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FDA Grants Orphan Drug Designation to Becker and Duchenne Agent RAG-18
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Key Takeaways
- RAG-18, targeting utrophin gene expression, received FDA orphan drug designation for Duchenne and Becker muscular dystrophies, offering development incentives and marketing exclusivity.
- Duchenne muscular dystrophy is a severe pediatric disorder with no cure, affecting 1/3500 to 1/6000 males, while Becker muscular dystrophy lacks FDA-approved treatments.
RAG-18 is an saRNA delivered to muscle tissue to increase UTRN expression and compensate for DMD defects regardless of the location of mutation on DMD gene.
Long-Cheng Li
According to a recent announcement, the FDA has granted orphan drug designation to Ractigen’s RAG-18, a first-of-its-kind small activating RNA candidate designed to specifically target and activate utrophin (UTRN) gene expression, for the treatment of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).1
DMD, caused by mutations of the dystrophin gene on the X chromosome, is the most common and lethal pediatric muscle disorder without a known cure. It is fairly prevalent, with a frequency of 1/3500 ~ 1/6000 in males, and an average life expectancy of 26 years. BMD, a minor form of DMD also resulting from a DMD mutation, is considered less common and severe than DMD; however, there are no FDA-approved drugs for this condition.
RAG-18, which activates UTRN gene expression in muscle cells via RNAa mechanism, has shown to effectively mitigate muscle damage in preclinical models. In addition to receiving orphan drug designation, the agent also gained rare pediatric drug designation by the FDA in July for the treatment of DMD and BMD. The newly applied orphan drug designation will allow Ractigen greater development incentives, including a 7-year marketing exclusivity from the date of market approval and a waiver of the new drug application fee.
"Receiving FDA Orphan Drug Designation marks a pivotal achievement for RAG-18. Combined with the recent Rare Pediatric Disease Designation, it reflects the groundbreaking work we’re doing with RNA activation (RNAa) and reinforces our commitment to making a real difference in the lives of those affected by rare diseases," Long-Cheng Li, founder and chief executive officer at Ractigen, said in a statement.1 "This recognition fuels our determination to push forward with RAG-18’s development, aiming to bring innovative and life-changing treatments to patients with DMD and BMD around the world."
READ MORE: European Commission Grants NLX-112 Orphan Medicinal Product Designation for Spinocerebellar Ataxia
UTRN, the chromosome-6-encoded autosomal paralog of dystrophin, with a high degree of structural and functional similarity to dystrophin, has been seen as a promising therapeutic approach for DMD. The major utrophin isoform in myofibers utrophin-A, is enriched in neuromuscular and myotendinous junctions of adult muscles and at the sarcolemma or regenerating myofibers. Small molecules such as heregulin, nabumetone, SMT C1100, and artificial transcription factors, have been shown to upregulate UTRN gene expression by activating the UTRN-A promoter.2
Previous studies have shown the existence of post-transcriptional inhibition of utrophin expression by several miRNAs targeting UTRN 3’ UTR. Suppressing one of those miRNA interactions with site-blocking oligonucleotides for let-7c resulted in the utrophin upregulation-mediated functional improvement in mdx mouse model.
In recent years, regulatory agencies have conditionally approved several RNA treatments for DMD, based on read-through or exon-skipping strategies. Despite the progress in drug development, some of these therapies are applicable to a low percentage of patients with the disease. In addition, the approval of previous therapies has been controversial due to the low efficacy in dystrophin restoration and the limited clinical efficacy demonstrated so far.3
There is still no approved BMD treatment to date. Currently, supportive therapy and rehabilitation are considered the cornerstones of BMD treatment. Corticosteroids, known as a mainstay of treatment for patients with significant muscle weakness, are recommended early in BMD treatment course, and should be started before physical disability develops.
