Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2       Pharmacodynamics
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 Western blot (% of ELEVIDYS               Study 1               Study 1                Study 2 micro-dystrophin compared                (Week 12)             (Week 12)              (Week 12) to control)                       Part 1                Part 2                Cohort 1 (n = 6)                                     (n = 20)
(n=21)
Mean change from baseline                   43.4                   40.7                  54.2 (SD)                                       (48.6)                 (32.3)                (42.6) 
Median change from baseline                 24.3                  40.8                   50.6 (Min, Max)                              (1.6, 116.3)           (0.0, 92.0)           (4.8, 153.9)  a
All patients received 1.33 x 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.

Pharmacokinetic Properties

12.3 Pharmacokinetics
Vector Distribution and Vector Shedding

Nonclinical Data
Biodistribution of ELEVIDYS was evaluated in tissue samples collected from healthy mice and Dmdmdx 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 (Cmax) 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.

12.6   Immunogenicity
The observed incidence of anti-AAVrh74 antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-AAVrh74 antibodies in the studies described below with the incidence of anti-AAVrh74 antibodies in other studies.

In ELEVIDYS clinical studies, patients were required to have baseline anti-AAVrh74 total binding antibodies of ≤1:400, measured using an investigational total binding antibody enzyme-linked immunosorbent assay (ELISA), and only patients with baseline anti-AAVrh74 total binding antibodies <1:400 were enrolled in those studies. The safety and efficacy of ELEVIDYS in patients with elevated anti-AAVrh74 total binding antibody titer (≥1:400) have not been evaluated [see Clinical Studies (14)].

Across clinical studies evaluating a total of 84 patients, elevated anti-AAVrh74 total binding antibodies titers were observed in all patients following a one-time ELEVIDYS infusion. Anti-AAVrh74 total binding antibody titers reached at least 1:409,600 in every subject, and the maximum titers exceeded 1:26,214,400 in certain subjects. The safety of re-administration of ELEVIDYS or any other AAVrh74 vector-based gene therapy in the presence of high anti-AAVrh74 total binding antibody titer has not been evaluated in humans [see Warnings and Precautions (5.4)].