Introduction

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

Uses for Delandistrogene Moxeparvovec (Systemic)

Delandistrogene moxeparvovec-rokl has the following uses:

Delandistrogene moxeparvovec-rokl is indicated for the treatment of ambulatory pediatric patients 4 through 5 years of age with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD Gene. Designated an orphan drug by FDA for the treatment of DMD.

This indication 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 was evaluated in 2 ongoing studies. Study 1 was comprised of 2 parts. In part 1, patients were randomized to receive delandistrogene moxeparvovec-rokl or placebo for 48 weeks; in part 2, patients were switched from their current assigned therapy to the other treatment arm. Study 2 was an open-label multicenter study. Both studies included ambulatory male patients 4–7 years of age with DMD. The mean change from baseline in microdystrophin levels in skeletal muscle at 12 weeks following treatment with delandistrogene moxeparvovec-rokl 1.33 x 10¹⁴ vector genomes (vg) per kg of body weight was 43.4 in study 1 part 1, 40.7 in study 1 part 2, and 54.2 in study 2. In Study 1, 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 was not statistically significant.

Delandistrogene Moxeparvovec (Systemic) 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: 1.33 ×10¹⁴ vector genomes (vg) per kg of body weight (or 10 mL/kg body weight).

• Calculate the dose as follows: dose (in mL) = patient body weight (in 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 over 1–2 hours through a peripheral venous catheter. Infuse at a rate of less than 10 mL/kg/hour. Consider application of a topical anesthetic to the infusion site prior to administration of IV insertion.

• 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.

• Re-administration is not recommended.

• See full prescribing information for instructions on preparation and handling, and administration.

Contraindications

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

Warnings/Precautions

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.

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

Delandistrogene moxeparvovec-rokl 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 delandistrogene moxeparvovec micro-dystrophin protein in skeletal muscle observed in treated patients. The effectiveness and safety of delandistrogene moxeparvovec-rokl have not been established in pediatric patients younger than 3 years of age. The effectiveness of delandistrogene moxeparvovec-rokl has not been established in pediatric patients 3 years of age and in pediatric patients 6 years of age and older.

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, increased liver function tests, pyrexia, and thrombocytopenia.

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: 1.33 ×10¹⁴ vector genomes (vg) per kg of body weight (or 10 mL/kg body weight).

• Calculate the dose as follows: dose (in mL) = patient body weight (in 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 over 1–2 hours through a peripheral venous catheter. Infuse at a rate of less than 10 mL/kg/hour. Consider application of a topical anesthetic to the infusion site prior to administration of IV insertion.

• 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.

• Re-administration is not recommended.

• See full prescribing information for instructions on preparation and handling, and administration.

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.