Eteplirsen

1 INDICATIONS AND USAGE EXONDYS 51 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. EXONDYS 51 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 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 [see Clinical Studies ( 14 )]. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. ( 1 )

2 DOSAGE AND ADMINISTRATION 30 milligrams per kilogram of body weight once weekly ( 2.1 ) Administer as an intravenous infusion over 35 to 60 minutes via an in-line 0.2 micron filter ( 2.1 , 2.3 ) Dilution required prior to administration ( 2.2 ) 2.1 Dosing Information The recommended dose of EXONDYS 51 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 EXONDYS 51 is missed, it may be administered as soon as possible after the scheduled time. 2.2 Preparation Instructions EXONDYS 51 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 EXONDYS 51 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of EXONDYS 51 needed and the correct number of vials to supply the full calculated dose. Allow 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 EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence, and may contain 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 white to off-white amorphous particles. With a syringe fitted with a 21-gauge or smaller non-coring needle, withdraw the calculated volume of EXONDYS 51 from the appropriate number of vials. Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100-150 mL. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than white to off-white amorphous particles. Administer the diluted solution via an in-line 0.2 micron filter. EXONDYS 51 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted EXONDYS 51 solution within 8 hours of dilution. If immediate use is not possible, the diluted solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused EXONDYS 51. 2.3 Administration Instructions Application of a topical anesthetic cream to the infusion site prior to administration of EXONDYS 51 may be considered. EXONDYS 51 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 EXONDYS 51 solution over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medications with EXONDYS 51 or infuse other medications concomitantly via the same intravenous access line. If a hypersensitivity reaction occurs, consider slowing the infusion or interrupting the EXONDYS 51 therapy [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )].

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥35% and higher than placebo) were balance disorder and vomiting ( 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 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. EXONDYS 51 was studied in a double-blind, placebo-controlled study for 24 weeks (Study 1), followed by an open label extension (Study 2). In Study 1, 12 patients were randomized to receive weekly intravenous infusions of EXONDYS 51 (n=8) or placebo (n=4) for 24 weeks. All 12 patients continued in Study 2 and received open-label EXONDYS 51 weekly for up to 208 weeks. In Study 1, 4 patients received placebo, 4 patients received EXONDYS 51 30 mg/kg, and 4 patients received EXONDYS 51 50 mg/kg (1.7 times the recommended dosage). In Study 2, 6 patients received EXONDYS 51 30 mg/kg/week and 6 patients received EXONDYS 51 50 mg/kg/week [see Clinical Studies ( 14 )] . Adverse reactions that occurred in 2 or more patients who received EXONDYS 51 and were more frequent than in the placebo group in Study 1 are presented in Table 1 (the 30 and 50 mg/kg groups are pooled). 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 [see Dosage and Administration ( 2.1 )]. The most common adverse reactions were balance disorder and vomiting. Table 1. Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week 1 EXONDYS 51 with Incidence at Least 25% More than Placebo (Study 1) 1 50 mg/kg/week = 1.7 times the recommended dosage Adverse Reactions EXONDYS 51 (N=8) Placebo (N=4) % % Balance disorder 38 0 Vomiting 38 0 Contact dermatitis 25 0 Adverse Reactions from Observational Clinical Studies The following adverse reactions have been identified during observational studies that were conducted as part of the clinical development program and continued postapproval. In open-label observational studies, 163 patients received at least one intravenous dose of EXONDYS 51, with doses ranging between 0.5 mg/kg (0.017 times the recommended dosage) and 50 mg/kg (1.7 times the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 months to 19 years. Most (85%) patients were Caucasian. The most common adverse reactions seen in greater than 10% of the study population were headache, cough, rash, and vomiting. Hypersensitivity reactions have occurred in patients treated with EXONDYS 51 [see Warnings and Precautions ( 5.1 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of EXONDYS 51. 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. Postmarketing adverse reactions that occurred during infusion include bronchospasm, cyanosis of the lips, and malaise. The following adverse reactions have also been reported in patients receiving EXONDYS 51: pyrexia, flushing, protein urine present, and dehydration.

12.3 Pharmacokinetics Following single or multiple intravenous infusions of EXONDYS 51 in male pediatric DMD patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline. The majority of drug elimination occurred within 24 hours. Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for eteplirsen C max and AUC range from 20 to 55%. Following single or multiple intravenous infusions of EXONDYS 51, the peak plasma concentrations (C max ) of eteplirsen occurred near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week). Distribution In vitro investigation suggested that plasma protein binding of eteplirsen in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss) of eteplirsen was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg. Twenty-four hours after the end of the infusion, mean concentrations of eteplirsen were 0.07% of C max . Accumulation of eteplirsen during once weekly dosing has not been observed. Elimination The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. Metabolism Eteplirsen did not appear to be metabolized by hepatic microsomes of any species tested, including humans. Excretion Renal clearance of eteplirsen accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration. Elimination half-life (t 1/2 ) of eteplirsen was 3 to 4 hours. Specific Populations Age: The pharmacokinetics of eteplirsen have been evaluated in male pediatric DMD patients. There is no experience with the use of EXONDYS 51 in patients 65 years of age or older. Sex: Sex effects have not been evaluated; EXONDYS 51 has not been studied in female patients. Race: Potential impact of race is not known because 89% of the patients in studies were Caucasians. Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of eteplirsen was evaluated in non-DMD subjects aged 51 to 75 years with mild (n=8, creatinine clearance ≥60 mL/min and <90 mL/min) or moderate (n=8, creatinine clearance ≥30 mL/min and <60 mL/min) renal impairment and matched healthy subjects (n=9, creatinine clearance >90 mL/min). Subjects received a single 30 mg/kg intravenous dose of eteplirsen. Subjects with mild and moderate renal impairment showed higher eteplirsen exposure compared to subjects with normal renal function. In subjects with mild and moderate renal impairment, exposure (AUC) increased approximately 1.4-fold and 2.4-fold, respectively. The effect of severe renal impairment or end-stage renal disease on eteplirsen pharmacokinetics and safety has not been studied. Estimated creatinine clearance values derived from the Cockcroft-Gault equation and the threshold definitions for mild, moderate, and severe renal impairment in otherwise healthy adults would not be generalizable to patients with DMD. Therefore, no specific dosage adjustment can be recommended for patients with renal impairment. Patients with Hepatic Impairment: EXONDYS 51 has not been studied in patients with hepatic impairment. Drug Interaction Studies In vitro data showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP, MRP2 and BSEP). Based on in vitro data on plasma protein binding, CYP or drug transporter interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for drug-drug interactions in humans.