Viltepso Drug Information

Monitoring to Assess Safety Serum cystatin C, urine dipstick, and urine protein-to-creatinine

ratio should be measured before starting VILTEPSO. Consider measurement of glomerular filtration rate prior to initiation of VILTEPSO. Monitoring for kidney toxicity during treatment is recommended. Obtain the urine samples prior to infusion of VILTEPSO or at least 48 hours after the most recent infusion.

Dosing Information

The recommended dosage of VILTEPSO is 80 mg/kg administered once weekly as a 60-minute intravenous infusion. If a dose of VILTEPSO is missed, it should be administered as soon as possible after the scheduled dose time.

Preparation Instructions Parenteral drug products should be inspected visually for particulate matter

and discoloration prior to administration, whenever solution and container permit. Prepare the VILTEPSO dose using aseptic technique. Calculate the total dose of VILTEPSO to be administered based on the patient's weight and the recommended dosage of 80 mg/kg.

Determine the volume of VILTEPSO needed and the correct number of vials to supply the full calculated dose. Allow vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 to 3 times.

Do not shake. Visually inspect each vial of VILTEPSO. VILTEPSO is a clear and colorless solution. Do not use if the solution in the vials is discolored or particulate matter is present.

Withdraw the calculated volume of VILTEPSO from the appropriate number of vials. If the volume of VILTEPSO required is less than 100 mL, dilution in 0.9% Sodium Chloride Injection, USP is required. Withdraw from the 100-mL infusion bag a volume of 0.9% Sodium Chloride Injection, USP, equivalent to the calculated volume of VILTEPSO and inject the VILTEPSO into the infusion bag, such that the total volume in the bag is 100 mL. If the volume of VILTEPSO required is 100 mL or more, dilution is not required, and the required amount of VILTEPSO should be placed into an empty infusion bag.

Visually inspect the infusion bag containing the solution for particulates. Gently invert the infusion bag to ensure equal distribution of product. Do not shake.

VILTEPSO contains no preservatives. Infusion should begin as soon as possible, but no more than 5 hours after preparation of VILTEPSO, and be completed within 6 hours of preparation (allowing for 1 hour of infusion time), if diluted solution is stored at 20°C to 26°C (68°F to 79°F). If immediate use is not possible, the solution may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F). Do not freeze. VILTEPSO is supplied in single-dose vials.

Discard unused VILTEPSO.

Administration Instructions

VILTEPSO is administered via intravenous infusion using a peripheral or central venous catheter. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, after infusion. Filtration of VILTEPSO is not required.

Infuse VILTEPSO over 60 minutes. Do not mix other medications with VILTEPSO or infuse other medications concomitantly via the same intravenous access line. VILTEPSO should be mixed with 0.9% Sodium Chloride Injection, USP, only.

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). 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

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.

Pregnancy Risk Summary There are no human or animal data available to assess the use of VILTEPSO during pregnancy. In the U.S. general population, major birth defects occur in 2 to 4%, and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

Pediatric Use VILTEPSO is indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, including pediatric patients. Juvenile Animal Toxicity Data Viltolarsen (0, 15, 60, 240, or 1200 mg/kg) was administered to juvenile male mice by subcutaneous injection on postnatal day (PND) 7 and by intravenous injection weekly from PND 14 to PND 70. The highest dose resulted in deaths because of renal toxicity. In surviving animals at 240 and 1200 mg/kg, there was a dose-dependent increase in the incidence and severity of renal tubular effects (including degeneration), which were not accompanied by clinical pathology correlates.

Reduced body weight gain and delayed sexual maturation were observed at the highest dose tested. At the no-effect dose for renal toxicity (60 mg/kg), plasma exposures were similar to that in humans at the recommended human dose of 80 mg/kg/week.