New Therapy for ALS Enters Clinical Trials

Investigators at Washington University School of Medicine in St. Louis, Missouri, have developed an investigational therapy that could benefit patients with an inherited form of amyotrophic lateral sclerosis (ALS), a fatal and rapidly progressive neurodegenerative disease.

Investigators found that the therapy—antisense oligonucleotides—was capable of reversing signs of neuromuscular damage and extending survival in animal models by 22%, according to data published in The Journal of Clinical Investigation. These findings led to the launch of a phase 1/2 clinical trial to investigate whether the therapy could potentially benefit patients with ALS.

Of the 10% of inherited cases of ALS, 1 in 5 instances is caused by mutations in the SOD1 gene. When mutations occur in the SOD1 gene, the SOD1 protein becomes overly active. Researchers postulated that decreasing protein levels may be an effective way to help patients with these mutations.

For the study, which was conducted in collaboration with Ionis Pharmaceuticals, the investigators tested 2 antisense oligonucleotides (oligos) DNA-based compounds—capable of blocking the body from creating SOD1 protein—in genetically modified mice and rats carrying a mutated form of the human SOD1 gene.

In the mice cohorts, researchers administered either anti-SOD1 oligo or placebo at day 50 and a second dose about 6 weeks later. Mice that received the oligo were found to maintain their weight 26 days longer and lived 37 days longer compared with those given the placebo. Overall, a 22% increase in life span was noted in those receiving the investigational therapy.

Similar results were observed in rats. Rat cohorts that received oligo maintained their weight more than 9 weeks longer and survived 8 to 9 weeks longer than the rats in the placebo group.

"This drug had an impressive effect in mice and rats with just 1 or 2 doses," said Timothy Miller, MD, PhD, the David Clayson professor of neurology at Washington University, in a recent statement. "We don't know yet if this works in people, but we're very hopeful. We've completed the first phase of safety testing, and now, we're working on finding the right dose."

Reversed signs of neuromuscular damage in the animals were also observed. Nine-week-old mice that carried the SOD1 gene mutation and were treated with an anti-SOD1 oligo displayed steadily improved muscle function over the following 8 weeks. Additionally, while both the rat and mice groups showed rising signs of neurological damage, the placebo mice exhibited rising signs of neurological damage more than twice as quickly.

In an interview with Rare Disease Report^®, study author Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital, expressed her optimism for the treatment. “I think these approaches to decrease [the] amount of mutant protein made for SOD1 ALS will be hopefully game-changing,” she said. “The treatment is on target—and hopefully will make a great impact on disease course.”

The phase 1/2 clinical trial was designed to evaluate the safety of using the oligos in adults with ALS. Researchers report that initial safety testing did not reveal any obvious hazards and now, the focus is to find the most effective way to decrease SOD1 levels without causing harmful side effects by exploring different doses and regimens. The current anticipated completion date for the trial is January 2, 2019.

"The phase ½ trial is really still a safety trial," Dr Miller explained. "There are not enough patients in it to really be able to accurately see an effect on disease. But we're on the cusp of testing the hypothesis that people with ALS caused by mutations in SOD1 can benefit from this treatment. We predict the effect will be good, but we can't know until we test it."

There are 20,000 individuals living with amyotrophic lateral sclerosis (ALS) in the United States. The average survival time post-diagnosis is just 3 to 5 years, and there are only 2 FDA-approved treatments available that offer modest slowing of disease progression.