Delandistrogene Moxeparvovec-Rokl

1 INDICATIONS AND USAGE ELEVIDYS is indicated for the treatment of patients 4 years of age and older with Duchenne muscular dystrophy (DMD), who are ambulatory and have a confirmed mutation in the DMD gene [see Clinical Pharmacology ( 12.2 ), Clinical Studies ( 14 )] . ELEVIDYS is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients 4 years of age and older with Duchenne muscular dystrophy (DMD) who are ambulatory and have a confirmed mutation in the DMD gene. ( 1 , 12.2 , 14 ) Limitations of Use: ELEVIDYS is not recommended in patients with: Preexisting liver impairment (defined as gamma-glutamyl transferase [GGT] > 2 x upper limit of normal or total bilirubin > the upper limit of normal not due to Gilbert's syndrome) or active hepatic viral infection due to the high risk of acute serious liver injury and acute liver failure. Recent vaccination (within 4 weeks of treatment) due to immunogenicity and potential safety concerns. Active or recent (within 4 weeks) infections due to safety concerns. Limitations of Use: ELEVIDYS is not recommended in patients with: Preexisting liver impairment (defined as gamma-glutamyl transferase [GGT] > 2 x upper limit of normal or total bilirubin > the upper limit of normal not due to Gilbert's syndrome) or active hepatic viral infection due to the high risk of acute serious liver injury and acute liver failure. Recent vaccination (within 4 weeks of treatment) due to immunogenicity and potential safety concerns. Active or recent (within 4 weeks) infections due to safety concerns.

2 DOSAGE AND ADMINISTRATION For single-dose intravenous infusion only. ELEVIDYS is for single-dose intravenous infusion only. Select patients for treatment with ELEVIDYS with anti-AAVrh74 total binding antibody titers <1:400. ( 2.1 ) Postpone in patients with active or recent (within 4 weeks) infections. ( 2.1 ) Assess liver function, platelet counts and troponin-I before ELEVIDYS infusion. ( 2.1 ) Recommended dosage: 10 to 70 kg: 1.33 × 10 14 vector genomes (vg) per kg of body weight; 70 kg or greater: 9.31 × 10 15 vg. ( 2.2 ) One day prior to infusion, initiate a corticosteroid regimen for a minimum of 60 days. Recommend modifying corticosteroid dose for patients with liver function abnormalities. ( 2.2 ) Administer as an intravenous infusion over 1-2 hours. Infuse at a rate of less than 10 mL/kg/hour. ( 2.4 ) 2.1 Critical Dosing Information Instruct patients to maintain proximity to an appropriate healthcare facility, as determined by the healthcare provider, for at least 2 months following ELEVIDYS infusion. Prior to ELEVIDYS infusion: Select patients for treatment with ELEVIDYS with anti-AAVrh74 total binding antibody titers <1:400. An FDA-authorized test for the detection of anti-AAVrh74 total binding antibodies is not currently available. Currently available tests may vary in accuracy and design. Avoid ELEVIDYS administration in patients with elevated anti-AAVrh74 total binding antibody titers (≥1:400) [Clinical Pharmacology ( 12.6 )] . Due to the increased risk of serious systemic immune response, postpone ELEVIDYS in patients with active or recent (within 4 weeks) infections [see Warnings and Precautions ( 5.2 )]. Assess liver function (clinical examination and laboratory testing including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), albumin, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and total bilirubin) [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 )] . Do not re-administer ELEVIDYS. 2.2 Recommended Dose The recommended dose of ELEVIDYS is 1.33 × 10 14 vector genomes per kilogram (vg/kg) of body weight (or 10 mL/kg body weight) for patients weighing less than 70 kg or 9.31 × 10 15 vg total fixed dose for patients weighing 70 kg or greater. For the number of vials required, refer to Table 10 [see How Supplied/Storage and Handling ( 16.1 )] . Calculate the dose as follows: ELEVIDYS dose (in mL) = patient body weight (rounded to the nearest kilogram) x 10 The multiplication factor 10 represents the per kilogram dose (1.33 × 10 14 vg/kg) divided by the amount of vector genome copies per mL of the ELEVIDYS suspension (1.33 × 10 13 vg/mL). Number of ELEVIDYS vials needed = ELEVIDYS dose (in mL) divided by 10. Example: Calculation of volume needed for a 19.5 kg patient 19.5 kg rounded to the nearest kilogram = 20 kg 20 kg × 10 = 200 mL Number of ELEVIDYS vials needed = 200 divided by 10, rounded to the nearest number of vials = 20 vials Administer corticosteroids to reduce the risk of immune responses to the AAVrh74 vector after administration of ELEVIDYS [see Clinical Pharmacology ( 12.6 )] . Start corticosteroids 1 day prior to ELEVIDYS infusion based on the schedule outlined in Table 1 below. Continue this regimen for a minimum of 60 days after the infusion, unless earlier tapering is clinically indicated. Table 1: Recommended pre- and post-infusion oral corticosteroid dosing a Patient continues to receive this dose b Corticosteroids other than prednisone and prednisolone have not been studied for use as a peri-ELEVIDYS infusion corticosteroid Baseline corticosteroid dosing a Peri-ELEVIDYS infusion corticosteroid dose (prednisone equivalent) b Recommended maximum total daily oral dose (prednisone equivalent) b Daily or intermittent dose Start 1 day prior to infusion: 1 mg/kg/day (and continue baseline dose) 60 mg/day High dose for 2 days per week Start 1 day prior to infusion: 1 mg/kg/day taken on days without high-dose corticosteroid treatment (and continue baseline dose) 60 mg/day Not on corticosteroids Start 1 week prior to infusion: 1.5 mg/kg/day 60 mg/day Modify oral corticosteroid doses according to Table 2 for patients with liver function abnormalities (e.g., GGT >= 3 times baseline, total bilirubin > ULN) following ELEVIDYS infusion. Consider IV bolus corticosteroids instead of oral corticosteroids for GGT or bilirubin elevations that do not respond after 1 week of increased oral corticosteroids. Consult with a specialist experienced in immunosuppressive therapy for additional interventions as needed. Obtain prompt consultation with a specialist (e.g., gastroenterologist or hepatologist) if acute serious liver injury or impending acute liver failure is suspected. Taper the additional peri-ELEVIDYS corticosteroids for patients previously taking corticosteroids at baseline back to baseline dose over 2 weeks, or longer as needed. Taper the peri-ELEVIDYS corticosteroids for patients not previously taking corticosteroids at baseline back to no corticosteroids over 4 weeks, or longer as needed. Do not stop corticosteroids abruptly. Table 2: Recommended oral corticosteroid regimen dose modification for liver function abnormalities following ELEVIDYS infusion a Peri-ELEVIDYS infusion corticosteroid dosing Modified oral corticosteroid dose following ELEVIDYS infusion (prednisone equivalent) b c Recommended maximum total daily oral dose (prednisone equivalent) b c a GGT >= 3 times baseline and/or other clinically significant liver function abnormalities (e.g., total bilirubin > ULN) following infusion. b Consider IV bolus corticosteroids instead of oral corticosteroids for GGT or bilirubin elevations that do not respond after 1 week of increased oral corticosteroids. Consult with a specialist experienced in immunosuppressive therapy for additional interventions as needed. c Corticosteroids other than prednisone and prednisolone have not been studied for use as a peri-ELEVIDYS infusion corticosteroid. Baseline + 1 mg/kg/day Increase to 2 mg/kg/day (and continue baseline dose) 120 mg/day Baseline + 1 mg/kg/day taken on days without high-dose corticosteroid treatment Increase to 2 mg/kg/day taken on days without high-dose corticosteroid treatment (and continue baseline dose) 120 mg/day 1.5 mg/kg/day Increase from 1.5 mg/kg/day to 2.5 mg/kg/day 120 mg/day 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 maximum or smaller stainless steel needles Preparing ELEVIDYS infusion 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. Thawed ELEVIDYS is stable for up to 24 hours at room temperature (up to 25°C [77ºF]). Inspect vials to ensure no ice crystals are present prior to preparation. When thawed, swirl gently. Do not shake. Do not refreeze. Do not place back in the refrigerator. 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. Remove the plastic flip-off cap from the vials and disinfect the rubber stopper with a sterilizing agent (e.g., alcohol wipes). Withdraw 10 mL of ELEVIDYS from each vial provided in the customized ELEVIDYS kit (refer to Table 10 ). 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. Maintain syringes at room temperature prior to and during administration. 2.4 Administration Recommended supplies and materials: Syringe infusion pump 0.2-micron PES* in-line filter with a large surface area. To avoid the risk of occlusions, the use of smaller pediatric in-line filters (e.g., less than 10 cm 2 surface area) is not recommended. PVC* (non-DEHP*) IV infusion tubing, and polyurethane 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: ELEVIDYS should be administered in a setting where treatment for infusion-related reactions is immediately available [see Warnings and Precautions ( 5.4 )] . Do not infuse ELEVIDYS at a rate of 10 mL/kg/hour or faster. Consider application of a topical anesthetic to the infusion site prior to administration of IV insertion. Recommend inserting a back-up catheter. Flush the intravenous access line with 0.9% Sodium Chloride Injection prior to the ELEVIDYS infusion at the same infusion rate. 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. 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 12 hours after drawing into syringe. Discard the ELEVIDYS-containing syringe(s) if infusion of the drug has not been completed within the 12-hour timeframe. In the event of an infusion-related reaction during administration [see Warnings and Precautions ( 5.4 )]: Slow or stop the infusion based on patient's clinical presentation. Discontinue infusion for anaphylaxis. Administer treatment as needed to manage infusion-related reaction. ELEVIDYS infusion may be restarted at a lower rate after the infusion-related reaction has resolved at the discretion of the physician, based on severity of patient's clinical presentation. If the ELEVIDYS infusion needs to be stopped and restarted, ELEVIDYS should be infused within 12 hours after drawing into the syringe [see How Supplied/Storage and Handling ( 16.2 )] . 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, AST, ALT, GGT, albumin, aPTT, INR, and total bilirubin) weekly for the first 3 months. Continue monitoring if clinically indicated, until results are unremarkable (e.g., normal clinical exam, GGT and total bilirubin levels return to near baseline levels) [see Warnings 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 Warnings and Precautions ( 5.3 )] . Continue monitoring if clinically indicated, until results return to near baseline levels or stabilize.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5%) were vomiting and nausea, liver injury, pyrexia, thrombocytopenia, and troponin-I increased. ( 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. The safety data described in this section reflect exposure to a one-time intravenous infusion of ELEVIDYS in 156 male patients with a confirmed mutation of the DMD gene in four clinical studies, including one completed open-label study, one ongoing open-label study, and two studies that included a double-blind, placebo-controlled period. Prior to ELEVIDYS infusion, patients in the ELEVIDYS treatment group had a mean age of 6.7 years (range: 3 to 20) and mean weight of 24.6 kg (range: 12.5 to 80.1). 144 patients received the recommended dose of 1.33 × 10 14 vg/kg, and 12 received a lower dose. Table 3 below presents adverse reactions from these four 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), the first month (myocarditis, troponin-I increased) or within the first 2 months (immune-mediated myositis, liver injury). Vomiting may occur as early as on the day of the infusion. Table 3. Adverse reactions (Incidence ≥5%) following treatment with ELEVIDYS in Clinical Studies Adverse reactions ELEVIDYS (N=156) % a Includes: AST increased, ALT increased, GGT increased, GLDH increased, GLDH level abnormal, Hepatotoxicity, Hepatic enzyme increased, Hypertransaminasemia, Liver function test increased, Liver injury, Transaminases increased, Blood bilirubin increased b Includes: Thrombocytopenia, Platelet count decreased c Transient, mild, asymptomatic decrease in platelet counts d Includes: Troponin I increased, Troponin increased, Troponin I abnormal Vomiting 65 Nausea 43 Liver injury a 40 Pyrexia 28 Thrombocytopenia b c 8 Troponin-I increased d 8 In clinical trials, immune-mediated myositis was observed in 2 of 6 patients with deletion mutations involving exon 8 and/or 9 in the DMD gene [see Contraindications ( 4 ), and Warnings and Precautions ( 5.5 )] . In the double-blind, placebo-controlled trial, Study 3 Part 1, patients 4 to 7 years of age (N=125) received either ELEVIDYS (N=63) at the recommended dose of 1.33 × 10 14 vg/kg or placebo (N=62). Table 4 below presents the most frequent adverse reactions from Study 3 Part 1. Table 4. Adverse reactions occurring in ELEVIDYS-treated patients and at least twice more frequently than with placebo in Study 3 Part 1 a Includes: AST increased, ALT increased, GGT increased, GLDH increased, GLDH level abnormal, Hepatotoxicity, Hepatic enzyme increased, Hypertransaminasemia, Liver function test increased, Liver injury, Transaminases increased. b Includes: platelet count decreased, thrombocytopenia c Transient, mild, asymptomatic decrease in platelet counts Adverse reactions ELEVIDYS (N=63) % Placebo (N=62) % Vomiting 64 19 Nausea 40 13 Liver injury a 41 8 Pyrexia 32 24 Thrombocytopenia bc 3 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ELEVIDYS. 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. Hepatobiliary Disorders: Acute liver injury, acute liver failure, including fatal outcome and life-threatening mesenteric vein thrombosis [see Warnings and Precautions ( 5.1 )] Infections and Infestations : Bacterial and viral respiratory infections, including fatal outcome [see Warnings and Precautions ( 5.2 )] Immune System Disorders: Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred during or up to several hours following ELEVIDYS administration [see Warnings and Precautions ( 5.4 )] . Musculoskeletal and connective tissue disorders: Immune-mediated myositis [see Warnings and Precautions ( 5.5 )].

12.3 Pharmacokinetics Vector Distribution and Vector Shedding Nonclinical Data Biodistribution of ELEVIDYS was evaluated in tissue samples collected from healthy mice and DMD mdx mice following intravenous administration in toxicology studies. At 12 weeks following ELEVIDYS administration at dose levels of 1.33 ×10 14 to 4.02 ×10 14 vg/kg, vector DNA was detected in all major organs with the highest quantities detected in the liver, followed by lower levels in the heart, adrenal glands, skeletal muscle, and aorta. ELEVIDYS was also detected at low levels in the spinal cord, sciatic nerve and gonads (testis). Protein expression of micro-dystrophin was highest in cardiac tissue, exceeding physiologic dystrophin expression levels in healthy mice, with lower levels in the skeletal muscle and diaphragm. In some studies, micro-dystrophin was also detected at low levels in the liver. Clinical Data Following IV administration, ELEVIDYS vector genome undergoes distribution via systemic circulation and distributes into target muscle tissues followed by elimination in the urine and feces. ELEVIDYS biodistribution and tissue transduction are detected in the target muscle tissue groups and quantified in the gastrocnemius or biceps femoris biopsies obtained from patients with mutations in the DMD gene. Evaluation of ELEVIDYS vector genome exposure in clinical muscle biopsies at Week 12 post-dose expressed as copies per nucleus revealed ELEVIDYS drug distribution and transduction with a mean change from baseline of 2.91 and 3.44 copies per nucleus at the recommended dose of 1.33 × 10 14 vg/kg for Study 1 and Study 2 Cohort 1, respectively. In Study 2 Cohorts 1-3, the biodistribution and vector shedding of ELEVIDYS in the serum and excreta were quantified, respectively. The mean maximum concentration (C max ) in the serum was 0.0055 × 10 13 copies/mL and 2.78 × 10 6 copies/mL in the urine, 7.86 × 10 7 copies/mL in the saliva, and 4.87 × 10 7 copies/μg in the feces. The median time to achieve maximum concentration (T max ) was 5.8 hours post-dose in the serum, followed by 6.7 hours, 6.5 hours and 13 days post-dose in the saliva, urine, and feces, respectively. The median time to achieve first below limit of quantification (BLOQ) sample followed by 2 consecutive BLOQ samples was 55 days post-dose for serum. The median time to achieve complete elimination as the first below limit of detection (BLOD) sample followed by 2 consecutive BLOD samples were 49.8 days, 78 days and 162 days post-dose for saliva, urine and feces, respectively. The estimated elimination half-life of ELEVIDYS vector genome in the serum is approximately 12 hours, and the majority of the drug is expected to be cleared from the serum by 1-week post-dose. In the excreta, the estimated elimination half-life of ELEVIDYS vector genome is approximately 40 hours, 55 hours, and 60 hours in the urine, feces, and saliva, respectively. As an AAV-based gene therapy that consists of a protein capsid containing the transgene DNA genome of interest, ELEVIDYS capsid proteins are broken down through proteasomal degradation following AAV entry into target cells. As such, ELEVIDYS is not likely to exhibit the drug-drug interaction potential mediated by known drug metabolizing enzymes (cytochrome P450-based) and drug transporters.