Viltepso (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 CLINICAL STUDIES

The effect of VILTEPSO on dystrophin production was evaluated in one study in DMD patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping (Study 1; NCT02740972).

Study 1 was a multicenter, 2-period, dose-finding study conducted in the United States and Canada.

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 open-label VILTEPSO 40 mg/kg once weekly (0.5 times the recommended dosage) (N=8) or 80 mg/kg once weekly (N=8). Study 1 enrolled ambulatory male patients 4 years to less than 10 years of age (median age 7 years) on a stable corticosteroid regimen for at least 3 months.

Efficacy was assessed based on change from baseline in dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 25. Muscle biopsies (left or right biceps brachii) were collected from patients at baseline and following 24 weeks of VILTEPSO treatment, and analyzed for dystrophin protein level by Western blot normalized to myosin heavy chain (primary endpoint) and mass spectrometry (secondary endpoint).

In patients who received VILTEPSO 80 mg/kg once weekly, mean dystrophin levels increased from 0.6% (SD 0.8) of normal at baseline to 5.9% (SD 4.5) of normal by Week 25, with a mean change in dystrophin of 5.3% (SD 4.5) of normal levels (p=0.01) as assessed by validated Western blot (normalized to myosin heavy chain); the median change from baseline was 3.8%. All patients demonstrated an increase in dystrophin levels over their baseline values. As assessed by mass spectrometry (normalized to filamin C), mean dystrophin levels increased from 0.6% (SD 0.2) of normal at baseline to 4.2% (SD 3.7) of normal by Week 25, with a mean change in dystrophin of 3.7% (SD 3.8) of normal levels (nominal p=0.03, not adjusted for multiple comparisons); the median change from baseline was 1.9%.

Individual patient dystrophin levels in patients evaluated in Study 1 are shown in Figure 2and Table 2.

Figure 2: Dystrophin Expression in Individual Patients (Study 1)

Patients Treated With VILTEPSO 80 mg/kg/week (n=8)

Note: Solid lines represent individual patient data. Dystrophin was measured using Western blot and normalized to myosin heavy chain.

Table 2: Dystrophin Expression in Individual Patients (Study 1)

aData were normalized by myosin heavy chain
Patient Number	Western Blot % Normal Dystrophin a
	Baseline	Week 25	Change from Baseline
1	0.46	1.14	0.69
2	0.40	3.97	3.57
3	0.46	2.97	2.51
4	0.09	10.40	10.31
5	0.51	14.42	13.91
6	2.61	7.40	4.79
7	0.43	3.06	2.63
8	0.09	4.07	3.98

)].

• Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VILTEPSO. (
  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 ].
  )
• Recommended dosage is 80 milligrams per kilogram of body weight once weekly. (
  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.
  )
• Administer as an intravenous infusion over 60 minutes. (
  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.
  ,
  2.4 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.
  )
• If the volume of VILTEPSO required is less than 100 mL, dilution in 0.9% Sodium Chloride Injection, USP, is required. (
  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.

  • 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.
  )

VILTEPSO is a clear and colorless solution available as follows:

• Injection: 250 mg/5 mL (50 mg/mL) solution in a single-dose vial

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.