saRNA Therapy Gets Rare Pediatric Disease Designation for DMD

Long-Cheng Li, MD

Credit: Ractigen Therapeutics

The FDA has granted Rare Pediatric Disease Designation to Ractigen Therapeutics’ saRNA therapy RAG-18 for the potential treatment of Duchenne muscular dystrophy (DMD) and Becker Muscular Dystrophy (BMD) due to mutations in the dystrophin gene.¹

"Receiving the RPDD for RAG-18 is a milestone for Ractigen and reinforces our commitment to developing innovative therapies for rare diseases. This designation not only accelerates the development of RAG-18 but also opens opportunities for future advancements in RNAa therapies. We are dedicated to improving the lives of patients with DMD and other rare diseases,” Long-Cheng Li, MD, Founder and chief executive officer, Ractigen Therapeutics, said in a statement.¹

RAG-18 is designed to use RNAa mechanisms to specifically activate the UTRN gene expression in muscle cells to produce utrophin protein, which is structurally and functionally similar to dystrophin. Ractigen hopes that its upregulation can serve as a functional replacement for missing dystrophin in muscle cells regardless of specific mutations. The company stated that in preclinical data, RAG-18 delivered via Ractigen's proprietary LiCOTM (lipid-conjugated oligonucleotide) technology effectively mitigated muscle damage.

Ractigen also has other saRNA therapies in its pipeline, with 2 others targeting neuromuscular diseases: RAG-06 for spinal muscular atrophy and RAG-17 for amyotrophic lateral sclerosis (ALS). The company’s lead candidate is an saRNA therapy, RAG-01, which is being evaluated for non-muscle invasive bladder cancer in a phase 1 trial.

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A couple of months ago, in May 2024, Ractigen announced that China’s National Medical Products Administration (NMPA) had approved its Investigational New Drug (IND) application for RAG-17, allowing the company to initiate a phase 1 trial of the therapy in patients with ALS due to mutations in SOD1.²

“This marks a pivotal moment for our company, as RAG-17 is our first siRNA drug targeting the central nervous system to receive CDE approval. We are excited to advance this therapy into clinical trials for ALS patients and are optimistic about its potential to bring meaningful benefits to those with SOD1 mutation,” Li said in a statement at that time.²

“I hold a strong sense of optimism for RAG-17. Its innovative approach and promising preliminary results give me great confidence in its potential. I believe this drug could offer significant hope and tangible benefits to the ALS community, especially for those with the SOD1 mutation,” Lei Cai, ALS advocate and patient, added to the statement.²

Recent milestone news in the DMD space came last month, when the FDA approved Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys), an adeno-associated virus (AAV) vector-based gene therapy for patients with DMD, for an expanded indication including ambulatory patients (via traditional approval) and nonambulatory patients (via accelerated approval) with a confirmed mutation in the DMD gene who are 4 years of age or older and who do not have any deletion in exon 8 or exon 9 in the gene.³

The approval came despite the phase 3 EMBARK trial, data from which the approval was based on, not meeting its primary endpoint. However, key secondary endpoints of change in time to rise (TTR) and time to walk/run 10 meters (10MWR) had small but significant differences from placebo, and a composite, prespecified global statistical test including NSAA, TTR, 10MWR, Stride Velocity 95th Centile, 100MWR, and ascend 4 steps test was statistically significant compared with placebo (P = .0044).⁴

“The initial approval of Elevidys was a significant milestone, and the expanded indication means clinicians now have a treatment option for the great majority of boys and young men living with Duchenne. This expansion speaks to the success of the science, the evidence, and the improvements in the trajectory of the disease we have seen to date across studies,” Jerry Mendell, MD, the coinventor of Elevidys and the senior advisor for Medical Affairs at Sarepta said in a statement.³

REFERENCES

1. Ractigen Announces U.S. FDA Rare Pediatric Disease Designation (RPDD) Granted to RAG-18 for the treatment of Duchenne Muscular Dystrophy. July 25, 2024. https://www.prnewswire.com/news-releases/ractigen-announces-us-fda-rare-pediatric-disease-designation-rpdd-granted-to-rag-18-for-the-treatment-of-duchenne-muscular-dystrophy-302206562.html#:~:text=SUZHOU%2C%20China%2C%20July%2025%2C,company's%20lead%20saRNA%20product%20candidates
2. Ractigen Therapeutics Receives IND Approval from China’s NMPA to Initiate Phase 1 Clinical Trials for RAG-17 in SOD1-ALS Patients. News release. Ractigen. May 15, 2024. https://www.ractigen.com/ractigen-therapeutics-receives-ind-approval-from-chinas-nmpa-to-initiate-phase-1-clinical-trials-for-rag-17-in-sod1-als-patients/

3. Sarepta Therapeutics Announces Expanded US FDA Approval of ELEVIDYS to Duchenne Muscular Dystrophy Patients Ages 4 and Above. News release. Sarepta Therapeutics, Inc. June 20, 2024. Accessed June 20, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-us-fda-acceptance-efficacy?_ga=2.242068545.254033713.1708093077-1826905377.1708093076
4. Mendell JR, Muntoni F, McDonald CM, et al. Safety and efficacy of delandistrogene moxeparvovec versus placebo in Duchenne muscular dystrophy: Phase 3 EMBARK primary results. Presented at: ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland.