral Sclerosis (ALS) [news release]. Cambridage, MA: Biogen. May 1, 2019. Accessed May 3, 2019. http://investors.biogen.com/news-releases/news-release-details/biogen-present-new-interim-data-its-phase-12-clinical-study
3. Experimental Drug Shows Promise for Genetic Form of ALS [news release]. Philadelphia, PA: American Academy of Neurology. May 1, 2019. Accessed May 3, 2019.