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

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

In 61 subjects who received ELEVIDYS in clinical studies, ELEVIDYS micro-dystrophin protein expression from muscle biopsies (gastrocnemius) was quantified by western blot and localized by immunofluorescence staining (fiber intensity and percentage ELEVIDYS micro-dystrophin).

ELEVIDYS micro-dystrophin expression (expressed as change from baseline) as measured by western blot was the primary objective of Study 1 and Study 2. Muscle biopsies were obtained at baseline prior to ELEVIDYS infusion and at Week 12 after ELEVIDYS infusion in all subjects. The absolute quantity of ELEVIDYS micro-dystrophin was measured by western blot assay, adjusted by muscle content and expressed as a percent of control (levels of wild-type dystrophin in subjects without DMD or Becker muscular dystrophy) in muscle biopsy samples. Results of subjects receiving 1.33 × 10¹⁴ vg/kg ELEVIDYS are presented in Table 5.

Table 5. ELEVIDYS Micro-Dystrophin Expression in Studies 1 and 2 (Western Blot Assay)^abcd:

^a All patients received 1.33 × 10¹⁴ vg/kg, as measured by ddPCR
^b Muscle biopsies were obtained from the gastrocnemius
^c Change from baseline was statistically significant
^d Adjusted for muscle content. Control was level of wild-type (normal) dystrophin in normal muscle.

For subjects aged 4 through 5 years who received 1.33 × 10¹⁴ vg/kg of ELEVIDYS, the mean (SD) ELEVIDYS micro-dystrophin expression levels (change from baseline) at Week 12 following ELEVIDYS infusion were 95.7% (N=3, SD: 17.9%) in Study 1 Parts 1 and 2 and 51.7% (N=11, SD: 41.0%) in Study 2 Cohort 1.

Assessment of ELEVIDYS micro-dystrophin levels can be meaningfully influenced by differences in sample processing, analytical technique, reference materials, and quantitation methodologies. Therefore, valid comparisons of ELEVIDYS micro-dystrophin measurements obtained from different assays cannot be made.

Vector Distribution and Vector Shedding

Nonclinical Data

Biodistribution of ELEVIDYS was evaluated in tissue samples collected from healthy mice and Dmd ^mdx mice following intravenous administration in toxicology studies. At 12 weeks following ELEVIDYS administration at dose levels of 1.33 × 10¹⁴ to 4.02 × 10¹⁴ vg/kg, vector DNA was detected in all major organs with the highest quantities detected in the liver, followed by lower levels in the heart, adrenal glands, skeletal muscle, and aorta. ELEVIDYS was also detected at low levels in the spinal cord, sciatic nerve and gonads (testis). Protein expression of ELEVIDYS micro-dystrophin was highest in cardiac tissue, exceeding physiologic dystrophin expression levels in healthy mice, with lower levels in the skeletal muscle and diaphragm. In some studies, micro-dystrophin was also detected at low levels in the liver.

Clinical Data

Following IV administration, ELEVIDYS vector genome undergoes distribution via systemic circulation and distributes into target muscle tissues followed by elimination in the urine and feces. ELEVIDYS biodistribution and tissue transduction are detected in the target muscle tissue groups and quantified in the gastrocnemius or biceps femoris biopsies obtained from patients with mutations in the DMD gene. Evaluation of ELEVIDYS vector genome exposure in clinical muscle biopsies at Week 12 post-dose expressed as copies per nucleus revealed ELEVIDYS drug distribution and transduction with a mean change from baseline of 2.91 and 3.44 copies per nucleus at the recommended dose of 1.33 × 10¹⁴ vg/kg for Study 1 and Study 2 Cohort 1, respectively.

In Study 2 Cohort 1, the biodistribution and vector shedding of ELEVIDYS in the serum and excreta were quantified, respectively. The mean maximum concentration (C_max) in the serum was 0.0049 × 10¹³ copies/mL and 4.11 × 10⁵ copies/mL in the urine, 4.72 × 10⁷ copies/mL in the saliva, and 2.32 × 10⁷ copies/μg in the feces. The median time to achieve maximum concentration (T_max) was 5.3 hours post-dose in the serum, followed by 6.7 hours, 6.4 hours and 13.5 days post-dose in the saliva, urine, and feces, respectively. The median time to achieve first below limit of quantification (BLOQ) sample followed by 2 consecutive BLOQ samples were 63 days post-dose for serum. The median time to achieve complete elimination as the first below limit of detection (BLOD) sample followed by 2 consecutive BLOD samples were 49.8 days, 123 days and 162 days post-dose for saliva, urine and feces, respectively. The estimated elimination half-life of ELEVIDYS vector genome in the serum is approximately 12 hours, and the majority of the drug is expected to be cleared from the serum by 1-week post-dose. In the excreta, the estimated elimination half-life of ELEVIDYS vector genome is 40 hours, 55 hours, and 60 hours in the urine, feces, and saliva, respectively. As an AAV-based gene therapy that consists of a protein capsid containing the transgene DNA genome of interest, ELEVIDYS capsid proteins are broken down through proteasomal degradation following AAV entry into target cells. As such, ELEVIDYS is not likely to exhibit the drug-drug interaction potential mediated by known drug metabolizing enzymes (cytochrome P450-based) and drug transporters.

No animal studies have been performed to evaluate the effects of ELEVIDYS on carcinogenicity, mutagenesis, or impairment of fertility.

Accelerated approval was primarily based on data from Study 1 and Study 2 described below.

Study 1 is an ongoing multi-center study including:

• Part 1: a 48-week, randomized, double-blind, placebo-controlled period
• Part 2: a 48-week period that began following completion of Part 1. Patients who received placebo during Part 1 were treated with ELEVIDYS, and patients treated with ELEVIDYS during Part 1 received placebo.

The study population consisted of male ambulatory DMD patients (N=41) aged 4 through 7 years with either a confirmed frameshift mutation, or a premature stop codon mutation between exons 18 to 58 in the DMD gene.

Patients were randomized 1:1 to receive either ELEVIDYS (N=20) or placebo (N=21), as a single intravenous infusion via a peripheral limb. Randomization was stratified by age (i.e., aged 4 to 5 years vs. aged 6 to 7 years). In the ELEVIDYS group, eight patients received 1.33 × 10¹⁴ vg/kg of ELEVIDYS, and 12 patients received lower doses. Key demographic and baseline characteristics are presented in Table 6 below.

Table 6. Key Demographic and Baseline Characteristics (Part 1):

All subjects were on a stable dose of corticosteroids for DMD for at least 12 weeks prior to ELEVIDYS infusion. All randomized subjects had baseline anti-AAVrh74 antibody titers <1:400 as determined by an investigational total binding antibody ELISA.

One day prior to treatment with ELEVIDYS or placebo, the subject’s background dose of corticosteroid for DMD was increased to at least 1 mg/kg of a corticosteroid (prednisone equivalent) daily and was continued at this level for at least 60 days after the infusion, unless earlier tapering was clinically indicated.

The primary objectives of Study 1 were to evaluate expression of ELEVIDYS micro-dystrophin in skeletal muscle, and to evaluate the effect of ELEVIDYS on the North Star Ambulatory Assessment (NSAA) total score.

Results of ELEVIDYS micro-dystrophin measured by western blot are presented in Table 5 [see Clinical Pharmacology (12.2)].

The change in NSAA total score was assessed from baseline to Week 48 after infusion of ELEVIDYS or placebo. The difference between the ELEVIDYS and placebo groups was not statistically significant (p=0.37). The least squares (LS) mean changes in NSAA total score from baseline to Week 48 was 1.7 (standard error [SE]: 0.6) points for the ELEVIDYS group and 0.9 (SE: 0.6) points for the placebo group.

Exploratory subgroup analyses showed that for subjects aged 4 through 5 years, the LS mean changes (SE) in NSAA total score from baseline to Week 48 were 4.3 (0.7) points for the ELEVIDYS group, and 1.9 (0.7) points for the placebo group, a numerical advantage for ELEVIDYS. For subjects aged 6 through 7 years, the LS mean changes (SE) in NSAA total score from baseline to Week 48 were -0.2 (0.7) points for the ELEVIDYS group and 0.5 (0.7) points for the placebo group, a numerical disadvantage for ELEVIDYS.

Study 2 is an ongoing, open-label, multi-center study which includes a cohort of 20 ambulatory male DMD subjects aged 4 through 7 years. All 20 subjects have a confirmed frameshift mutation, canonical splice site mutation, or premature stop codon mutation in the DMD gene.

At study entry, 75% of subjects were white with a mean age of 5.81 years (range: 4.38 to 7.94), mean weight of 21.2 kg (range: 15.2 to 33.1), mean NSAA total score of 22.1 points (range: 18 to 26), and mean time to rise from floor of 4.2 seconds (range: 2.4 to 8.2). Subjects received corticosteroids for DMD before infusion according to Table 1 [see Dosage and Administration (2.2)]. All subjects had baseline anti-AAVrh74 antibodies titers <1:400 as determined by the investigational total binding antibody ELISA and received a single intravenous infusion of 1.33 × 10¹⁴ vg/kg ELEVIDYS.

The primary objective of the study was to evaluate the effect of ELEVIDYS micro-dystrophin expression as measured by western blot. Results are presented in Table 5 [see Clinical Pharmacology (12.2)].