Evaluating Brogidirsen for Exon 44 Skipping in DMD: Early-Phase Insights

Advancements in Duchenne muscular dystrophy (DMD) treatments have shown promise in alleviating the burden of this severe muscular disorder, but their mutation specificity and limited efficacy leave room for further development.

That’s why a recent phase 1/2 open-label trial published in Cell Reports Medicine in January of 2025 explored the safety and efficacy of brogidirsen, a dual-targeting phosphorodiamidate morpholino oligomer (PMO). Brogidirsen is uniquely engineered with two connected 12-mer sequences which are designed to modulate splicing at exon 44 of the DMD gene, restoring the reading frame and enabling production of truncated yet functional dystrophin protein. This approach is intended for patients with specific DMD mutations—an estimated 6.2 percent of the DMD population—that would benefit from exon 44 skipping.

Study Design
The trial enrolled six ambulant boys aged four to 13 years with DMD mutations amenable to exon 44 skipping. Conducted at two sites in Japan, the study followed a two-part design:

• Part 1 (dose escalation over 4 weeks): Two patient cohorts were administered escalating intravenous doses. Cohort 1 received 1.62 mg/kg for the initial two-week period, followed by 40 mg/kg for the subsequent two weeks. Cohort 2 received 10 mg/kg for two weeks followed by 80 mg/kg for two weeks.
• Part 2 (24-week evaluation): Patients continued at either 40 mg/kg or 80 mg/kg based on tolerability from part 1.

Patients underwent regular assessments, including muscle biopsies, pharmacokinetic sampling, motor function testing, and high-throughput plasma proteomics.

Safety and Tolerability
In terms of brogidirsen’s safety profile, the therapy was generally well tolerated across all dose levels. The most frequent drug-related adverse events included elevations in urinary biomarkers (for example, β2 microglobulin and albumin/creatinine ratio), primarily in the lower-dose cohort. No serious adverse events were attributed to the study drug, and no patients discontinued treatment due to safety concerns.

Efficacy
Looking at its efficacy, the study reported notable increases in both exon 44 skipping and dystrophin protein levels in muscle biopsy samples.

• Exon 44 Skipping: Mean exon skipping increased by 32.1 percent from baseline across all patients (p=0.03), with slightly higher levels in the 80 mg/kg group.
• Dystrophin Expression: Mean protein levels reached 20.55 percent of normal (p=0.0022) in the total population, with higher levels in the 80 mg/kg group (24.47 percent) compared to 40 mg/kg (16.63 percent).

Although functional motor scores did not show significant improvement, patients generally maintained their baseline function over the 24-week period. Given the age of participants and typical progression rates in DMD, this may represent a stabilization of disease trajectory during the treatment window.

Plasma Biomarkers and In Vitro Validation
In addition, both plasma proteomic profiling and patient-derived cell assays show that brogidirsen induces biomarker shifts consistent with decreased muscle pathology and drives potent, dose-dependent exon 44 skipping leading to dystrophin restoration.

Plasma proteomics revealed reductions in muscle damage-associated proteins such as titin (TTN), myomesin 2 (MYOM2), and myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF) during treatment. The calcium-dependent enzyme PADI2, previously associated with DMD pathology, also decreased. Levels of CNTF, a cytokine linked to neuromuscular maintenance, increased.

In vitro studies using patient-derived cells supported the in vivo findings. These models showed dose-dependent exon 44 skipping and dystrophin restoration, with a half-maximal effective concentration (EC₅₀) of 7.12 μM, consistent across multiple cell types.

Limitations
While these early findings suggest that brogidirsen can induce exon skipping and dystrophin expression at levels higher than those reported for previously approved exon-skipping agents, interpretation is limited by several factors:

• The small cohort size (n=6)
• Short treatment period
• Open-label design
• Natural baseline expression of dystrophin in some participants due to alternative splicing

Furthermore, no non-responders were observed, which limits evaluation of variability in treatment effect.

Clinical Implications and Further Research Directions
This phase 1/2 trial supports the safety and potential biological activity of brogidirsen in a targeted DMD population. Additional studies with larger cohorts, longer follow-up, and controlled designs will be needed to determine clinical efficacy and long-term impact. A phase 2 extension trial is ongoing to further assess these outcomes.

Reference:

1. Komaki H, Takeshita E, Kunitake K, et al. Phase 1/2 trial of brogidirsen: Dual-targeting antisense oligonucleotides for exon 44 skipping in Duchenne muscular dystrophy. Cell Rep Med. 2025;6(1):101901. doi:10.1016/j.xcrm.2024.101901