GENETIC MECHANISM OF DMD.
In Duchenne muscular dystrophy (DMD), mutations in the DMD gene result in structurally compromised dystrophin. The most common mutations are exon deletions.3
- During protein synthesis, these mutations are incorporated into the pre-messenger ribonucleic acid (pre-mRNA) transcript.4
- Pre-mRNA splicing proceeds without the required exons, resulting in an out-of-frame mature mRNA.4
- The out-of-frame mature mRNA results in failed translation of dystrophin.3
MECHANISM OF EXONDYS 51 IN DMD.
EXONDYS 51 is designed to bind to exon 51 pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping.1
Exon skipping is intended to allow for production of an internally truncated dystrophin protein.1
EXONDYS 51: EXON SKIPPING
CONFIRMED, AS MEASURED BY RT-PCR.1
The exon-skipping mechanism of action (MoA) of EXONDYS 51 has been confirmed in a variety of clinical studies using reverse transcriptase polymerase chain reaction (RT-PCR). Skipping occurred at the correct location as confirmed by DMD gene sequencing.1
|STUDY1,6||STUDY DESCRIPTION||# OF PATIENTS WITH CONFIRMED EXON SKIPPING IN SKELETAL MUSCLE BIOPSY* (IN-FRAME mRNA)|
|Study 1 and Study 2||
24-week, randomized, double-blind, placebo-controlled, crossover study of safety, efficacy and PK of EXONDYS 51 in patients with DMD amenable to exon 51 skipping; followed by a >4-year, open-label extension study
|Dose-ranging||12-week, open-label study of the safety, efficacy and PK of EXONDYS 51 in patients with DMD amenable to exon 51 skipping||17/17 (100%)|
|Proof-of-concept||Single-dose, placebo-controlled, dose-escalation study to assess the safety and ability of EXONDYS 51 to induce dystrophin production in patients with DMD amenable to exon 51 skipping||7/7 (100%)|
*MoA confirmed by RT-PCR. Skipping occurred at the correct location as confirmed by DMD gene sequencing.1
RT-PCR = reverse transcriptase polymerase chain reaction
MoA = mechanism of action
mRNA = messenger ribonucleic acid
PK = pharmacokinetics
DMD PATIENT WITH
DELETIONS OF EXONS 48-50
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EXONDYS 51 (eteplirsen) 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 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
Hypersensitivity reactions, including bronchospasm, chest pain, cough, tachycardia and urticaria, have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the EXONDYS 51 therapy.
Adverse reactions in DMD patients (N=8) treated with EXONDYS 51 30 or 50 mg/kg/week by intravenous (IV) infusion with an incidence of at least 25% more than placebo (N=4) (Study 1, 24 weeks) were (EXONDYS 51, placebo): balance disorder (38%, 0%), vomiting (38%, 0%) and contact dermatitis (25%, 0%). The most common adverse reactions were balance disorder and vomiting. Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of EXONDYS 51 is not recommended.
The most common adverse reactions from observational clinical studies (N=163) seen in greater than 10% of patients were headache, cough, rash, and vomiting.
Please see the full Prescribing Information for EXONDYS 51 (eteplirsen).
EXONDYS 51 [package insert]. Cambridge, MA: Sarepta Therapeutics Inc.
US Food and Drug Administration. FDA grants accelerate approval to first drug for Duchenne muscular dystrophy. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm521263.htm. Published September, 2016. Accessed February 15, 2022.
Aartsma-Rus A, et al. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle & Nerve. 2006;1:135-144.
Wood MJA, Gait MJ, Yin H. RNA-targeted splice-correction therapy for neuromuscular disease. Brain. 2010:133;957–972.
Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligoneucleotides. Nature Reviews Drug Discovery 2012;11:125-140.
Data on file.