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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.

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

RAG-17, an investigational therapy from <a href="https://www.ractigen.com/" rel="nofollow">Ractigen Therapeutics</a> to treat <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), has been designated an orphan drug by the U.S. Food and Drug Administration (FDA).
Orphan drug status is given to medicines intended to treat life-threatening or chronically debilitating diseases that affect fewer than 200,000 individuals in the U.S. It provides a range of incentives to support and speed RAG-17’s development, including fee waivers and seven years of marketing exclusivity if the FDA approves the therapy.
RAG-17 is designed to target and dampen the expression, or activity, of the SOD1 gene, whose mutations are strongly linked to ALS development.
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<h3>Up to 20% of familial ALS cases associated with SOD1 mutations</h3>
“The FDA’s decision to grant orphan drug designation is an important and valuable milestone for RAG-17, and highlights the significant unmet medical need for people living with this severe disease,” Long-Cheng Li, MD, Ractigen’s founder, president and CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/03/03/2620288/0/en/Ractigen-Therapeutics-Receives-FDA-Orphan-Drug-Designation-for-the-novel-oligonucleotide-conjugate-RAG-17-for-the-Treatment-of-Amyotrophic-Lateral-Sclerosis-ALS.html">company press release</a>.
ALS is marked by the progressive loss of motor neurons, the nerve cells that govern movement. Early <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> typically include muscle cramps, twitching, weakness, and stiffness. Over time, the ability to control muscle movement deteriorates and patients have difficulty with movement, as well as trouble swallowing, speaking, and breathing.
The <a href="https://alsnewstoday.com/causes-of-als/">disease’s causes</a> are not yet fully understood, but several factors, including <a href="https://alsnewstoday.com/als-and-genetics/">genetic mutations</a>, have been linked to an increased risk of ALS.
Up to 20% of all genetically defined, or familial, ALS cases are associated with SOD1 gene mutations. This gene provides instructions to produce an enzyme called superoxide dismutase (SOD1), which neutralizes a byproduct of normal cellular processes that is harmful to cells, known as free radicals.
Exactly how SOD1 mutations are linked to ALS is not clear. It is thought that the production of a dysfunctional SOD1 enzyme could be toxic to motor neurons, or that abnormally high levels of free radicals can damage cells.
Small interference RNA (siRNA) molecule development might prevent or treat diseases such as ALS. These molecules mediate a process that regulates gene activity. More specifically, siRNAs can silence messenger RNAs, which are generated from DNA and contain the genetic information to produce proteins.
RAG-17 is an siRNA designed to target and silence SOD1 expression in patients with relevant mutations.
Its chemistry is based on a proprietary delivery platform called Smart Chemistry-Aided Delivery (SCAD), in which the siRNA is conjugated to an accessory oligonucleotide. The SCAD technology allows access to tissues other than the liver, such as the central nervous system (the brain and spinal cord).
RAG-17 is designed to have a durable and potent activity in the central nervous system, the company reports.
According to Ractigen, preclinical studies showed that this therapy has a significantly higher potency in disease models of ALS (e.g., a mouse model with an SOD1 mutation) than benchmark compounds.
“We are eager to bring RAG-17 to ALS patients as soon as possible, as we believe this therapy can have significantly higher efficacy in patients with the SOD1 mutation, compared to the other modalities,” Li said.

Tag: SOD1 mutations

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

FDA names RAG-17, targeting ALS gene mutations, an orphan drug