2.1 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 [see Warnings and Precautions (5.1)].

2.2 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.

2.3 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.

1. 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.
2. Allow vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 to 3 times. Do not shake.
3. 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.
4. Withdraw the calculated volume of VILTEPSO from the appropriate number of vials.
   1. 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.
   2. 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.
5. Visually inspect the infusion bag containing the solution for particulates. Gently invert the infusion bag to ensure equal distribution of product. Do not shake.
6. 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.
7. VILTEPSO is supplied in single-dose vials. Discard unused VILTEPSO.

2.4 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.

5.1 Kidney Toxicity

Kidney toxicity was observed in animals who received viltolarsen [see Use in Specific Populations (8.4)]. Although kidney toxicity was not observed in the clinical studies with VILTEPSO, the clinical experience with VILTEPSO is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking VILTEPSO. Because of the effect of reduced skeletal muscle mass on creatinine measurements, serum creatinine may not be a reliable measure of kidney function in DMD patients. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VILTEPSO. Consider also measuring glomerular filtration rate using an exogenous filtration marker before starting VILTEPSO. During treatment, monitor urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio every three months. Only urine expected to be free of excreted VILTEPSO should be used for monitoring of urine protein. Urine obtained on the day of VILTEPSO infusion prior to the infusion, or urine obtained at least 48 hours after the most recent infusion, may be used.  Alternatively, use a laboratory test that does not use the reagent pyrogallol red, as this reagent has the potential to cross react with any VILTEPSO that is excreted in the urine and thus lead to a false positive result for urine protein.

If a persistent increase in serum cystatin C or proteinuria is detected, refer to a pediatric nephrologist for further evaluation.

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.

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.

8.1 Pregnancy

8.2 Lactation

8.4 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 [see Clinical Studies (14)].

8.5 Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with VILTEPSO.

8.6 Patients with Renal Impairment

VILTEPSO has not been studied in patients with renal impairment. Viltolarsen is mostly excreted unchanged in the urine, and renal impairment may increase its exposure. However, because of the effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment based on estimated glomerular filtration rate. Patients with known renal function impairment should be closely monitored during treatment with VILTEPSO.

12.1 Mechanism of Action

VILTEPSO is designed to bind to exon 53 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon 53 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 53 skipping.

12.2 Pharmacodynamics

After treatment with VILTEPSO 80 mg/kg once weekly, all patients evaluated (N=8) were found to produce mRNA for a truncated dystrophin protein, as measured by reverse transcription polymerase chain reaction (RT-PCR), and demonstrated exon 53 skipping, as measured by DNA sequence analysis.

In Study 1, all patients who received VILTEPSO 80 mg/kg once weekly for 20 to 24 weeks showed an increase from baseline in dystrophin protein expression, as quantified by a validated Western blot method (mean 5.3%; median 3.8%; range 0.7% to 13.9% of normal levels when normalized to myosin heavy chain; p-value 0.01). Mass spectrometry, immunofluorescence staining, and RT-PCR results were supportive of the Western blot data [see Clinical Studies (14)]. Expected localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with viltolarsen was confirmed by immunofluorescence staining.

12.3 Pharmacokinetics

The pharmacokinetics of viltolarsen was evaluated in DMD patients following administration of intravenous (IV) doses ranging from 1.25 mg/kg/week (0.016 times the recommended dosage) to 80 mg/kg/week (the recommended dosage). Viltolarsen exposure increased proportionally with dose, with minimal accumulation with once-weekly dosing. Inter-subject variability (as %CV) for Cmax and AUC ranged from 16% to 27% respectively.

VILTEPSO is administered as an IV infusion over 60 minutes. Bioavailability is assumed to be 100%, and median Tmax was around 1 hour (end of infusion).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

VILTEPSO injection is supplied in single-dose vials. The solution is clear and colorless.

• Single-dose vials containing 250 mg/5 mL (50 mg/mL) viltolarsen          NDC 73292-011-01

16.2 Storage and Handling

Store VILTEPSO at 2°C to 8°C (36°F to 46°F). Do not freeze.

Kidney Toxicity

Inform patients nephrotoxicity has occurred with drugs similar to VILTEPSO. Advise patients of the importance of monitoring for kidney toxicity by their healthcare providers during treatment with VILTEPSO [see Warnings and Precautions (5.1)].

Manufactured for:
NS Pharma, Inc.
Paramus, NJ 07652