Elevidys - Drug Monograph

Introduction

Elevidys (delandistrogene moxeparvovec-rokl) is a novel gene therapy approved by the FDA in June 2023 for the treatment of Duchenne muscular dystrophy (DMD). This adeno-associated virus (AAV)-based therapy represents a significant advancement in the treatment of this devastating genetic disorder, offering the first gene therapy option for eligible DMD patients.

Mechanism of Action

Elevidys is a recombinant AAV vector-based gene therapy designed to deliver a gene encoding a shortened, functional version of dystrophin to muscle cells. The therapy utilizes an AAVrh74 vector with a muscle-specific promoter to target skeletal and cardiac muscle tissue. Once administered, the vector delivers a transgene that encodes micro-dystrophin, a shortened protein that contains key functional domains of dystrophin. This micro-dystrophin integrates into the muscle fiber membrane, helping to stabilize the dystrophin-associated protein complex and potentially slow disease progression.

Indications

Elevidys is indicated for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. This accelerated approval was based on expression of the Elevidys micro-dystrophin transgene, with continued approval contingent upon verification of clinical benefit in confirmatory trials.

Dosage and Administration

• Recommended dose: 1.33 × 10¹⁴ vector genomes (vg)/kg body weight administered as a single intravenous infusion
• Route: Intravenous infusion via a peripheral limb vein
• Infusion rate: Administer over approximately 60-90 minutes
• Premedication: Corticosteroids (e.g., prednisone 1 mg/kg/day or equivalent) should be administered starting 1 day before infusion and continuing for at least 60 days
• Special populations: Not studied in patients with hepatic or renal impairment

Pharmacokinetics

• Absorption: Administered directly into systemic circulation via IV infusion
• Distribution: Primarily distributes to skeletal and cardiac muscle tissues with AAVrh74 tropism
• Metabolism: Degraded by various proteolytic pathways; not metabolized by hepatic cytochrome P450 enzymes
• Elimination: Clearance occurs through immune-mediated mechanisms and degradation; vector DNA may persist in transduced cells

Contraindications

• History of serious allergic reaction to Elevidys or any of its components
• Patients with pre-existing immunity to AAVrh74 (anti-AAVrh74 antibody titer >1:400)

Warnings and Precautions

• Acute serious liver injury: Monitor liver function before infusion and weekly for the first 3 months
• Immune-mediated myositis: May occur as early as 2 weeks post-infusion
• Myocarditis and cardiomyopathy: Monitor cardiac function regularly
• Thromboembolic events: Consider prophylactic anticoagulant therapy
• AAV vector integration: Theoretical risk of insertional mutagenesis
• Pre-existing immunity: Screen for anti-AAVrh74 antibodies before treatment

Drug Interactions

• Immunosuppressive therapies may affect immune response to the vector
• Corticosteroids are required concomitantly and may interact with other medications
• No formal drug interaction studies have been conducted

Adverse Effects

• Vomiting (38%)
• Nausea (25%)
• Liver function test increased (25%)
• Pyrexia (13%)
• Thrombocytopenia (13%)

• Acute liver injury
• Immune-mediated myositis
• Myocarditis
• Thrombocytopenia

Monitoring Parameters

• Liver function: ALT, AST, total bilirubin weekly for first 3 months
• Cardiac function: Echocardiogram and ECG at baseline and regularly during follow-up
• Platelet counts: Weekly for first 3 months
• Anti-AAVrh74 antibodies: Before treatment
• Vector shedding: In bodily secretions for initial weeks post-infusion
• Clinical response: Motor function assessments regularly

Patient Education

• Inform patients and caregivers about the potential risks and benefits of treatment
• Discuss the importance of regular monitoring and follow-up appointments
• Educate about signs of liver injury (jaundice, dark urine, abdominal pain)
• Advise about potential need for isolation precautions due to vector shedding
• Emphasize adherence to corticosteroid regimen
• Discuss realistic expectations regarding treatment outcomes

References

1. FDA Approval Letter: Elevidys (delandistrogene moxeparvovec-rokl). June 2023 2. Mendell JR, et al. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy. JAMA Neurol. 2023 3. ClinicalTrials.gov: Study SRP-9001-103 (ENDURANCE) 4. Sarepta Therapeutics. Elevidys Prescribing Information. 2023 5. Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2018 6. Chamberlain JS, et al. Expression of Functional Dystrophin Following Gene Transfer. Nat Commun. 2019