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Vyondys 53

Last reviewed on RxList: 10/13/2020
Drug Description

What is Vyondys 53 and how is it used?

Vyondys 53 (golodirsen) 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.

What are side effects of Vyondys 53?

Side effects of Vyondys 53 include:


VYONDYS 53 (golodirsen) injection is a sterile, aqueous, preservative-free, concentrated solution for dilution prior to intravenous administration. VYONDYS 53 is a clear to slightly opalescent, colorless liquid. VYONDYS 53 is supplied in single-dose vials containing 100 mg golodirsen (50 mg/mL). VYONDYS 53 is formulated as an isotonic phosphate buffered saline solution with an osmolality of 260 to 320 mOSM and a pH of 7.5. Each milliliter of VYONDYS 53 contains: 50 mg golodirsen; 0.2 mg potassium chloride; 0.2 mg potassium phosphate monobasic; 8 mg sodium chloride; and 1.14 mg sodium phosphate dibasic, anhydrous, in water for injection. The product may contain hydrochloric acid or sodium hydroxide to adjust pH.

Golodirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Golodirsen contains 25 linked subunits. The sequence of bases from the 5' end to 3' end is GTTGCCTCCGGTTCTGAAGGTGTTC. The molecular formula of golodirsen is C305H481N138O112P25 and the molecular weight is 8647.28 daltons. The structure of golodirsen is:

VYONDYS 53 (golodirsen) Structural Formula - Illustration

Side Effects & Drug Interactions


  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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 the VYONDYS 53 clinical development program, 58 patients received at least one intravenous dose of VYONDYS 53, ranging between 4 mg/kg (0.13 times the recommended dosage) and 30 mg/kg (the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 to 13 years. Most (86%) patients were Caucasian.

VYONDYS 53 was studied in 2 double-blind, placebo-controlled studies.

In Study 1 Part 1, patients were randomized to receive once-weekly intravenous infusions of VYONDYS 53 (n=8) in four increasing dose levels from 4 mg/kg to 30 mg/kg or placebo (n=4), for at least 2 weeks at each level. All patients who participated in Study 1 Part 1 (n=12) were continued into Study 1 Part 2, an open-label extension, during which they received VYONDYS 53 at a dose of 30 mg/kg IV once weekly [see Clinical Studies].

In Study 2, patients received VYONDYS 53 (n=33) 30 mg/kg or placebo (n=17) IV once weekly for up to 96 weeks, after which all patients received VYONDYS 53 at a dose of 30 mg/kg.

Adverse reactions observed in at least 20% of treated patients in the placebo-controlled sections of Studies 1 and 2 are shown in Table 1.

Table 1: Adverse Reactions That Occurred in At Least 20% of VYONDYS 53-Treated Patients and at a Rate Greaterthan Placebo in Studies 1 and 2

Adverse Reaction VYONDYS 53
(N = 41) %
(N = 21) %
Headache 41 10
Pyrexia 41 14
Fall 29 19
Abdominal pain 27 10
Nasopharyngitis 27 14
Cough 27 19
Vomiting 27 19
Nausea 20 10

Other adverse reactions that occurred at a frequency greater than 5% of VYONDYS 53-treated patients and at a greater frequency than placebo were: administration site pain, back pain, pain, diarrhea, dizziness, ligament sprain, contusion, influenza, oropharyngeal pain, rhinitis, skin abrasion, ear infection, seasonal allergy, tachycardia, catheter site related reaction, constipation, and fracture.

Hypersensitivity reactions have occurred in patients treated with VYONDYS 53 [see WARNINGS AND PRECAUTIONS].


No Information provided

Warnings & Precautions


Included as part of the PRECAUTIONS section.


Hypersensitivity Reactions

Hypersensitivity reactions, including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation have occurred in VYONDYS 53-treated patients, some requiring treatment. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the VYONDYS 53 therapy [see DOSAGE AND ADMINISTRATION].

Renal Toxicity

Renal toxicity was observed in animals who received golodirsen [see Use In Specific Populations]. Although renal toxicity was not observed in the clinical studies with VYONDYS 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in patients taking VYONDYS 53. Because of the effect of reduced skeletal muscle mass on creatinine measurements, creatinine may not be a reliable measure of renal function in DMD patients. Measurement of glomerular filtration rate (GFR) by 24-hour urine collection prior to initiation of therapy is recommended. Monthly monitoring for proteinuria by dipstick urinalysis and monitoring of serum cystatin C every three months is recommended. In the case of a confirmed dipstick proteinuria of 2+ or greater or elevated serum cystatin C, a 24-hour urine collection to quantify proteinuria and assess GFR should be performed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility


Carcinogenicity studies have not been conducted with golodirsen.


Golodirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment Of Fertility

Fertility studies in animals were not conducted with golodirsen. No effects of golodirsen on the male reproductive system were observed following weekly subcutaneous administration (0, 120, 300, or 600 mg/kg to male mice or weekly intravenous administration (0, 80, 200, or 400 mg/kg) to male monkeys. Plasma exposure (AUC) at the highest doses tested in mouse and monkey are approximately 10 and 45 times that in humans at the recommended weekly intravenous dose of 30 mg/kg.

Use In Specific Populations


Risk Summary

There are no human or animal data available to assess the use of VYONDYS 53 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.


Risk Summary

There are no human or animal data to assess the effect of VYONDYS 53 on milk production, the presence of golodirsen in milk, or the effects of VYONDYS 53 on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VYONDYS 53 and any potential adverse effects on the breastfed infant from VYONDYS 53 or from the underlying maternal condition.

Pediatric Use

VYONDYS 53 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, including pediatric patients [see Clinical Studies].

Intravenous administration of golodirsen (0, 100, 300, or 900 mg/kg) to juvenile male rats once weekly for 10 weeks (postnatal days 14 to 77) did not result in postnatal developmental (e.g., neurobehavioral, immune function, or male reproductive) toxicity. However, at the highest dose tested (900 mg/kg/week), golodirsen resulted in the death of animals because of renal impairment or failure. In surviving animals (including one animal at the lowest dose tested), there was a dose-dependent increase in the incidence and severity of renal tubular effects (including degeneration/regeneration, fibrosis, vacuolation, and dilatation), which correlated with changes in clinical pathology parameters, reflecting a dose-dependent impairment of renal function. In addition, decreases in bone area, mineral content, and mineral density were observed at the highest dose tested (900 mg/kg week) but with no effect on bone growth. A no-effect dose for renal toxicity was not identified; the lowest dose tested (100 mg/kg/week) was associated with plasma exposures (AUC) approximately 2.5 times that in humans at the recommended human dose of 30 mg/kg/week.

Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with VYONDYS 53.

Patients With Renal Impairment

Renal clearance of golodirsen is reduced in non-DMD adults with renal impairment, based on estimated glomerular filtration rate calculated using the Modification of Diet and Renal Disease (MDRD) equation [see CLINICAL PHARMACOLOGY]. 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 VYONDYS 53.

Overdosage & Contraindications


No Information provided



Clinical Pharmacology


Mechanism Of Action

Golodirsen 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 [see Clinical Studies].


After treatment with VYONDYS 53, all patients evaluated (n=25) in Study 1 Part 2 [see Clinical Studies] had an increase in skipping of exon 53 demonstrated by reverse transcription polymerase chain reaction (RT-PCR), compared to baseline.

In Study 1 Part 2 [see Clinical Studies], dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal after 48 weeks of treatment with VYONDYS 53. The mean change from baseline in dystrophin after 48 weeks of treatment with VYONDYS 53 was 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%. This increase in dystrophin protein expression positively correlated with the level of exon skipping. Correct localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with golodirsen was demonstrated by immunofluorescence staining.


The pharmacokinetics of golodirsen was evaluated in DMD patients following administration of intravenous doses ranging from 4 mg/kg/week to 30 mg/kg/week (i.e., recommended dosage). Golodirsen exposure increased proportionally with dose, with minimal accumulation with once-weekly dosing. Inter-subject variability (as %CV) for Cmax and AUC ranged from 38% to 72%, and 34% to 44%, respectively.


Steady-state volume of distribution was similar between DMD patients and healthy subjects. The mean golodirsen steady-state volume of distribution was 668 mL/kg (%CV=32.3) at a dose of 30 mg/kg. Golodirsen plasma protein binding ranged from 33% to 39% and is not concentration dependent.


Golodirsen elimination half-life (SD) was 3.4 (0.6) hours, and plasma clearance was 346 mL/hr/kg at the 30 mg/kg dose.


Golodirsen is metabolically stable. No metabolites were detected in plasma or urine.


Golodirsen is mostly excreted unchanged in the urine. The elimination half-life (t½) was 3.4 hours.

Specific Populations


The pharmacokinetics of golodirsen have been evaluated in male pediatric DMD patients. There is no experience with the use of VYONDYS 53 in DMD patients 65 years of age or older.


Sex effects have not been evaluated; VYONDYS 53 has not been studied in female patients.


The potential impact of race is not known because 92% of the patients in studies were Caucasians.

Patients With Renal Impairment

The effect of renal impairment on the pharmacokinetics of golodirsen was evaluated in non-DMD subjects aged 41 to 65 years with Stage 2 chronic kidney disease (CKD) (n=8, estimated glomerular filtration rate (eGFR) ≥60 and <90 mL/min/1.73 m²) or Stage 3 CKD (n=8, eGFR ≥30 and <60 mL/min/1.73 m²) and matched healthy subjects (n=8, eGFR ≥90 mL/min/1.73 m²). Subjects received a single 30 mg/kg IV dose of golodirsen.

In subjects with Stage 2 or Stage 3 CKD, exposure (AUC) increased approximately 1.2-fold and 1.9-fold, respectively. There was no change in the Cmax in subjects with Stage 2 CKD; in subjects with Stage 3 CKD, there was a 1.2-fold increase in Cmax compared with subjects with normal renal function. The effect of Stage 4 or Stage 5 CKD on golodirsen pharmacokinetics and safety has not been studied.

Estimated GFR values derived from MDRD equations and the threshold definitions for various CKD stages in otherwise healthy adults would not be generalizable to pediatric patients with DMD. Therefore, no specific dosage adjustment can be recommended for patients with renal impairment [see Use In Specific Populations].

Patients With Hepatic Impairment:

VYONDYS 53 has not been studied in patients with hepatic impairment.

Drug Interaction Studies

Golodirsen did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 in vitro. Golodirsen was a weak inducer of CYP1A2 and did not induce CYP2B6 or CYP3A4. Golodirsen was not metabolized by human hepatic microsomes and was not a substrate or strong inhibitor of any of the key human drug transporters tested (OAT1, OAT3, OCT2, OATP1B1, MATE1, P-gp, BCRP, and MRP2, OATP1B3 and MATE2-K). Based on in vitro data, golodirsen has a low potential for drug-drug interactions in humans.

Animal Toxicology And/Or Pharmacology

Kidney toxicity was observed in studies in male mice and rats; findings in urinary bladder were observed in male mice.

In male mice, golodirsen was administered weekly for 12 weeks by intravenous injection (0, 12, 120, or 960 mg/kg) or for 26 weeks by subcutaneous injection (0, 120, 300, or 600 mg/kg). In the 12-week study, microscopic findings in kidney (tubular dilatation, basophilic or eosinophilic casts, vacuolation), correlated with increases in serum markers of renal function (e.g., urea nitrogen, creatinine), were observed primarily at the highest dose tested; hypertrophy of the transitional epithelium of the ureter or urinary bladder was observed at all doses. In the 26-week study, renal tubular degeneration and degeneration of the transitional epithelium of the urinary bladder were observed at all doses.

In male rats, intravenous administration of golodirsen (0, 60, 100, 300, or 600 mg/kg) weekly for 13 weeks resulted in tubular degeneration at all but the lowest dose tested; at the high dose, the microscopic changes were accompanied by increases in serum urea nitrogen.

In male monkeys, intravenous administration of golodirsen (0, 80, 200, or 400 mg/kg) weekly for 39 weeks resulted in microscopic changes in kidney (basophilia, dilatation, or mononuclear cell infiltration) at all doses, which correlated with increases in serum markers of renal function (urea nitrogen, creatinine) at the highest dose tested.

Clinical Studies

The effect of VYONDYS 53 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; NCT02310906).

Study 1 Part 1 was a double-blind, placebo-controlled, dose-titration study in 12 DMD patients. Patients were randomized 2:1 to receive VYONDYS 53 or matching placebo. VYONDYS 53treated patients received four escalating dose levels, ranging from 4 mg/kg/week (less than the recommended dosage) to 30 mg/kg/week by intravenous infusion for 2 weeks at each dose level.

Study 1 Part 2 was a 168-week, open-label study assessing the efficacy and safety of VYONDYS 53 at a dose of 30 mg/kg/week in the 12 patients enrolled in Part 1, plus 13 additional treatment-naive patients with DMD amenable to exon 53 skipping. At study entry (either in Part 1 or Part 2), patients had a median age of 8 years and were on a stable dose of corticosteroids for at least 6 months. Efficacy was assessed based on change from baseline in the dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 48 of Part 2. Muscle biopsies were obtained at baseline prior to treatment and at Week 48 of Part 2 in all VYONDYS 53-treated patients (n=25) and were analyzed for dystrophin protein level by Western blot. Mean dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal by Week 48 of Study 1 Part 2, with a mean change in dystrophin of 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%.

Individual patient dystrophin levels from Study 1 are shown in Table 2.

Table 2: Dystrophin Expression by Individual Patient From Study 1

Patient Number Western Blot % Normal Dystrophin Patient number Western Blot % Normal Dystrophin
Baseline Part 2 Week 48 Change from baseline Baseline Part 2 Week 48 Change from baseline
1 0.08 0.09 0.01 14 0.22 0.28 0.06
2 0.11 0.11 0.01 15 0.14 0.21 0.07
3 0.21 0.22 0.01 16 0.05 0.42 0.37
4 0.05 0.12 0.08 17 0.07 1.03 0.97
5 0.03 0.12 0.09 18 0.02 1.57 1.55
6 0.06 0.14 0.09 19 0.12 1.17 1.05
7 0.12 0.37 0.25 20 0.03 1.72 1.69
8 0.11 1.06 0.95 21 0.11 1.77 1.66
9 0.06 0.54 0.48 22 0.31 4.30 3.99
10 0.05 0.97 0.92 23 0.11 0.36 0.25
11 0.06 1.55 1.49 24 0.03 0.91 0.88
12 0.07 1.91 1.84 25 0.07 1.29 1.22
13 0.10 3.25 3.15        

Medication Guide


Hypersensitivity Reactions

Advise patients and/or caregivers that hypersensitivity reactions, including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation have occurred in patients who were treated with VYONDYS 53. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity [see WARNINGS AND PRECAUTIONS].

Renal Toxicity

Inform patients nephrotoxicity has occurred with drugs similar to VYONDYS 53. Advise patients of the importance of monitoring for renal toxicity by their healthcare providers during treatment with VYONDYS 53 [see WARNINGS AND PRECAUTIONS].

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