WARNINGS-                                                                                                                        ­ • Hypersensitivity Reactions:                                                                            Hypersensitivity reactions, including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation have occurred in patients who were treated with the drug.. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the therapy. 

ADVERSE REACTIONS

The most common adverse reactions (incidence =20% and higher than placebo) were headache, pyrexia, fall, abdominal pain, nasopharyngitis, cough, vomiting, and nausea. 

CONTRAINDICATIONS                                                                                                      None 

WARNINGS AND PRECAUTIONS

­ • Hypersensitivity Reactions:                                                                            Hypersensitivity reactions, including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation have occurred in patients who were treated with VYONDYS 53. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the VYONDYS 53 therapy. 

• Renal Toxicity:                                                                                                        Based on animal data, may cause renal toxicity. Renal function should be monitored;   creatinine may not be a reliable measure of renal function in DMD patients.

 PATIENT COUNSELING INFORMATION

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 

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 

Manufactured for: Sarepta Therapeutics, Inc. Cambridge, MA 02142 USA

 CLINICAL PHARMACOLOGY

1. 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 (14)].

2. Pharmacodynamics

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

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.

3. Pharmacokinetics

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 onceweekly dosing. Inter-subject variability (as %CV) for Cmax and AUC ranged from 38% to 72%, and 34% to 44%, respectively.

Distribution

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.

Elimination

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. Metabolism Golodirsen is metabolically stable.

No metabolites were detected in plasma or urine. Excretion Golodirsen is mostly excreted unchanged in the urine. The elimination half-life (t1/2) was 3.4 hours.

Specific Populations

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

Race:                                                                                                                              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 nonDMD 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 Reference ID: 4532753 =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 

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.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy 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. 

2. Lactation 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.

 3.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 

4.Geriatric Use 

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

5. 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 Modifica

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.