Golodirsen

1 INDICATIONS AND USAGE 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. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VYONDYS 53 [see Clinical Studies ( 14 )] . 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 (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 VYONDYS 53. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. ( 1 )

2 DOSAGE AND ADMINISTRATION Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VYONDYS 53 ( 2.1 ) 30 milligrams per kilogram once weekly ( 2.2 ) Administer as an intravenous infusion over 35 to 60 minutes via an in-line 0.2 micron filter ( 2.2 , 2.4 ) Dilution required prior to administration ( 2.3 ) 2.1 Monitoring to Assess Safety Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VYONDYS 53. Consider measurement of glomerular filtration rate prior to initiation of VYONDYS 53. Monitoring for kidney toxicity during treatment is recommended. Obtain the urine samples prior to infusion of VYONDYS 53 or at least 48 hours after the most recent infusion [see Warnings and Precautions ( 5.2 )] . 2.2 Dosing Information The recommended dosage of VYONDYS 53 is 30 milligrams per kilogram administered once weekly as a 35 to 60-minute intravenous infusion via an in-line 0.2 micron filter. If a dose of VYONDYS 53 is missed, it may be administered as soon as possible after the scheduled dose. 2.3 Preparation Instructions VYONDYS 53 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique. Calculate the total dose of VYONDYS 53 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of VYONDYS 53 needed and the correct number of vials to supply the full calculated dose. Allow the vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake. Visually inspect each vial of VYONDYS 53. The solution is a clear to slightly opalescent, colorless liquid, and may contain trace amounts of small, white to off-white amorphous particles. Do not use if the solution in the vials is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles. With a syringe fitted with a 21-gauge or smaller bore non-coring needle, withdraw the calculated volume of VYONDYS 53 from the appropriate number of vials. Dilute the withdrawn VYONDYS 53 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100 to150 mL. Gently invert 2 to 3 times to mix. Do not shake. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles. Administer the diluted solution via an in-line 0.2 micron filter. VYONDYS 53 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted VYONDYS 53 within 4 hours of dilution. If immediate use is not possible, the diluted product may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard unused VYONDYS 53. 2.4 Administration Instructions Application of a topical anesthetic cream to the infusion site prior to administration of VYONDYS 53 may be considered. VYONDYS 53 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion. Infuse the diluted VYONDYS 53 over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medications with VYONDYS 53 or infuse other medications concomitantly via the same intravenous access line with VYONDYS 53. If a hypersensitivity reaction occurs, consider slowing the infusion, interrupting, or discontinuing the VYONDYS 53 therapy [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ,) and Adverse Reactions ( 6.1 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] The most common adverse reactions (incidence ≥20% and higher than placebo) were headache, pyrexia, fall, abdominal pain, nasopharyngitis, cough, vomiting, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sarepta Therapeutics, Inc. at 1-888-SAREPTA (1-888-727-3782) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 ( 14 )] . 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 Greater than Placebo in Studies 1 and 2 Adverse Reaction VYONDYS 53 (N = 41) % Placebo (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 ( 5.1 )]. 6.2 Postmarketing 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 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]

12.3 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 once-weekly dosing. Inter-subject variability (as %CV) for C max 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 (t 1/2 ) 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 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 m 2 ) or Stage 3 CKD (n=8, eGFR ≥30 and <60 mL/min/1.73 m 2 ) and matched healthy subjects (n=8, eGFR ≥90 mL/min/1.73 m 2 ). 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 C max in subjects with Stage 2 CKD; in subjects with Stage 3 CKD, there was a 1.2-fold increase in C max 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 ( 8.6 )]. 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.