Brogidirsen Demonstrates Long-Term Safety and Stable Motor Function in DMD

Long-term data from an investigator-initiated clinical program suggest that treatment with investigational exon-skipping therapy brogidirsen (NS-089/NCNP-02) was safe, and may sustain motor function in patients with Duchenne muscular dystrophy (DMD) amenable to exon 44 skipping.

Trial Overview and Key Findings

Results from an ongoing phase 2 extension study evaluating weekly brogidirsen administration over approximately 4.5 years were presented at the 2026 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 8-11, in Orlando, Florida.¹ The data derive from a phase 2 open-label extension study that enrolled patients who had previously completed a first-in-human phase 1/2 trial (NCT04129294). Participants in the extension study continued receiving weekly intravenous brogidirsen at doses of either 40 mg/kg or 80 mg/kg.

Led by Hirofumi Komaki, MD, PhD, managing director at the National Center of Neurology and Psychiatry in Tokyo, Japan, the trial includes 6 participants with DMD amenable to exon 44 skipping were enrolled in the long-term follow-up analysis. Three participants received the 40 mg/kg dose and three received 80 mg/kg, with investigators evaluating safety and efficacy outcomes over approximately 4.5 years of continued treatment.¹

All told, functional outcomes suggested stabilization of disease progression in several participants. According to the study authors, some patients experienced improvements or maintenance of motor performance from the start of therapy based on North Star Ambulatory Assessment (NSAA) evaluations. Among participants who progressed to wheelchair use during the study period—a typical milestone in the natural history of DMD—total scores on the PUL 2.0 assessment were maintained, indicating preserved upper limb function.

Biochemical analyses also suggested potential biologic activity. Serum creatine kinase levels, a biomarker commonly associated with muscle damage in DMD, declined during the first 24 weeks of treatment in the initial phase 1/2 study and remained relatively stable during the extension study.

Across this period, brogidirsen appeared generally well tolerated. No serious or severe adverse events, including hypersensitivity reactions such as anaphylaxis, were reported, and no patients discontinued treatment due to adverse events.1

Drug Background

Brogidirsen is an antisense oligonucleotide designed to induce skipping of exon 44 in the dystrophin transcript. By excluding this exon during RNA processing, the therapy aims to restore the reading frame of the dystrophin gene in patients whose mutations are amenable to exon 44 skipping. This mechanism is intended to enable production of a shorter but partially functional dystrophin protein.

The drug was developed by the National Center of Neurology and Psychiatry in collaboration with Nippon Shinyaku Co., Ltd. For context, preclinical studies demonstrated efficient exon skipping and restoration of dystrophin expression in patient-derived cellular models, ultimately supporting initiation of early-phase clinical trials to evaluate safety and potential efficacy in humans.

Clinical Context

DMD is a rare, progressive X-linked neuromuscular disorder caused by mutations in the dystrophin gene, which encodes a structural protein critical for maintaining muscle cell membrane integrity. The absence of functional dystrophin leads to muscle degeneration, chronic inflammation, and eventual replacement of muscle tissue with fibrotic and fatty tissue. Patients typically lose ambulation during adolescence and experience progressive respiratory and cardiac complications that contribute to premature mortality.

Management of DMD currently involves multidisciplinary care and pharmacologic interventions intended to slow disease progression. Corticosteroids remain the mainstay of therapy for preserving muscle strength and delaying loss of ambulation. In recent years, several exon-skipping therapies have received regulatory approval for specific dystrophin mutations, including eteplirsen, golodirsen, viltolarsen, and casimersen. These agents aim to restore partial dystrophin production by modifying pre-mRNA splicing, allowing the production of a truncated but functional dystrophin protein.2

However, existing therapies target only certain mutation subsets, leaving additional genotypes without disease-modifying treatment options. Therapies capable of targeting exon 44 represent a potential approach for another segment of the DMD population.

Interpretation, Limitations, and Next Steps

Although the long-term follow-up provides encouraging safety observations, interpretation of the efficacy findings should be cautious. The extension study included only six participants and lacked a randomized comparator group, limiting the ability to determine whether the observed functional outcomes differ from the expected natural history of DMD.

Functional assessments such as NSAA and PUL scores can vary over time, and small cohorts may be particularly susceptible to variability in disease progression. Additionally, the abstract did not report quantitative dystrophin expression levels or imaging biomarkers that might further clarify the biological impact of the therapy.

Further clinical development is ongoing. A separate phase 2 study, the DISCOVER trial (NCT05996003), sponsored by NS Pharma, Inc., is currently evaluating the safety and efficacy of brogidirsen in a broader population of patients with DMD amenable to exon 44 skipping.³ Larger controlled trials will likely be needed to determine whether the therapy can produce clinically meaningful improvements in functional outcomes and disease progression.

REFERENCES
1. Komaki H. Safety and efficacy of brogidirsen after 4.5 years of weekly administration in DMD patients: results from an ongoing open-label extension study. Presented at 2026 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference; March 8-11, 2026; Orlando, Florida.
2. Gloss D, Moxley RT, Ashwal S, Oskoui M. Practice guideline update summary: corticosteroid treatment of Duchenne muscular dystrophy. Neurology. 2016;86(5):465-472.
3. Tang A, Yokota T. Brogidirsen and Exon 44 Skipping for Duchenne Muscular Dystrophy: Advances and Challenges in RNA-Based Therapy. Genes (Basel). 2025;16(7):777. Published 2025 Jun 30. doi:10.3390/genes16070777