Viltolarsen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Viltolarsen is a exon 53 of the dystrophin pre-mRNA that is FDA approved 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.. Common adverse reactions include Upper respiratory infections.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
DOSAGE 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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Viltolarsen in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Viltolarsen in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Viltolarsen FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Viltolarsen in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Viltolarsen in pediatric patients.
Contraindications
None
Warnings
Kidney Toxicity Kidney toxicity was observed in animals who received viltolarsen. 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.
Adverse Reactions
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.
Postmarketing Experience
There is limited information regarding Viltolarsen Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Viltolarsen Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Viltolarsen in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Viltolarsen in women who are pregnant.
Labor and Delivery
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.
Nursing Mothers
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.
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.
Geriatic Use
DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with VILTEPSO.
Gender
There is no FDA guidance on the use of Viltolarsen with respect to specific gender populations.
Race
There is no FDA guidance on the use of Viltolarsen with respect to specific racial populations.
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.
Hepatic Impairment
There is no FDA guidance on the use of Viltolarsen in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Viltolarsen in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Viltolarsen in patients who are immunocompromised.
Administration and Monitoring
Administration
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.
Monitoring
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
IV Compatibility
There is limited information regarding the compatibility of Viltolarsen and IV administrations.
Overdosage
There is limited information regarding Viltolarsen overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Viltolarsen Pharmacology in the drug label.
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.
Structure
There is limited information regarding Viltolarsen Structure in the drug label.
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. Expected localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with viltolarsen was confirmed by immunofluorescence staining.
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).
Distribution
The mean viltolarsen steady-state volume of distribution was 300 mL/kg (%CV=14 at a dose of 80 mg/kg. Viltolarsen plasma protein binding ranged from 39% to 40% and is not concentration dependent.
Elimination
Metabolism
Data from in vitro metabolism indicate that viltolarsen is metabolically stable. No metabolites were detected in plasma or urine.
Excretion
VILTEPSO is excreted mainly as an unchanged drug in the urine. Viltolarsen elimination half-life was 2.5 (%CV=8) hours, and plasma clearance was 217 mL/hr/kg (%CV=22).
Specific Populations
Age, Sex & Race
The pharmacokinetics of viltolarsen have been evaluated only in male pediatric DMD patients.There is no experience with VILTEPSO in patients 65 years of age or older. No marked differences in any PK parameters were observed between White and Asian patients.
Patients with Renal or Hepatic Impairment
VILTEPSO has not been studied in patients with renal or hepatic impairment. Viltolarsen was found to be metabolically stable, and hepatic metabolism does not contribute to the elimination of viltolarsen. In addition, viltolarsen was mainly excreted unchanged in the urine. Viltolarsen is eliminated renally, and renal impairment is expected to result in increasing exposure of viltolarsen. 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 glomerular filtration rate estimated by serum creatinine.
In Vitro Drug Interaction Studies
Viltolarsen did not inhibit CYP3A4/5, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, or UGT2B7. Viltolarsen did not induce CYP1A2, CYP2B6, or CYP3A4.
Viltolarsen is not metabolized by CYP enzymes and is not a substrate of transporters BCRP, BSEP, MDR1, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K. Viltolarsen did not inhibit the transporters tested (OATP1B1, OATP1B3, OAT3, BCRP, MDR1, BSEP, OAT1, OCT1, OCT2, MATE1, and MATE2-K).
Based on in vitro data, viltolarsen has a low potential for drug-drug interactions with major CYP enzymes and drug transporters in humans.
Nonclinical Toxicology
Carcinogenesis
Carcinogenicity studies of viltolarsen have not been conducted.
Mutagenesis
Viltolarsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.
Impairment of Fertility
Intravenous administration of viltolarsen (0, 60, 240, or 1000 mg/kg) to male mice weekly prior to and during mating to untreated females did not have adverse effects on fertility. Plasma exposure (AUC) at the highest dose was approximately 18 times that in humans at the recommended human dose of 80 mg/kg/week.
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%.
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
Storage
Store VILTEPSO at 2°C to 8°C (36°F to 46°F). Do not freeze.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
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
Precautions with Alcohol
Alcohol-Viltolarsen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
VILTEPSO
Look-Alike Drug Names
There is limited information regarding Viltolarsen Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.