Initial results from an open-label phase 1/2 study of BMN 351, an antisense oligonucleotide for exon 51-skip amenable Duchenne muscular dystrophy

Topic:

Clinical Trials

Poster Number: 418 O

Author(s):

Giovanni Baranello, MD, PhD, UCL Gt Ormond St Inst Child Health, London, UK, Marcos Madruga-Garrido, Neurolinkia, Sevilla, Spain and Hospital Viamed Santa Ángela de la Cruz, Sevilla, Spain, Erik Niks, MD, PhD, Leiden University Medical Center, Leiden, Netherlands, Marika Pane, MD, Fondazione Policlinico Universitario A. Gemelli, Valeria Sansone, MD, The NeMO Clinical Center in Milan, Neurorehabilitation Unit, Milan, Italy, Hai Liu, BioMarin Pharmaceutical Inc., Orli Rosen, BioMarin Pharmaceutical Inc., Cigdem Ayanoglu, Yeditepe University, Istanbul, Turkey, David Neil, MD, BioMarin Pharmaceuticals, Haluk Topaloglu, Yeditepe University, Istanbul, Turkey

BMN 351 (nivudirsen), an antisense phosphorothioate (PS) oligonucleotide modified to improve safety and efficacy, targets a novel dystrophin exon 51 binding site. BMN 351-201 (EUCT#2023-506737-30-00) is an open-label, phase 1/2, dose-escalation study of BMN 351 in ambulatory participants with DMD amenable to exon 51 skipping, aged 4-10 years. The primary objective is safety; additional objectives include exon skipping, dystrophin expression, and functional assessments. Cohort 1A (n=3) received single ascending doses of intravenous BMN 351 (0.6, 1.5, 3, and 6mg/kg). Then, cohorts 1A and 1B (n=3) received 6mg/kg, and cohort 2 (n=6) received 9mg/kg weekly. Cohort 3 enrollment (n=6; 12mg/kg) is ongoing.

By the July 2025 data cut, 12 boys (5.0-9.0 years) enrolled and received BMN 351. In cohorts 1 and 2, mean treatment duration was 52.7 and 27.5 weeks and mean number of doses was 47 and 24. Eleven participants experienced grade 1 or 2 treatment-related adverse events (AEs). No AEs led to dose reductions or permanent discontinuation. One serious treatment-unrelated AE occurred (grade 3 influenza).

Ten participants had post-treatment muscle biopsies by the data cut. BMN 351 provided mean±SD exon skipping of 3.51%±3.62% (n=2; 6mg/kg) at week (W)13 and 2.99%±2.77% (n=4; 6mg/kg) and 5.86%±4.48% (n=4; 9mg/kg) at W25. Mean±SD dystrophin change from baseline (% normal muscle, alpha-actin normalized) by western blot was 1.01%±1.06% (n=2; 6mg/kg) at W13 and 1.27%±0.85% (n=4; 6mg/kg) and 4.50%±4.71% (n=4; 9mg/kg) at W25. By liquid chromatography-mass spectrometry, dystrophin change from baseline was 1.68%±1.16% (n=2; 6mg/kg) at W13 and 1.85%±0.55% (n=4; 6mg/kg) and 4.76%±4.45% (n=4; 9mg/kg) at W25. Functional outcomes relative to natural history and additional cohort 2 data will be presented.

Interim analyses demonstrated acceptable safety and positive dystrophin changes in boys with DMD receiving BMN 351 ≤9mg/kg. PS chemistry-based PK/PD modeling predicts dystrophin will continue to rise toward steady state; confirmatory studies are planned.