Delandistrogene Moxeparvovec

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.

ELEVIDYS is a preservative-free, sterile, clear, colorless liquid that may have some opalescence and may contain white to off-white particles. ELEVIDYS is a suspension for intravenous infusion with a nominal concentration of 1.33 × 10 13 vg/mL. ELEVIDYS is provided in a customized kit containing ten to seventy 10 mL single-dose vials, with each kit constituting a dosage unit based on the patient's body weight [see How Supplied/Storage and Handling ( 16.1 )] . ELEVIDYS is a suspension for intravenous infusion with a nominal concentration of 1.33 × 10 13 vg/mL. ( 3 ) ELEVIDYS is provided in a customized kit containing ten to seventy 10 mL single-dose vials, with each kit constituting a dosage unit based on the patient's body weight. ( 3 )

ELEVIDYS is contraindicated in patients with any deletion in exon 8 and/or exon 9, including a deletion of any portion or the entirety of these exons, in the DMD gene [see Warnings and Precautions ( 5.5 )] . ELEVIDYS is contraindicated in patients with any deletion in exon 8 and/or exon 9, including a deletion of any portion or the entirety of these exons, in the DMD gene. ( 4 )

Serious Infections: Serious infections with fatal outcomes may occur due to concomitant administration of corticosteroids, additional immunosuppressants, and ELEVIDYS. Monitor patients for signs and symptoms of infection; treat appropriately. ( 5.2 ) Myocarditis: Acute, serious, life-threatening myocarditis and troponin-I elevations have been observed. Monitor troponin-I before ELEVIDYS infusion, and weekly for the first month after ELEVIDYS infusion. ( 5.3 ) Infusion-related Reactions: Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or stop the infusion and give appropriate treatment. Once symptoms resolve, restart infusion at a slower infusion rate. Discontinue infusion for anaphylaxis. ( 2.4 , 5.4 ) Immune-mediated Myositis: Severe to life-threatening immune-mediated myositis has been reported with ELEVIDYS in patients with deletions including portions of exons 1 to 17 and /or exons 59 to 71 of the DMD gene. Consider additional immunomodulatory treatment if symptoms of myositis occur (e.g., unexplained increased muscle pain, tenderness, or weakness). ( 5.5 ) Pre-existing Immunity against AAVrh74: Perform baseline testing for presence of anti-AAVrh74 total binding antibodies prior to ELEVIDYS administration. ( 5.6 )

5.1 Acute Serious Liver Injury and Acute Liver Failure Acute serious liver injury marked by elevations of liver enzymes (e.g., GGT, ALT) and total bilirubin and acute liver failure, has occurred with ELEVIDYS. Onset of the liver injury typically begins within 8 weeks after administration of ELEVIDYS. In non-ambulatory patients treated with ELEVIDYS, acute liver failure with fatal outcome has occurred in the clinical and post-marketing settings. Life-threatening mesenteric vein thrombosis, complicated by bowel ischemia and necrosis, and portal hypertension have been reported following acute liver injury associated with ELEVIDYS in a non-ambulatory patient [see Adverse Reactions ( 6.2 )] . 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 or acute liver failure. 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, 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 )] . Most cases resolved spontaneously or with systemic corticosteroids and resolved without clinical sequelae within 2 months. Prior to ELEVIDYS administration, perform liver enzyme test [see Dosage and Administration ( 2.1 )] . Monitor liver function (clinical examination, AST, ALT, GGT, albumin, aPTT, INR, and total bilirubin) weekly for the first 3 months following ELEVIDYS infusion. 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 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 )] . Obtain prompt consultation with a specialist (e.g., gastroenterologist or hepatologist) if acute serious liver injury or impending acute liver failure is suspected.

5.2 Serious Infections Increased susceptibility to serious infections may occur due to concomitant administration of corticosteroid regimen and additional immunosuppressants, and ELEVIDYS. Serious respiratory infections, including with fatal outcomes, have occurred in patients taking immunosuppressant corticosteroids required for ELEVIDYS administration [see Adverse Reactions ( 6.2 )] . Monitor patients for signs and symptoms of infection before and after ELEVIDYS administration and treat appropriately. Administer immunizations according to best clinical practices and immunization guidelines prior to initiation of the corticosteroid regimen required before ELEVIDYS infusion [see Drug Interactions ( 7 )] . Avoid administration of ELEVIDYS to patients with active infections.

5.3 Myocarditis Acute, serious, life-threatening myocarditis and troponin-I elevations have been observed within 24 hours to more than 1 year following ELEVIDYS infusion [see Adverse Reactions ( 6.1 ) ]. If a patient experiences myocarditis, those with pre-existing left ventricle ejection fraction (LVEF) impairment may be at higher risk of adverse outcomes. Patients with moderate to severe LVEF impairment have not been studied in clinical trials with ELEVIDYS. 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, until results return to near baseline levels or stabilize. 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 Infusion-related Reactions Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred during or up to several hours following ELEVIDYS administration. Closely monitor patients during and for at least 3 hours after the end of infusion for signs and symptoms of infusion-related reactions including tachycardia, tachypnea, lip swelling, difficulty breathing, nasal flaring, urticaria, flushing, lip pruritus, rash, cheilitis, vomiting, nausea, rigors and pyrexia. ELEVIDYS should be administered in a setting where treatment for infusion-related reactions is immediately available. In the event of an infusion-related reaction, administration of ELEVIDYS may be slowed or stopped based on the severity of the patient's clinical presentation. Administer treatment as needed to manage infusion-related reactions based on the severity of patient's signs and symptoms. [see Dosage and Administration ( 2.4 )] . If the infusion was stopped, ELEVIDYS infusion may be restarted at a lower rate once patient's symptoms have resolved, at the discretion of the physician. Discontinue infusion for anaphylaxis.

5.5 Immune-mediated Myositis Immune-mediated myositis, including serious and life-threatening events, has occurred approximately 1 month following ELEVIDYS infusion [see Adverse Reactions ( 6 ) ]. Signs and symptoms include severe muscle weakness, including dysphagia, dyspnea, dysphonia, and hypophonia. These immune reactions may be due to a T-cell based response against specific regions of the micro-dystrophin transgenic protein. Severe to life-threatening immune-mediated myositis has been reported in patients with deletions including portions of exons 1-17 and/or exons 59-71 of the DMD gene. ELEVIDYS is contraindicated in patients with any deletion in exon 8 and/or exon 9, including a deletion of any portion or the entirety of these exons, in the DMD gene due to the increased risk for a severe immune-mediated myositis reaction [see Contraindications ( 4 )] . Regardless of genetic mutation, advise patients to contact a physician immediately if they experience any unexplained increased muscle pain, tenderness, or weakness, including dysphagia, dyspnea, dysphonia, or hypophonia as these may be symptoms of myositis. Consider additional immunomodulatory treatment based on patient's clinical presentation and medical history if these symptoms occur. […]

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 )].

Prior to initiating the corticosteroid regimen required before ELEVIDYS administration, consider the patient's vaccination status. Patients should, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines. Vaccinations should be completed at least 4 weeks prior to initiation of the corticosteroid regimen.

8.1 Pregnancy Risk Summary ELEVIDYS is not intended for use in pregnant women. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary There is no information available on the presence of ELEVIDYS in human milk, the effects on the breastfed infant, or the effects on milk production.

8.4 Pediatric Use The safety and effectiveness of ELEVIDYS for the treatment of Duchenne muscular dystrophy has been established in pediatric patients at least 4 years of age with a confirmed mutation in the DMD gene. The use of ELEVIDYS in pediatric patients was supported by evidence from three adequate and well controlled clinical studies which included 144 pediatric patients aged 4 years of age and older [see Adverse Reactions ( 6 ), 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. Treatment with ELEVIDYS 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 or acute liver failure [see Warnings and Precautions ( 5.1 )] . In clinical trials, liver function test increase was commonly reported in patients following ELEVIDYS infusion [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 )] .

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 single-stranded DNA 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 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 micro-dystrophin protein expression predominantly in skeletal muscle (including diaphragm) and cardiac muscle. In clinical studies, muscle biopsy analyses have confirmed 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.