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

Potential therapy likely to treat patients with SOD1 mutations

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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RAG-17, an investigational therapy from Ractigen Therapeutics to treat amyotrophic lateral sclerosis (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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“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 company press release.

ALS is marked by the progressive loss of motor neurons, the nerve cells that govern movement. Early disease symptoms 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 disease’s causes are not yet fully understood, but several factors, including genetic mutations, 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.