Delandistrogene Moxeparvovec-rokl (Monograph)

Brand name: Elevidys
Drug class: Gene Therapy

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

Introduction

Delandistrogene moxeparvovec-rokl is an adeno-associated virus vector-based gene therapy.

Uses for Delandistrogene Moxeparvovec-rokl

Delandistrogene moxeparvovec-rokl has the following uses:

Delandistrogene moxeparvovec-rokl is indicated for the treatment of ambulatory patients ≥4 years of age with Duchenne muscular dystrophy (DMD) who have a confirmed mutation in the DMD gene.

Delandistrogene moxeparvovec-rokl also is indicated for the treatment of patients ≥4 years of age with DMD who are non-ambulatory and have a confirmed mutation in the DMD gene. The DMD indication in non-ambulatory patients is approved under accelerated approval based on expression of delandistrogene moxeparvovec micro-dystrophin in skeletal muscle observed in treated patients. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Delandistrogene moxeparvovec-rokl has been designated an orphan drug by FDA for the treatment of DMD.

Delandistrogene moxeparvovec-rokl was evaluated in 2 double-blind, placebo-controlled studies and one open-label study in male patients with a confirmed mutation in the DMD gene. Study 1, which included ambulatory DMD patients 4–7 years of age, was comprised of two 48-week periods. In part 1, patients were randomized to receive a single IV infusion of delandistrogene moxeparvovec-rokl or placebo; in part 2, patients were switched from their current assigned therapy to the other treatment arm. The mean change from baseline at 12 weeks in microdystrophin levels was 43.4 in part 1 of the study and 40.7 in part 2 of the study. The effect of delandistrogene moxeparvovec-rokl on the North Star Ambulatory Assessment (NSAA) total score was also evaluated; however, the difference between active treatment and placebo at 48 weeks was not statistically significant. Study 2 was an open-label study which included ambulatory and non-ambulatory DMD patients 3–20 years of age. The mean change from baseline in microdystrophin levels at 12 weeks following treatment with a single IV infusion of delandistrogene moxeparvovec-rokl was 51 in the ambulatory patients and 40.1 in the non-ambulatory patients. In Study 3, ambulatory DMD patients 4–7 years of age were randomized to receive a single IV infusion of delandistrogene moxeparvovec-rokl or placebo. The change in NSAA total score from baseline to week 52 was not significantly different between the delandistrogene moxeparvovec-rokl and placebo groups; however, changes of clinical relevance were noted in the secondary endpoints of time to rise from the floor, 10-meter walk/run, and time to ascend 4 steps.

Delandistrogene Moxeparvovec-rokl Dosage and Administration

General

Delandistrogene moxeparvovec-rokl is available in the following dosage form(s) and strength(s):

Suspension for IV infusion with a nominal concentration of 1.33 × 10¹³ vg/mL.
Commercially available 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.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Delandistrogene moxeparvovec-rokl is for single-dose IV infusion only.

Select patients for treatment with delandistrogene moxeparvovec-rokl with anti-AAVrh74 total binding antibody titers <1:400. Measure baseline anti-AAVrh74 antibody titers using a Total Binding Antibody enzyme-linked immunosorbent assay (ELISA). Administration of delandistrogene moxeparvovec-rokl is not recommended in patients with elevated anti-AAVrh74 total binding antibody titers (≥1:400).
Recommended dosage in patients 10 to 70 kg: 1.33 ×10¹⁴ vector genomes (vg) per kg (vg/kg) of body weight (or 10 mL/kg body weight).
Recommended dosage in patients 70 kg or greater: 9.31 ×10¹⁵ vg total fixed dose.
There are limited safety data available in non-ambulatory patients weighing 70 kg or greater, who received the maximum dose of delandistrogene moxeparvovec-rokl, 9.31 × 10¹⁵ vg, in clinical trials.
Calculate the dose as follows: dose (in mL) = patient body weight (rounded to the nearest kg) x 10. The multiplication factor 10 represents the per kg dose (1.33 × 10¹⁴ vg/kg) divided by the amount of vector genome copies per mL of the suspension (1.33 × 10¹³ vg/mL). Number of vials needed = dose (in mL) divided by 10 (round to the nearest number of vials).
Administer as an IV infusion using a syringe infusion pump with an in-line 0.2-micron filter over approximately 1–2 hours through a peripheral limb vein. Infuse at a rate of less than 10 mL/kg/hour. Do not administer as an IV push and do not infuse into the same IV access line with any other product. Consider application of a topical anesthetic to the infusion site prior to administration of IV insertion.
Administer in a setting where treatment for infusion-related reactions is immediately available.
Postpone treatment in patients with concurrent infections until the infection has resolved.
Assess liver function, platelet counts, and troponin-I levels before delandistrogene moxeparvovec-rokl infusion.
To reduce the risk of an immune response, administer a corticosteroid regimen one day prior to infusion and continue for a minimum of 60 days after the infusion. Corticosteroid dose modifications are recommended for patients with liver function abnormalities.
See full prescribing information for additional information on preparation and administration, and instructions on how to manage infusion-related reactions.

Cautions for Delandistrogene Moxeparvovec-rokl

Contraindications

Patients with any deletion in exon 8 and/or exon 9 in the DMD gene.

Warnings/Precautions

Infusion-related Reactions

Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred during or up to several hours following administration of delandistrogene moxeparvovec-rokl. 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.

Delandistrogene moxeparvovec-rokl 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 delandistrogene moxeparvovec-rokl 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. If the infusion was stopped, the infusion may be restarted at a lower rate once patient’s symptoms have resolved, at the discretion of the physician. Discontinue infusion for anaphylaxis.

Acute Serious Liver Injury

Acute serious liver injury has been observed with delandistrogene moxeparvovec-rokl. Administration of delandistrogene moxeparvovec-rokl 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 delandistrogene moxeparvovec-rokl 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 delandistrogene moxeparvovec-rokl.

In clinical studies, increased liver function tests (including increases in GGT, GLDH, ALT, AST, or total bilirubin) was commonly reported typically within 8 weeks following delandistrogene moxeparvovec-rokl infusion, with the majority of cases being asymptomatic. Cases resolved spontaneously or with systemic corticosteroids and resolved without clinical sequelae within 2 months. No cases of liver failure were reported.

Prior to delandistrogene moxeparvovec-rokl administration, perform liver enzyme test. Monitor liver function (clinical exam, GGT, and total bilirubin) weekly for the first 3 months following delandistrogene moxeparvovec-rokl infusion. Continue monitoring if clinically indicated, until results are unremarkable (normal clinical exam, GGT and total bilirubin levels return to near baseline levels).

Systemic corticosteroid treatment is recommended for patients before and after delandistrogene moxeparvovec-rokl infusion. Adjust corticosteroid regimen when indicated. If acute serious liver injury is suspected, consultation with a specialist is recommended.

Immune-mediated Myositis

In clinical trials, immune-mediated myositis has been observed approximately 1 month following delandistrogene moxeparvovec-rokl 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 delandistrogene moxeparvovec-rokl treatment in patients with mutations in the DMD gene in exons 1 to 17 and/or exons 59 to 71. Patients with deletions in these regions may be at risk for a severe immune-mediated myositis reaction. Delandistrogene moxeparvovec-rokl 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.

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.

Myocarditis

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

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 delandistrogene moxeparvovec-rokl.

Monitor troponin-I before delandistrogene moxeparvovec-rokl infusion and weekly for the first month following infusion. 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.

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 delandistrogene moxeparvovec-rokl, all subjects developed anti-AAVrh74 antibodies. Perform baseline testing for the presence of anti-AAVrh74 total binding antibodies prior to delandistrogene moxeparvovec-rokl administration.

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

Specific Populations

Pregnancy

Delandistrogene moxeparvovec-rokl 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.

Lactation

There is no information available on the presence of delandistrogene moxeparvovec-rokl in human milk, the effects on the breastfed infant, or the effects on milk production.

Pediatric Use

The safety and effectiveness of delandistrogene moxeparvovec-rokl for the treatment of Duchenne muscular dystrophy have been established in pediatric patients at least 4 years of age with a confirmed mutation in the DMD gene.

Geriatric Use

The safety and efficacy of delandistrogene moxeparvovec-rokl in geriatric patients with DMD have not been studied.

Hepatic Impairment

The safety and efficacy of delandistrogene moxeparvovec-rokl in patients with hepatic impairment or elevated GGT have not been studied.

Postpone delandistrogene moxeparvovec-rokl administration in patients with acute liver disease until resolved or controlled. Delandistrogene moxeparvovec 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.

In clinical trials, liver function test increase was commonly reported in subjects following delandistrogene moxeparvovec-rokl infusion.

Common Adverse Effects

Most common adverse reactions across studies (incidence ≥5%) were vomiting and nausea, liver injury, pyrexia, and thrombocytopenia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Prior to initiating the corticosteroid regimen required before delandistrogene moxeparvovec-rokl 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.

Actions

Mechanism of Action

Delandistrogene moxeparvovec-rokl is a gene therapy product 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 delandistrogene moxeparvovec-rokl 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 delandistrogene moxeparvovec-rokl micro-dystrophin protein expression predominantly in skeletal muscle (including diaphragm) and cardiac muscle. In clinical studies, muscle biopsy analyses have confirmed delandistrogene moxeparvovec-rokl micro-dystrophin expression in skeletal muscle.

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

Delandistrogene moxeparvovec-rokl micro-dystrophin has been demonstrated to localize to the sarcolemma.

Advice to Patients

Infusion-related reactions including hypersensitivity and anaphylaxis have occurred during and after delandistrogene moxeparvovec infusion. Possible symptoms of infusion-related reactions are fast heart rate, fast breathing, swollen lips, being short of breath, nostrils widening, hives, red and blotchy skin, itchy or inflamed lips, rash, vomiting, nausea, chills, and fever. Contact a healthcare provider immediately if the patient experiences such a reaction.
Delandistrogene moxeparvovec can increase certain liver enzyme levels and cause acute serious liver injury. Patients will receive oral corticosteroid medication before and after infusion with delandistrogene moxeparvovec-rokl. 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 or vomits a dose of corticosteroid.
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.
Myocarditis (inflammation of the heart) has been observed within days following delandistrogene moxeparvovec-rokl 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.
Patient's immunizations should be up-to-date with current immunization guidelines prior to initiation of the corticosteroid regimen required before delandistrogene moxeparvovec infusion. Vaccinations should be completed at least 4 weeks prior to initiation of the corticosteroid regimen.
Due to the concomitant administration of corticosteroids, an infection (e.g., cold, flu, gastroenteritis, otitis media, bronchiolitis, etc.) before or after delandistrogene moxeparvovec 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 delandistrogene moxeparvovec 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 delandistrogene moxeparvovec-rokl infusion.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.