The purpose of the study is to assess the efficacy, safety, and tolerability of zeleciment rostudirsen (DYNE-251) administered intravenously (IV) every 4 weeks to ambulatory Duchenne muscular dystrophy (DMD) participants, 4 to 18 years of age, with dystrophin mutations amenable to exon 51 skipping.

The study consists of three periods: a Screening period (up to 6 weeks), a Placebo-Controlled Period (72 weeks) and an open-label Long-Term Extension Period (96 weeks).

Inclusion Criteria:

• Ambulatory male with confirmed diagnosis of DMD and with a mutation in the dystrophin gene characterized by exon deletion amenable to exon 51 skipping .
• Rise From Floor (RFF) time must be < 10 seconds for both screening assessments .
• Receiving a stable daily or weekend dosage of glucocorticoids for at least 24 weeks prior to randomization with the expectation of maintaining a stable dose during the Placebo-Controlled Period of the study (unless dose adjustment is required by weight change)

Exclusion Criteria:

• Receipt of ongoing immunosuppressive therapy (other than glucocorticoids) within 12 weeks prior to randomization
• Use of any pharmacologic treatment (other than glucocorticoids) that may have an effect on muscle strength or function within 12 weeks prior to randomization
• Any change in prophylaxis/treatment for congestive heart failure (CHF) within 12 weeks prior to randomization
• Receipt of eteplirsen within 1 week prior to randomization
• Receipt of alternative exon-skipping or dystrophin-modifying therapy or zeleciment rostudirsen within 24 weeks prior to randomization
• Receipt of givinostat within 12 weeks prior to randomization
• Receipt of gene therapy at any time

Note: Other inclusion or exclusion criteria may apply