Viltolarsen

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 )

VILTEPSO is a clear and colorless solution available as follows: Injection: 250 mg/5 mL (50 mg/mL) solution in a single-dose vial Injection: 250 mg/5 mL (50 mg/mL) in a single-dose vial ( 3 )

None. None ( 4 )

Kidney Toxicity: Based on animal data, may cause kidney toxicity. Kidney function should be monitored; creatinine may not be a reliable measure of renal function in DMD patients. ( 5.1 , 13.2)

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.

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.

8.1 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.

8.2 Lactation Risk Summary There are no human or animal data to assess the effect of VILTEPSO on milk production, the presence of viltolarsen in milk, or the effects of VILTEPSO on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VILTEPSO and any potential adverse effects on the breastfed infant from VILTEPSO or from the underlying maternal condition.

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 )]. 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.

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.

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.