ELEVIDYS Suspension for solution for infusion Ref.[107289] Active ingredients: Delandistrogene moxeparvovec

5.1 Acute Serious Liver Injury

Acute serious liver injury has been observed with ELEVIDYS. Administration of ELEVIDYS 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 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, GLDH, 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)]. Cases resolved spontaneously or with systemic corticosteroids and resolved without clinical sequelae within 2 months. No cases of liver failure were reported.

Prior to ELEVIDYS administration, perform liver enzyme test [see Dosage and Administration (2.2)]. Monitor liver function (clinical exam, GGT, and total bilirubin) weekly for the first 3 months following ELEVIDYS infusion. Continue monitoring if clinically indicated, until results are unremarkable (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)]. If acute serious liver injury is suspected, a consultation with a specialist is recommended.

5.2 Immune-mediated Myositis

In clinical trials, immune-mediated myositis has been observed approximately 1 month following ELEVIDYS 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 ELEVIDYS treatment in patients with mutations in the DMD gene in exons 1 to 17 and/or exons 59 to 71 [see Clinical Studies (14)]. Patients with deletions in these regions may be at risk for a severe immune-mediated myositis reaction. ELEVIDYS 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 [see Contraindications (4)].

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.

5.3 Myocarditis

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

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. 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 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 ELEVIDYS all subjects developed anti-AAVrh74 antibodies. Perform baseline testing for the presence of anti-AAVrh74 total binding antibodies prior to ELEVIDYS administration [see Dosage and Administration (2.1)].

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

The most common adverse reactions (incidence ≥5%) reported in clinical studies were vomiting, nausea, liver function test increased, pyrexia, and thrombocytopenia.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Acute serious liver injury [see Warnings and Precautions (5.1)]
• Immune-mediated myositis [see Warnings and Precautions (5.2)]
• Myocarditis [see Warnings and Precautions (5.3)]

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 85 male subjects with a confirmed mutation of the DMD gene in three on-going clinical studies, including two open-label studies and one study that included a double-blind, placebo-controlled period. Prior to ELEVIDYS infusion, patients in the ELEVIDYS treatment group had a mean age of 7.08 years (range: 3 to 20) and mean weight of 25.91 kg (range: 12.5 to 80.1). 73 subjects 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 three 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), or within the first 2 months (immune-mediated myositis, liver function test increased). 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:

^a Includes: AST increased, ALT increased, GGT increased, GLDH increased, hepatic enzyme increased, transaminases increased, blood bilirubin increased
^b Transient, mild, asymptomatic decrease in platelet counts

In the double-blind, placebo-controlled trial (Study 1 Part 1), subjects 4 to 7 years of age (N=41) received either ELEVIDYS (N=20) at the recommended dose of 1.33 × 10¹⁴ vg/kg (n=8) or lower dose (n=12) or received placebo (N=21). Table 4 below presents the most frequent adverse reactions from Study 1 Part 1.

Table 4. Adverse reactions occurring in ELEVIDYS-treated subjects and at least 10% more frequently than in placebo in Study 1, Part 1:

^a Includes: AST increased, ALT increased, GGT increased, GLDH increased, hepatic enzyme increased, transaminases increased, blood bilirubin increased.

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.

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.

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.

ELEVIDYS 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 ELEVIDYS micro-dystrophin protein in skeletal muscle observed in DMD patients treated with ELEVIDYS. The effectiveness and safety of ELEVIDYS has not been established in pediatric patients younger than 3 years of age. The effectiveness of ELEVIDYS has not been established in pediatric patients 3 years of age and in pediatric patients 6 years of age and older [see Clinical Pharmacology (12.2), Clinical Studies (14)].

The safety and efficacy of ELEVIDYS in geriatric patients with DMD have not been studied.

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. ELEVIDYS 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 [see Warnings and Precautions (5.1)].

In clinical trials, liver function test increase was commonly reported in subjects following ELEVIDYS infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].