1 INDICATIONS AND USAGE VILTEPSO is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VILTEPSO [see Clinical Studies ( 14 )].

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

VILTEPSO is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VILTEPSO.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

( 1 )

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥15% in patients treated with VILTEPSO) were upper respiratory tract infection, injection site reaction, cough, and pyrexia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NS Pharma at 1-866 NSPHARM (1-866-677-4276) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials with VILTEPSO, 32 patients have been exposed to VILTEPSO once weekly, ranging between 40 mg/kg (0.5 times the recommended dosage) and 80 mg/kg (the recommended dosage), including 16 patients treated for greater than 12 months and 8 patients treated for greater than 24 months as part of an ongoing open-label extension study.

All patients were male and had genetically confirmed DMD.

Study 1 was a multicenter, 2-period, dose-finding study conducted in the United States and Canada in males 4 years to less than 10 years of age on a stable corticosteroid regimen for at least 3 months.

During the initial period (first 4 weeks) of Study 1, patients were randomized (double-blind) to VILTEPSO or placebo.

All patients then received 20 weeks of VILTEPSO 40 mg/kg once weekly (0.5 times the recommended dose) (N=8), or 80 mg/kg once weekly (N=8) [see Clinical Studies ( 14 )].

Study 2 was a multicenter, parallel-group, open-label, dose-finding study conducted in Japan.

Eligible patients included ambulatory and non-ambulatory males 5 years to less than 18 years of age who were assigned to receive intravenous VILTEPSO 40 mg/kg once weekly (0.5 times the recommended dose) (N=8) or 80 mg/kg once weekly (N=8) for 24 weeks.

Adverse reactions reported in ≥10% of patients treated with VILTEPSO 80 mg/kg/wk in pooled Studies 1 and 2 are displayed in Table 1 .

The most common adverse reactions (incidence ≥15% in patients treated with VILTEPSO) were upper respiratory tract infection, injection site reaction, cough, and pyrexia.

Patients in the pooled analysis were treated with VILTEPSO for 20 to 24 weeks.

Table 1: Adverse Reactions Reported in ≥10% of DMD Patients Treated with VILTEPSO 80 mg/kg Once Weekly (Pooled Studies 1 and 2) * Upper respiratory tract infection includes the following terms: upper respiratory tract infection, nasopharyngitis, and rhinorrhea.

** Injection site reaction includes the following terms: injection site bruising, injection site erythema, injection site reaction, and injection site swelling.

Adverse Reaction VILTEPSO 80 mg/kg Once Weekly (n=16) % Upper respiratory tract infection* 63 Injection site reaction** 25 Cough 19 Pyrexia 19 Contusion 13 Arthralgia 13 Diarrhea 13 Vomiting 13 Abdominal pain 13 Ejection fraction decreased 13 Urticaria 13 6.2 Immunogenicity As with all oligonucleotides, there is potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies may be misleading.

For Study 1, samples collected from all 16 patients at Day 1 (pre-dose), Week 5, Week 13, and Week 24 were assessed for anti-viltolarsen antibodies.

All samples were determined to be antibody negative.

For the same study, serum samples collected from all 16 patients at Day 1 (pre-dose), Week 13, and Week 24 were analyzed for anti-dystrophin antibodies.

Anti-dystrophin antibodies were detected in 1 out of 16 patients (6.25%) at Weeks 13 and 24; however, at Weeks 37, 49, 73, and 97, no anti-dystrophin antibodies were detected in the same patient.

Further, this patient achieved a change from baseline in dystrophin levels that was comparable to the mean change in his dosage group (80 mg/kg/week) and there were no adverse events reported with this antibody production.

For Study 2, all samples collected from the 16 patients were determined to be both anti-viltolarsen antibody and anti-dystrophin antibody negative.

Overall, there was a lack of observed immunogenicity, which indicates that viltolarsen is not highly immunogenic.