2.1 Patient Selection

Select patients for treatment with ELEVIDYS with anti-AAVrh74 total binding antibody titers <1:400. An FDA-authorized test for the detection of AAVrh74 total binding antibodies is not currently available. Currently available tests may vary in accuracy and design.

2.2 Dose

The recommended dose of ELEVIDYS is 1.33 × 1014 vector genomes per kilogram (vg/kg) of body weight (or 10 mL/kg body weight). For the number of vials required, refer to Table 7 [see How Supplied/Storage and Handling (16.1)].

Calculate the dose as follows:

ELEVIDYS dose (in mL) = patient body weight (in kilogram) x 10

The multiplication factor 10 represents the per kilogram dose (1.33 × 1014 vg/kg) divided by the amount of vector genome copies per mL of the ELEVIDYS suspension (1.33 × 1013 vg/mL).

Number of ELEVIDYS vials needed = ELEVIDYS dose (in mL) divided by 10 (round to the nearest number of vials).

Example: Calculation of volume needed for a 19.6 kg patient

19.6 kg × 10 = 196 mL

Number of ELEVIDYS vials needed = 196 divided by 10, rounded to the nearest number of vials = 20 vials

Prior to ELEVIDYS infusion:

• Due to the increased risk of serious systemic immune response, postpone ELEVIDYS in patients with infections until the infection has resolved. Clinical signs or symptoms of infection should not be evident at the time of ELEVIDYS administration [see Patient Counseling Information (17)].
• Assess liver function [see Dosage and Administration (2.4), Warnings and Precautions (5.1), Use in Specific Populations (8.6)].
• Obtain platelet count and troponin-I levels [see Dosage and Administration (2.4), Warnings and Precautions (5.3)].
• Measure baseline anti-AAVrh74 antibody titers using a Total Binding Antibody enzyme-linked immunosorbent assay (ELISA) [see Dosage and Administration (2), Clinical Pharmacology (12.6)].

ELEVIDYS administration is not recommended in patients with elevated anti-AAVrh74 total binding antibody titers (≥1:400). Re-administration of ELEVIDYS is not recommended [see Warnings and Precautions (5.4), Clinical Pharmacology (12.6)].

Immune responses to the AAVrh74 vector can occur after administration of ELEVIDYS [see Clinical Pharmacology (12.6)]. To reduce the risk associated with an immune response, corticosteroids should be administered starting 1 day prior to ELEVIDYS infusion. Initiate a corticosteroid regimen following the appropriate schedule (see Table 1). This regimen is recommended for a minimum of 60 days after the infusion, unless earlier tapering is clinically indicated. Table 2 includes the recommended corticosteroid regimen dose modification for patients with liver function abnormalities following ELEVIDYS infusion. If acute serious liver injury is suspected, a consultation with a specialist is recommended.

For patients previously taking corticosteroids at baseline, taper off the additional peri-ELEVIDYS corticosteroids (back to baseline corticosteroid dose) over 2 weeks, or longer as needed. For patients not previously taking corticosteroids at baseline, taper the added peri-ELEVIDYS corticosteroids off (back to no corticosteroids) over 4 weeks, or longer, as needed, and the corticosteroids should not be stopped abruptly.

2.3 Preparation

General precautions

• Prepare ELEVIDYS using aseptic technique.
• Verify the required dose of ELEVIDYS based on the patient's body weight.
• Confirm that the kit contains sufficient number of vials to prepare the ELEVIDYS infusion for the patient.
• Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever suspension and container permit. ELEVIDYS may contain white to off-white particles.

Recommended supplies and materials:

• 60 mL siliconized polypropylene syringes
• 21-gauge or smaller stainless steel needles

Preparing ELEVIDYS infusion

1. Thaw ELEVIDYS before use.
   • When thawed in the refrigerator, ELEVIDYS vials are stable for up to 14 days in the refrigerator (2°C to 8°C [36º F to 46º F]) when stored in the upright position.
   • Frozen ELEVIDYS vials will thaw in approximately 2 hours when placed at room temperature (up to 25°C [77ºF]) when removed from original packaging.
2. Inspect vials to ensure no ice crystals are present prior to preparation.
3. When thawed, swirl gently.
   • Do not shake.
   • Do not refreeze.
   • Do not place back in the refrigerator.
4. Visually inspect each vial of ELEVIDYS. ELEVIDYS is a clear, colorless liquid that may have some opalescence. ELEVIDYS may contain white to off-white particles.
   • Do not use if the suspension in the vials is cloudy or discolored.
5. Remove the plastic flip-off cap from the vials and disinfect the rubber stopper with a sterilizing agent (e.g., alcohol wipes).
6. Withdraw 10 mL of ELEVIDYS from each vial provided in the customized ELEVIDYS kit (refer to Table 7).
   • Do not use filter needles during preparation of ELEVIDYS.
   • Multiple syringes will be required to withdraw the required volume.
   • Remove air from the syringes and cap the syringes.
7. Maintain syringes at room temperature prior to and during administration.
   • Sealed ELEVIDYS thawed vials are stable up to 24 hours at room temperature (up to 25°C [77ºF]) when stored in upright position.

2.4 Administration

Recommended supplies and materials:

• Syringe infusion pump
• 0.2-micron PES* in-line filter
• PVC* (non-DEHP*), polyurethane IV infusion tubing and catheter

*PVC = Polyvinyl chloride, DEHP = Di(2-ethylhexyl) phthalate, PES = Polyether sulfone

Administer ELEVIDYS as a single-dose intravenous infusion through a peripheral venous catheter:

Consider application of a topical anesthetic to the infusion site prior to administration of IV insertion.

Recommend inserting a back-up catheter.

1. Flush the intravenous access line prior to the ELEVIDYS infusion at the same infusion rate.
2. Administer ELEVIDYS via intravenous infusion using a syringe infusion pump with an in-line 0.2-micron filter at a duration of approximately 1 to 2 hours, or longer at care team discretion, through a peripheral limb vein.
3. Infuse at a rate of less than 10 mL/kg/hour.
   • Do not administer ELEVIDYS as an intravenous push.
   • Do not infuse ELEVIDYS in the same intravenous access line with any other product.
   • Use ELEVIDYS within 4 hours after drawing into syringe. Discard the ELEVIDYS-containing syringe(s) if infusion of the drug has not started within the 4-hour timeframe.
4. Flush the intravenous access line with 0.9% Sodium Chloride Injection after the ELEVIDYS infusion.
   • Discard unused ELEVIDYS [see How Supplied/Storage and Handling (16.2)].
   • Dispose of the needle and syringe [see How Supplied/Storage and Handling (16.2)].

Monitoring Post-ELEVIDYS Administration

• Assess liver function (clinical exam, GGT, and total bilirubin) weekly for the first 3 months. Continue monitoring if clinically indicated, until results are unremarkable (normal clinical exam, GGT and total bilirubin levels return to near baseline levels) [see Warning and Precautions (5.1), Specific Populations (8.6)].
• Obtain platelet counts weekly for the first two weeks [see Adverse Reactions (6.1)]. Continue monitoring if clinically indicated.
• Measure troponin-I weekly for the first month [see Warning and Precautions (5.3)]. Continue monitoring if clinically indicated.

5.1 Acute Serious Liver Injury

Acute serious liver injury has been observed with ELEVIDYS. Administration of ELEVIDYS may result in elevations of liver enzymes (e.g., GGT, ALT) and total bilirubin, typically seen within 8 weeks.

Patients with preexisting liver impairment, chronic hepatic condition or acute liver disease (e.g., acute hepatic viral infection) may be at higher risk of acute serious liver injury. Postpone ELEVIDYS administration in patients with acute liver disease until resolved or controlled. Patients with hepatic impairment, acute liver disease, chronic hepatic condition or elevated GGT have not been studied in clinical trials with ELEVIDYS [see Specific Populations (8.6)].

In clinical studies, liver function test increased (including increases in GGT, GLDH, ALT, AST, or total bilirubin) was commonly reported typically within 8 weeks following ELEVIDYS infusion, with the majority of cases being asymptomatic [see Adverse Reactions (6.1)]. Cases resolved spontaneously or with systemic corticosteroids and resolved without clinical sequelae within 2 months. No cases of liver failure were reported.

Prior to ELEVIDYS administration, perform liver enzyme test [see Dosage and Administration (2.2)]. Monitor liver function (clinical exam, GGT, and total bilirubin) weekly for the first 3 months following ELEVIDYS infusion. Continue monitoring if clinically indicated, until results are unremarkable (normal clinical exam, GGT and total bilirubin levels return to near baseline levels) [see Dosage and Administration (2.4)].

Systemic corticosteroid treatment is recommended for patients before and after ELEVIDYS infusion [see Dosage and Administration (2.2)]. Adjust corticosteroid regimen when indicated [see Dosage and Administration (2.2)]. If acute serious liver injury is suspected, a consultation with a specialist is recommended.

5.2 Immune-mediated Myositis

In clinical trials, immune-mediated myositis has been observed approximately 1 month following ELEVIDYS infusion in patients with deletion mutations involving exon 8 and/or exon 9 in the DMD gene. Symptoms of severe muscle weakness, including dysphagia, dyspnea and hypophonia, were observed. In a life-threatening case of immune-mediated myositis, symptoms resolved during hospitalization following additional immunomodulatory treatment; muscle strength gradually improved but did not return to baseline level. These immune reactions may be due to a T-cell based response from lack of self-tolerance to a specific region encoded by the transgene corresponding to exons 1-17 of the DMD gene.

Limited data are available for ELEVIDYS treatment in patients with mutations in the DMD gene in exons 1 to 17 and/or exons 59 to 71 [see Clinical Studies (14)]. Patients with deletions in these regions may be at risk for a severe immune-mediated myositis reaction. ELEVIDYS is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene due to the increased risk for a severe immune-mediated myositis reaction [see Contraindications (4)].

Advise patients to contact a physician immediately if they experience any unexplained increased muscle pain, tenderness, or weakness, including dysphagia, dyspnea or hypophonia as these may be symptoms of myositis. Consider additional immunomodulatory treatment (immunosuppressants [e.g., calcineurin-inhibitor] in addition to corticosteroids) based on patient's clinical presentation and medical history if these symptoms occur.

5.3 Myocarditis

Acute serious myocarditis and troponin-I elevations have been observed following ELEVIDYS infusion in clinical trials.

Monitor troponin-I before ELEVIDYS infusion and weekly for the first month following infusion [see Dosage and Administration (2.4)]. Continue monitoring if clinically indicated. More frequent monitoring may be warranted in the presence of cardiac symptoms, such as chest pain or shortness of breath.

Advise patients to contact a physician immediately if they experience cardiac symptoms.

5.4 Pre-existing Immunity against AAVrh74

In AAV-vector based gene therapies, preexisting anti-AAV antibodies may impede transgene expression at desired therapeutic levels. Following treatment with ELEVIDYS all subjects developed anti-AAVrh74 antibodies. Perform baseline testing for the presence of anti-AAVrh74 total binding antibodies prior to ELEVIDYS administration [see Dosage and Administration (2.1)].

ELEVIDYS administration is not recommended in patients with elevated anti-AAVrh74 total binding antibody titers (≥1:400).

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.

The safety data described in this section reflect exposure to a one-time intravenous infusion of ELEVIDYS in 85 male subjects with a confirmed mutation of the DMD gene in three on-going clinical studies, including two open-label studies and one study that included a double-blind, placebo-controlled period. Prior to ELEVIDYS infusion, patients in the ELEVIDYS treatment group had a mean age of 7.08 years (range: 3 to 20) and mean weight of 25.91 kg (range: 12.5 to 80.1). 73 subjects received the recommended dose of 1.33 × 1014 vg/kg, and 12 received a lower dose. Table 3 below presents adverse reactions from these three clinical studies.

The most common adverse reactions (incidence ≥5%) across all studies are summarized in Table 3.

Adverse reactions were typically seen within the first 2 weeks (nausea, vomiting, thrombocytopenia, pyrexia), or within the first 2 months (immune-mediated myositis, liver function test increased). Vomiting may occur as early as on the day of the infusion.

In the double-blind, placebo-controlled trial (Study 1 Part 1), subjects 4 to 7 years of age (N=41) received either ELEVIDYS (N=20) at the recommended dose of 1.33 × 1014 vg/kg (n=8) or lower dose (n=12) or received placebo (N=21). Table 4 below presents the most frequent adverse reactions from Study 1 Part 1.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

ELEVIDYS is indicated for the treatment of ambulatory pediatric patients 4 through 5 years of age with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene. This indication is based on expression of ELEVIDYS micro-dystrophin protein in skeletal muscle observed in DMD patients treated with ELEVIDYS. The effectiveness and safety of ELEVIDYS has not been established in pediatric patients younger than 3 years of age. The effectiveness of ELEVIDYS has not been established in pediatric patients 3 years of age and in pediatric patients 6 years of age and older [see Clinical Pharmacology (12.2), Clinical Studies (14)].

8.5 Geriatric Use

The safety and efficacy of ELEVIDYS in geriatric patients with DMD have not been studied.

8.6 Hepatic Impairment

The safety and efficacy of ELEVIDYS in patients with hepatic impairment or elevated GGT have not been studied.

Postpone ELEVIDYS administration in patients with acute liver disease until resolved or controlled. ELEVIDYS therapy should be carefully considered in patients with preexisting liver impairment or chronic hepatic viral infection. These patients may be at increased risk of acute serious liver injury [see Warnings and Precautions (5.1)].

In clinical trials, liver function test increase was commonly reported in subjects following ELEVIDYS infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

12.1 Mechanism of Action

ELEVIDYS is the recombinant gene therapy product that is comprised of a non-replicating, recombinant, adeno-associated virus (AAV) serotype rh74 (AAVrh74) capsid and a ssDNA expression cassette flanked by inverted terminal repeats (ITRs) derived from AAV2. The cassette contains: 1) an MHCK7 gene regulatory component comprising a creatine kinase 7 promoter and an α-myosin heavy chain enhancer, and 2) the DNA transgene encoding the engineered ELEVIDYS micro-dystrophin protein.

Vector/Capsid: Clinical and nonclinical studies have demonstrated AAVrh74 serotype transduction in skeletal muscle cells. Additionally, in nonclinical studies, AAVrh74 serotype transduction has been demonstrated in cardiac and diaphragm muscle cells.

Promoter: The MHCK7 promoter/enhancer drives transgene expression and has been shown in animal models to drive transgenic ELEVIDYS micro-dystrophin protein expression predominantly in skeletal muscle (including diaphragm) and cardiac muscle. In clinical studies, muscle biopsy analyses have confirmed ELEVIDYS micro-dystrophin expression in skeletal muscle.

Transgene: DMD is caused by a mutation in the DMD gene resulting in lack of functional dystrophin protein. ELEVIDYS carries a transgene encoding a micro-dystrophin protein consisting of selected domains of dystrophin expressed in normal muscle cells.

ELEVIDYS micro-dystrophin has been demonstrated to localize to the sarcolemma.

12.2 Pharmacodynamics

In 61 subjects who received ELEVIDYS in clinical studies, ELEVIDYS micro-dystrophin protein expression from muscle biopsies (gastrocnemius) was quantified by western blot and localized by immunofluorescence staining (fiber intensity and percentage ELEVIDYS micro-dystrophin).

ELEVIDYS micro-dystrophin expression (expressed as change from baseline) as measured by western blot was the primary objective of Study 1 and Study 2. Muscle biopsies were obtained at baseline prior to ELEVIDYS infusion and at Week 12 after ELEVIDYS infusion in all subjects. The absolute quantity of ELEVIDYS micro-dystrophin was measured by western blot assay, adjusted by muscle content and expressed as a percent of control (levels of wild-type dystrophin in subjects without DMD or Becker muscular dystrophy) in muscle biopsy samples. Results of subjects receiving 1.33 × 1014 vg/kg ELEVIDYS are presented in Table 5.

For subjects aged 4 through 5 years who received 1.33 × 1014 vg/kg of ELEVIDYS, the mean (SD) ELEVIDYS micro-dystrophin expression levels (change from baseline) at Week 12 following ELEVIDYS infusion were 95.7% (N=3, SD: 17.9%) in Study 1 Parts 1 and 2 and 51.7% (N=11, SD: 41.0%) in Study 2 Cohort 1.

Assessment of ELEVIDYS micro-dystrophin levels can be meaningfully influenced by differences in sample processing, analytical technique, reference materials, and quantitation methodologies. Therefore, valid comparisons of ELEVIDYS micro-dystrophin measurements obtained from different assays cannot be made.

12.3 Pharmacokinetics

12.6 Immunogenicity

The observed incidence of anti-AAVrh74 antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-AAVrh74 antibodies in the studies described below with the incidence of anti-AAVrh74 antibodies in other studies.

In ELEVIDYS clinical studies, patients were required to have baseline anti-AAVrh74 total binding antibodies of ≤1:400, measured using an investigational total binding antibody enzyme-linked immunosorbent assay (ELISA), and only patients with baseline anti-AAVrh74 total binding antibodies <1:400 were enrolled in those studies. The safety and efficacy of ELEVIDYS in patients with elevated anti-AAVrh74 total binding antibody titer (≥1:400) have not been evaluated [see Clinical Studies (14)].

Across clinical studies evaluating a total of 84 patients, elevated anti-AAVrh74 total binding antibodies titers were observed in all patients following a one-time ELEVIDYS infusion. Anti-AAVrh74 total binding antibody titers reached at least 1:409,600 in every subject, and the maximum titers exceeded 1:26,214,400 in certain subjects. The safety of re-administration of ELEVIDYS or any other AAVrh74 vector-based gene therapy in the presence of high anti-AAVrh74 total binding antibody titer has not been evaluated in humans [see Warnings and Precautions (5.4)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to evaluate the effects of ELEVIDYS on carcinogenicity, mutagenesis, or impairment of fertility.

16.1 How Supplied

ELEVIDYS is shipped frozen (≤ -60ºC [-76ºF]) in 10 mL vials.

ELEVIDYS is supplied as a customized kit to meet dosing requirements for each patient [see Dosage and Administration (2.1)]. Each kit contains:

• Ten (10) to seventy (70) single-dose vials of ELEVIDYS
• One alcohol wipe per vial

Each ELEVIDYS pack may contain a maximum of two different drug product lots.

The total number of vials in each kit corresponds to the dosing requirement for the individual patient, based on the patient's body weight, and is specified on the package [see Dosage and Administration (2.2)]. Each kit includes a specified number of ELEVIDYS vials (with a minimum of 10 vials for a patient with 10.0 – 10.4 kg body weight range, and a maximum of 70 vials for a patient with body weight of 69.5 kg and above).

Kit sizes and National Drug Codes (NDC) are provided in Table 7.

An ELEVIDYS 10 mL single-dose vial (NDC 60923-500-01) is not sold individually.

16.2 Storage and Handling

• ELEVIDYS is shipped and delivered at ≤ −60ºC [−76ºF].
• ELEVIDYS can be refrigerated for up to 14 days when stored at 2°C to 8°C (36º F to 46º F) in the upright position.
• Do not refreeze.
• Do not shake.
• Do not place back in the refrigerator once brought to room temperature.
• Follow local guidelines on handling of biological waste.

Inform caregivers that:

• ELEVIDYS can increase certain liver enzyme levels and cause acute serious liver injury. Patients will receive oral corticosteroid medication before and after infusion with ELEVIDYS. Weekly blood tests will be required to monitor liver enzyme levels for 3 months after treatment. Contact a healthcare provider immediately if the patient's skin and/or whites of the eyes appear yellowish, or if the patient misses a dose of corticosteroid or vomits it up [see Warnings and Precautions (5.1)].
• Immune-mediated myositis (an immune response affecting muscles) was observed in patients with a deletion mutation in the DMD gene that is contraindicated. Contact a physician immediately if the patient experiences any unexplained increased muscle pain, tenderness, or weakness, including difficulty swallowing, difficulty breathing or difficulty speaking, as these may be symptoms of myositis [see Warnings and Precautions (5.2)].
• Myocarditis (inflammation of the heart) has been observed within days following ELEVIDYS infusion. Weekly monitoring of troponin-I for the first month after treatment is required. Contact a healthcare provider immediately if the patient begins to experience chest pain and/or shortness of breath [see Warnings and Precautions (5.3)].
• Patient's immunizations should be up-to-date with current immunization guidelines prior to initiation of the corticosteroid regimen required before ELEVIDYS infusion. Vaccinations should be completed at least 4 weeks prior to initiation of the corticosteroid regimen [see Drug Interactions (7)].
• Due to the concomitant administration of corticosteroids, an infection (e.g., cold, flu, gastroenteritis, otitis media, bronchiolitis, etc.) before or after ELEVIDYS infusion could lead to more serious complications. Contact a healthcare provider immediately if symptoms suggestive of infection are observed (e.g., coughing, wheezing, sneezing, runny nose, sore throat, or fever).
• Vector shedding of ELEVIDYS occurs primarily through body waste. Practice proper hand hygiene, such as hand washing, when coming into direct contact with patient body waste. Place potentially contaminated materials that may have the patient's bodily fluids/waste in a sealable bag and dispose into regular trash. These precautions should be followed for one month after ELEVIDYS infusion.

Manufactured for: Sarepta Therapeutics, Inc.
Cambridge, MA 02142 USA
U.S. license number 2308