BMN 351

What is BMN 351?

BMN 351 is an antisense oligonucleotide (ASO) designed to induce skipping of exon 51 of dystrophin pre-mRNA and production of internally deleted but functional dystrophin protein.^[3] It is a nucleic acid-based substance, provided as a concentrate for solution for infusion.^[2] The product name used in registry records is "Exon 51 specific phosphorothioate oligonucleotide".^[2] BMN 351 is an investigational substance with no marketing authorisation in the product records; the authorisation holder is BioMarin Pharmaceutical Inc.^[2]

How does BMN 351 work?

Duchenne muscular dystrophy is caused by mutations of the DMD gene that prevent the expression of functional dystrophin protein.^[3] BMN 351 works as an antisense oligonucleotide: it binds to dystrophin pre-mRNA and causes exon 51 to be skipped during processing. This allows the cell to produce a shorter but still functional dystrophin protein.^[3] In a mouse model of exon 51 skip-amenable DMD, weekly intravenous doses of BMN 351 produced dose-dependent exon skipping in heart and quadriceps muscles, with mean dystrophin levels of 17% to 55% twelve weeks after dosing.^[3]

Which conditions is BMN 351 studied for?

• Duchenne muscular dystrophy (DMD) — a genetic muscle-wasting disease caused by mutations in the DMD gene that prevent production of functional dystrophin. Both registered trials of BMN 351 include participants with DMD.^[2][1]

How is BMN 351 given?

BMN 351 is given by intravenous infusion. The pharmaceutical form in the registry is a concentrate for solution for infusion.^[2] In the Phase 2 extension study, the dose reported in the registry is 12 mg per kilogram given by intravenous infusion.^[1] In the completed Phase 1/2 study, the dose was not reported in the register.^[2] In a mouse model, BMN 351 was given weekly by intravenous injection at 6 mg/kg or 18 mg/kg for 25 weeks.^[3]

What do the clinical trials show?

Two clinical trials of BMN 351 in Duchenne muscular dystrophy are listed in the registries. The first is a Phase 1/2, open-label, dose escalation study that assessed safety, tolerability, pharmacokinetics (how the drug moves through the body), and pharmacodynamics (what the drug does to the body) of multiple intravenous doses.^[2] This trial enrolled 18 participants and is completed.^[2] The second is a Phase 2, open-label extension study to evaluate long-term safety and efficacy in 13 participants; it is authorised.^[1]

What are the trials measuring?

The primary outcome in both trials is the incidence of adverse events and serious adverse events, together with physical examination, safety laboratory test parameters, ECG parameters, and echocardiography.^[2][1] The extension study also measures efficacy, although the registry does not list a separate efficacy endpoint.^[1]

Who can take part in these trials?

Both trials enrolled participants with Duchenne muscular dystrophy. The Phase 1/2 study enrolled 18 participants; the Phase 2 extension study enrolled 13 participants.^[2][1] The registries do not provide further details on age or other inclusion criteria.

What side effects are known?

In the mouse study, liver samples demonstrated findings consistent with antisense oligonucleotide accumulation; the authors note that mice are considered especially sensitive to this compared to humans and other non-clinical species.^[3] The clinical trial registries list the incidence of adverse events and serious adverse events as a primary outcome, but no specific side effect data from the completed trial are reported in the registry records.^[2][1]