An experimental drug for a rare, inherited form of amyotrophic lateral sclerosis (ALS) has shown promise in phase 1/2 clinical trials, according to results published in the New England Journal of Medicine. 

The drug, tofersen (Biogen Inc), is an antisense oligonucleotide, which is a DNA-based molecule. This molecule interferes with the genetic instructions for building proteins and is designed to block the production of the SOD1 protein. 

Approximately 10% of ALS cases are inherited, with one-fifth of those caused by mutations in SOD1. ALS kills the nerve cells that control breathing, eating, and walking, according to the press release. Very few patients survive more than 5 years after diagnosis and current treatments are only modestly effective at slowing the pace of the disease.

There is currently no cure for ALS and there are approximately 20,000 people in the United States living with the disease. 

The phase 1/2 trial, conducted at Washington University School of Medicine in St. Louis, included 50 individuals with SOD1 ALS. The participants were randomly selected to receive either tofersen intravenously or a placebo. 

For every 1 person receiving a placebo, 3 received tofersen. Each participant received 5 dosages over a 12-week period. The drug and the placebo were injected into the fluid surrounding the spinal cord, according to the press release. Participants receiving tofersen were divided into 4 dosage groups: 20 mg, 40 mg, 60 mg, or 100 mg per dose. 

The study was not designed to evaluate the efficacy of treating ALS, but to show evidence of tofersen’s safety. The results are what researchers were hoping for and a phase 3 trial is currently underway. The study did prove, however, that tofersen lowered SOD1 protein levels in cerebrospinal fluid around the brain and spinal cord. Concentration dropped by an average of 2% in the low dose group and 33% in the high dose group, according to the press release. 

"Sometimes patients say, 'Why is all this work being done in the 2% who have SOD1 ALS? What about the 98%?'…But the same technology that can turn off the SOD1 gene can be used to turn off other targets, and in fact, there are many companies working on other targets. Everything we have learned with SOD1 ALS could end up aiding new approaches to fighting other forms of ALS or other neurological conditions,” co-principal investigator and Director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, Merit Cudkowicz, MD, said in the press release. 

Tofersen was generally well tolerated. Most of the adverse effects, such as pain and headache, were linked back to the spinal tap used to administer the treatment. According to the researchers, 2 deaths were reported in the tofersen group and 1 in the placebo group. 

Reference:
Experimental drug shows early promise against inherited form of ALS, trial indicates (news release), St. Louis, MO, July 8, 2020; ScienceDaily, Accessed July 9, 2020