Phase 1/2 Trial Testing IONIS-SOD1Rx for ALS Launched After Positive Findings in Animal Models

IONIS-SOD1Rx (BIIB067), an investigational therapy for amyotrophic lateral sclerosis (ALS) developed by Biogen and Ionis Pharmaceuticals, was shown to prolong survival and reverse neuromuscular damage in mouse and rat models of ALS.

Based on these positive findings, a Phase 1/2 clinical trial (NCT02623699) has been launched to evaluate the safety profile of IONIS-SOD1Rx, testing different doses and regimens. One of the trial’s goals is to provide the first evidence of the treatment’s effectiveness by assessing its effects on SOD1 protein levels in the cerebrospinal fluid of patients. Initial safety data did not identify any major adverse events.

The randomized, placebo-controlled trial is currently recruiting participants, and aims to enroll an estimated 84 ALS patients with an SOD1 gene mutation. 

Data was published in the study, “Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models,” was published in The Journal of Clinical Investigation.

About 5-10 percent of ALS cases are inherited. Among those, some are caused by mutations in the SOD1 gene, which causes the SOD1 protein to be excessively active. By reducing levels of this protein, IONIS-SOD1Rx is expected to slow the progression of the disease.

IONIS-SOD1Rx is a next-generation antisense therapy. It consists of an oligonucleotide, a small synthetic DNA molecule designed to bind specific genetic targets, optimized to act on the central nervous system. IONIS-SOC1Rx is targeted to the messenger RNA (mRNA) of the SOD1 gene, which is a messenger copy of the gene “read” by cells to produce the SOD1 protein.

When IONIS-SOD1Rx binds to SOD1 mRNA, it prevents it from being read, and consequently halts the production of the SOD1 protein.

In collaboration with Biogen and Ionis Pharmaceuticals, researchers at the Washington University School of Medicine in St. Louis tested two different antisense oligonucleotides in mouse and rat models of ALS with a mutated form of the SOD1 gene. 

They observed that mice receiving two doses of anti-SOD1 oligonucleotides were able to significantly maintain their weight and survived longer, compared with those given the placebo. On average, a 22% improvement in lifespan was seen.

Extended survival — eight to nine weeks longer — also was seen in rat models of ALS treated with the same anti-SOD1 oligonucleotides, which reinforced its therapeutic potential.

“This drug had an impressive effect in mice and rats with just one or two doses,” Timothy Miller, MD, PhD, a professor of neurology at Washington University and senior author of the study, said in a press release.

The therapy was also capable of reversing ALS-like neuromuscular damage caused by SOD1 mutations in mice. Treatment with the oligonucleotides significantly preserved the connections between motor nerve cells and muscles and prevented nerve cell loss. Muscle function also steadily improved after treatment. In addition, the therapy was able to stem the rise of a proposed biomarker of ALS, called phospho-neurofilament heavy chain levels.

“These results define a highly potent, new SOD1 ASO [antisense oligonucleotide] ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy,” the researchers wrote in the study.

“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. The phase one/two trial is really still a safety trial,” Miller said. “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.”