Arrowhead to seek OK later this year to test RNA therapy for ALS

Company planning for first trial of ARO-SOD1 in people

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Arrowhead Pharmaceuticals will seek permission later this year for the first clinical trial of ARO-SOD1, its RNA-based therapy for amyotrophic lateral sclerosis (ALS), according to a company press release.

Further details about Arrowhead’s plans for testing its investigational RNA therapy are expected at a company Research and Development Day slated for June 1 in New York City.

Developed using the company’s proprietary Targeted RNAi Molecule platform — dubbed the TRiM platform — the treatment is designed to reduce levels of the superoxide dismutase 1 (SOD1) protein in people with ALS associated with SOD1 mutations.

Such mutations are found in up to 20% of familial ALS cases and in as many as 2% of sporadic cases — among people with no family history of the disease. These gene mutations lead to the production of an abnormal version of the SOD1 protein that’s prone to clumping up in nerve cells, where it is thought to drive cellular toxicity and neurodegeneration.

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RNA therapy ARO-SOD1 showed promise in preclinical studies

ARO-SOD1 is an RNA interference (RNAi) therapy, which essentially works to silence or turn off a gene that contributes to disease.

To make a protein, a gene’s DNA is first transcribed into an intermediate molecule called messenger RNA (mRNA), which then serves as a template for producing the final protein.

ARO-SOD1 contains a small molecule that binds to SOD1 mRNA and triggers its degradation, preventing the production of SOD1 protein. For people with SOD1 mutations, it’s expected to prevent the buildup of the abnormal version of SOD1, thereby slowing disease progression.

The treatment is designed to be delivered by injection directly into the spinal canal — called an intrathecal administration. That type of delivery enables a therapy to be well distributed in the central nervous system (CNS), comprised of the brain and spinal cord.

Arrowhead’s TRiM platform was recently expanded to include an optimized intrathecal administration method, according to the company. ARO-SOD1 will be the first of Arrowhead’s clinical candidates to employ the technology.

In preclinical studies, ARO-SOD1 was found to be highly active against SOD1 mRNA across multiple different models. Specifically, a single intrathecal injection in rats with SOD1 mutations led to a 95% reduction in SOD1 mRNA in the spinal cord.

Evidence also indicates the therapy is long lasting. In non-human primates, SOD1 mRNA remained at least 80% depleted three months after a single intrathecal dose.

Given that finding, its possible ARO-SOD1 could be effective when administered only four times a year or less, according to Arrowhead.

The first development candidate to utilize this new delivery platform, ARO-SOD1, is on track for a clinical trial application (CTA) filing in the third quarter of 2023 to begin clinical studies.

The company plans to discuss the development of ARO-SOD1 and its TRiM platform for CNS delivery in greater detail at the Research and Development Day.

“The first development candidate to utilize this new delivery platform, ARO-SOD1, is on track for a clinical trial application (CTA) filing in the third quarter of 2023 to begin clinical studies,” Arrowhead stated in the release.

Ultimately, its goal is to have a pipeline of at least 20 clinical stage or marketed RNAi therapies by 2025.

Other RNA-based therapies also are in development for SOD1-associated ALS, including RAG-17, an investigational SOD1-targeting RNA therapy from Ractigen. Biogen’s tofersen, which works to reduce SOD1 levels by targeting SOD1 mRNA via a different mechanism, is now under review by the U.S. Food and Drug Administration, with a decision expected later this month.