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<a href="https://arrowheadpharma.com/">Arrowhead Pharmaceuticals</a> will seek permission later this year for the first clinical trial of ARO-SOD1, its RNA-based therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a <a href="https://www.businesswire.com/news/home/20230412005207/en/Arrowhead-Pharmaceuticals-to-Host-RD-Day-on-Pipeline-of-RNAi-Therapeutics">company press release</a>.
Further details about Arrowhead&#8217;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&#8217;s proprietary <a href="https://arrowheadpharma.com/science/">Targeted RNAi Molecule platform</a> — 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 <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> cases and in as many as 2% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic cases</a> — 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&#8217;s prone to clumping up in nerve cells, where it is thought to drive cellular toxicity and neurodegeneration.
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<h3>RNA therapy ARO-SOD1 showed promise in preclinical studies</h3>
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&#8217;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&#8217;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&#8217;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&#8217;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.
[quote align=&#8221;center&#8221;]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.[/quote]
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.
&#8220;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,&#8221; 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 <a href="https://alsnewstoday.com/news/fda-names-rag-17-targeting-als-gene-mutations-orphan-drug/">RAG-17</a>, an investigational SOD1-targeting RNA therapy from Ractigen. Biogen&#8217;s <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">tofersen</a>, which works to reduce SOD1 levels by targeting SOD1 mRNA via a different mechanism, is now <a href="https://alsnewstoday.com/news/decision-delayed-proposed-als-therapy-tofersen-until-april-2023/">under review</a> by the U.S. Food and Drug Administration, with a decision expected later this month.

Tag: Arrowhead Pharmaceuticals

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