Brand Name
Vyondys 53
Generic Name
Golodirsen
View Brand Information FDA approval date: December 12, 2019
Classification: Antisense Oligonucleotide
Form: Injection
What is Vyondys 53 (Golodirsen)?
VYONDYS 53 is indicated for the treatment of Duchenne muscular dystrophy 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 VYONDYS 53. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. VYONDYS 53 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy 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 VYONDYS 53. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.
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Brand Information
Vyondys 53 (golodirsen)
1INDICATIONS AND USAGE
VYONDYS 53 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the
2DOSAGE FORMS AND STRENGTHS
VYONDYS 53 is a clear to slightly opalescent, colorless liquid, and may contain trace amounts of small, white to off-white amorphous particles, and available as:
- Injection: 100 mg/2 mL (50 mg/mL) solution in a single-dose vial
3CONTRAINDICATIONS
VYONDYS 53 is contraindicated in patients with a serious hypersensitivity reaction to golodirsen or to any of the inactive ingredients in VYONDYS 53. Anaphylaxis has occurred in patients receiving VYONDYS 53
4ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
- Hypersensitivity Reactions
4.1Clinical 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
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
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
4.2Postmarketing Experience
The following adverse reactions have been identified during postapproval use of VYONDYS 53. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: anaphylaxis
5DESCRIPTION
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, and may contain trace amounts of small, white to off-white amorphous particles. 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 C
The structure of golodirsen is:
6CLINICAL STUDIES
The effect of VYONDYS 53 on dystrophin production was evaluated in one study in DMD patients with a confirmed mutation of the
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 53-treated 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 Sarepta 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