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<a href="https://arrowheadpharma.com/">Arrowhead Pharmaceuticals</a> has filed an application in Australia seeking the green light to launch 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).
The therapy is designed to reduce SOD1 protein levels in ALS patients carrying SOD1 mutations, which are estimated to account for about 2% of <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> cases and up to 20% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic cases</a>.
Pending clearance from the Australian Department of Health and Aged Care, Therapeutic Goods Administration, ARO-SOD1 may become the first candidate developed with Arrowhead&#8217;s proprietary <a href="https://arrowheadpharma.com/science/">Targeted RNAi Molecule (TRiM) platform</a> for delivery to the brain and spinal cord to enter clinical studies.
The AROSOD1-1001 Phase 1 trial is designed to assess the safety, tolerability, and pharmacological properties of ARO-SOD1 in people with ALS-SOD1. It is expected to enroll 24 adult patients who will receive ascending doses of the medication or a placebo.
“The ARO-SOD1 program entering clinical studies represents the further expansion of our proprietary TRiM platform, which now includes product candidates addressing a multitude of diverse disease areas that target the liver, lung, muscle, and CNS [central nervous system],” Chris Anzalone, PhD, president and CEO of Arrowhead, said in a <a href="https://www.businesswire.com/news/home/20230627815548/en/Arrowhead-Pharmaceuticals-Files-for-Regulatory-Clearance-to-Initiate-a-Phase-1-Study-of-ARO-SOD1">company press release</a>.
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<h3>ARO-SOD1 is designed to target SOD1 messenger RNA</h3>
Mutations in the SOD1 gene lead to the production of an abnormal SOD1 protein prone to aggregate and form clumps in nerve cells, which causes nerve cell death and contributes to ALS progression.
ARO-SOD1 is an RNA interference (RNAi) therapy designed to target the SOD1 messenger RNA (mRNA), an intermediate molecule that&#8217;s produced when the gene is read and serves as a template for protein production.
RNAi is a natural process of gene silencing in which small RNA molecules, called interfering RNAs, bind to a specific mRNA and target it for destruction, ultimately preventing protein production. Thus, by binding to SOD1 mRNA molecules, ARO-SOD1 can significantly lower the production of toxic SOD1 proteins.
The therapy is injected into the spinal canal — called an intrathecal administration — allowing the therapy to reach the CNS where it is expected to prevent the buildup of the abnormal SOD1 protein, and, consequently, slow disease progression.
<a href="https://alsnewstoday.com/news/arrowhead-will-seek-ok-test-rna-therapy-aro-sod1-clinical-trial/">Preclinical data</a> showed ARO-SOD1 was highly active against SOD1 mRNA across multiple different models. In a SOD1-ALS rat model, a single injection into the spinal canal was sufficient to reduce SOD1 mRNA by 95% in the spinal cord.
Also, studies with nonhuman primates showed the therapy has sustained effects, with 80% of SOD1 mRNA remaining depleted for three months after a single intrathecal dose.
According to Arrowhead, these findings suggest ARO-SOD1 may require four or less annual injections, much fewer than the monthly intrathecal injections required for <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen), an RNA-based therapy that recently <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">gained conditional approval</a> in the U.S. for the treatment of ALS patients with SOD1 mutations.

Application filed in Australia to launch first trial of ARO-SOD1

<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: ARO-SOD1

Application filed in Australia to launch first trial of ARO-SOD1

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