Nivudirsen Increases Dystrophin Expression in Phase 1/2 Interim Study of DMD Amenable to Exon 51 Skipping

Newly presented interim results from an ongoing phase 1/2 (NCT06280209) showed that treatment with investigational nivudirsen (BioMarin Pharmaceutical) demonstrated an acceptable safety profile and increased dystrophin expression at doses of 9 mg/kg or lower in ambulatory patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.¹

By the July 2025 data cutoff, 12 boys aged 5 to 9 years had enrolled and received nivudirsen for the early-stage study. In cohorts 1 and 2, the mean treatment duration was 52.7 weeks and 27.5 weeks, with a mean of 47 and 24 doses administered, respectively. Notably, 11 participants experienced treatment-related adverse events (AEs), all grade 1 or 2, and no events led to dose reductions or permanent discontinuation. Only 1 serious AE, grade 3 influenza, was reported and determined to be unrelated to treatment by the researchers.

Lead author Giovanni Baranello, MD, PhD, clinical associate professor of pediatric neurology and neuromuscular disorders at the University College London, presented the phase 1/2 data at recently concluded 2026 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 9-11, in Orlando, Florida. Nivudirsen, also known as BMN 351, is an antisense phosphorothioate oligonucleotide administered intravenously, that targets a novel dystrophin exon 51 binding site.

This open-label, phase 1/2, dose-escalation study consists of 2 parts to investigate the safety and tolerability of nivudirsen at escalating doses in 18 patients with DMD with genetic mutations amenable to exon 51 skipping, aged 4 to 10 years, up to 97 weeks. The primary objective of the study is to assess safety, with additional objectives including evaluation of exon skipping, dystrophin expression, and functional assessments. Researchers assigned participants to 1 of 3 cohorts, with cohort 1 further divided into cohorts 1A and 1B.

In cohort 1A (n = 3), participants initially received single ascending intravenous doses of nivudirsen (0.6, 1.5, 3, and 6 mg/kg) administered every 2 weeks with interim safety assessments prior to dose escalation, followed by transition to once-weekly dosing. Participants in cohort 1B (n = 3) then initiated once-weekly dosing at 6 mg/kg, whereas cohort 2 (n = 6) received once-weekly dosing at 9 mg/kg; enrollment for cohort 3 (n = 6), evaluating once-weekly dosing at 12 mg/kg, is ongoing.

READ MORE: Late Gadolinium Enhancement on Cardiac MRI Associated With Increased Fatigue in Women Carriers of Dystrophinopathies

By the data cutoff, authors noted that 10 participants had post-treatment muscle biopsies. At 13 weeks, participants who received 6 mg/kg of nivudirsen demonstrated mean exon skipping of 3.51% (±3.62%; n = 2). At 25 weeks, researchers observed that mean exon skipping was 2.99% (±2.77%) in the 6 mg/kg group (n = 4) and 5.86% (±4.48%) in the 9 mg/kg group (n = 4).

In a western blot analysis, findings showed mean dystrophin changes from baseline of 1.01% (±1.06%) at week 13 (6 mg/kg) and 1.27% (±0.85%; 6 mg/kg) and 4.50% (±4.71%; 9 mg/kg) at week 25. Additionally, similar findings were observed by liquid chromatography–mass spectrometry, with mean dystrophin changes of 1.68% (±1.16%) at 13 weeks (6 mg/kg) and 1.85% (±0.55%; 6 mg/kg) and 4.76% (±4.45%; 9 mg/kg) at 25 weeks.

All told, phosphorothioate chemistry–based pharmacokinetic and pharmacodynamic modeling predicts dystrophin levels may continue to increase toward steady state, and that confirmatory studies are planned. In a separate exploratory analysis, presented at the 2026 MDA Conference by lead author Kristin Obrochta Moss, PhD, senior scientist II at BioMarin Pharmaceutical, findings showed the impact of nivudirsen on muscle quality and composition in DMD.²

Using transcriptional analyses, including RNA sequencing and targeted droplet digital PCR assays, investigators examined cell-type–specific and pathway-specific changes in muscle tissue with limited biopsy material. In a hDMDdel52/mdx mouse model, bulk RNA sequencing identified a transcriptome-wide signature of disease that shifted toward normal following nivudirsen treatment. Of note, differentially expressed genes were notable in pathways related to muscle development, extracellular matrix, and adaptive immune response.

For this study, quantitative ddPCR assays were used to develop a composite score representing the ratio of predominantly myoblast-expressed to myofiber-expressed genes. At the conclusion of the analysis, the myoblast-to-myofiber index was elevated in untreated DMD mice and decreased toward wild-type levels with nivudirsen treatment, correlating with improved muscle function as measured by gait score.

In human samples, investigators observed a similar set of disease-associated transcripts was confirmed. The myoblast-to-myofiber transcript ratio was elevated compared with healthy controls and decreased after 13 to 25 weeks of nivudirsen treatment in the ongoing phase 1/2 study. Overall, these findings suggested that near–full-length dystrophin produced by nivudirsen may positively affect DMD muscle by shifting gene expression toward a healthy profile.

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REFERENCES
1. Baranello G, Madruga-Garrido M, de la Cruz Á, et al. Initial results from an open-label phase 1/2 study of BMN 351, an antisense oligonucleotide for exon 51-skip amenable Duchenne muscular dystrophy. Presented at: MDA Clinical & Scientific Conference; March 8-11, 2026; Orlando, Florida. Abstract 418.
2. Moss KO, Abbasi M, Staskus L, et al. Transcriptional biomarker for muscle composition measures BMN 351 treatment response in DMD. Presented at: MDA Clinical & Scientific Conference; March 8-11, 2026; Orlando, Florida. Abstract 273.