VYONDYS 53 Solution for injection Ref.[10301] Active ingredients:

After treatment with VYONDYS 53, all patients evaluated (n=25) in Study 1 Part 2 [see Clinical Studies (14)] had an increase in skipping of exon 53 demonstrated by reverse transcription polymerase chain reaction (RT-PCR), compared to baseline.

In Study 1 Part 2 [see Clinical Studies (14)], dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal after 48 weeks of treatment with VYONDYS 53. The mean change from baseline in dystrophin after 48 weeks of treatment with VYONDYS 53 was 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%. This increase in dystrophin protein expression positively correlated with the level of exon skipping. Correct localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with golodirsen was demonstrated by immunofluorescence staining.

Correct localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with golodirsen was demonstrated by immunofluorescence staining.

The pharmacokinetics of golodirsen was evaluated in DMD patients following administration of intravenous doses ranging from 4 mg/kg/week to 30 mg/kg/week (i.e., recommended dosage). Golodirsen exposure increased proportionally with dose, with minimal accumulation with once-weekly dosing. Inter-subject variability (as CV) for C_max and AUC ranged from 38 to 72%, and 34% to 44%, respectively.

Distribution

Steady-state volume of distribution was similar between DMD patients and healthy subjects. The mean golodirsen steady-state volume of distribution was 668 mL/kg (CV=32.3) at a dose of 30 mg/kg. Golodirsen plasma protein binding ranged from 33 to 39% and is not concentration dependent.

Elimination

Golodirsen elimination half-life (SD) was 3.4 (0.6) hours, and plasma clearance was 346 mL/hr/kg at the 30 mg/kg dose.

Metabolism

Golodirsen is metabolically stable. No metabolites were detected in plasma or urine.

Excretion

Golodirsen is mostly excreted unchanged in the urine. The elimination half-life (t_1/2) was 3.4 hours.

Specific Populations

Age

The pharmacokinetics of golodirsen have been evaluated in male pediatric DMD patients. There is no experience with the use of VYONDYS 53 in DMD patients 65 years of age or older.

Sex

Sex effects have not been evaluated; VYONDYS 53 has not been studied in female patients.

Race

The potential impact of race is not known because 92% of the patients in studies were Caucasians.

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of golodirsen was evaluated in non-DMD subjects aged 41 to 65 years with Stage 2 chronic kidney disease (CKD) (n=8, estimated glomerular filtration rate (eGFR) ≥60 and <90 mL/min/1.73 m²) or Stage 3 CKD (n=8, eGFR ≥30 and <60 mL/min/1.73 m²) and matched healthy subjects (n=8, eGFR ≥90 mL/min/1.73 m²). Subjects received a single 30 mg/kg IV dose of golodirsen.

In subjects with Stage 2 or Stage 3 CKD, exposure (AUC) increased approximately 1.2-fold and 1.9-fold, respectively. There was no change in the C_max in subjects with Stage 2 CKD; in subjects with Stage 3 CKD, there was a 1.2-fold increase in C_max compared with subjects with normal renal function. The effect of Stage 4 or Stage 5 CKD on golodirsen pharmacokinetics and safety has not been studied.

Estimated GFR values derived from MDRD equations and the threshold definitions for various CKD stages in otherwise healthy adults would not be generalizable to pediatric patients with DMD. Therefore, no specific dosage adjustment can be recommended for patients with renal impairment [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

VYONDYS 53 has not been studied in patients with hepatic impairment.

Drug Interaction Studies

Golodirsen did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 in vitro. Golodirsen was a weak inducer of CYP1A2 and did not induce CYP2B6 or CYP3A4. Golodirsen was not metabolized by human hepatic microsomes and was not a substrate or strong inhibitor of any of the key human drug transporters tested (OAT1, OAT3, OCT2, OATP1B1, MATE1, P-gp, BCRP, and MRP2, OATP1B3 and MATE2-K). Based on in vitro data, golodirsen has a low potential for drug-drug interactions in humans.

Carcinogenesis

Carcinogenicity studies have not been conducted with golodirsen.

Mutagenesis

Golodirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Fertility studies in animals were not conducted with golodirsen. No effects of golodirsen on the male reproductive system were observed following weekly subcutaneous administration (0, 120, 300, or 600 mg/kg to male mice or weekly intravenous administration (0, 80, 200, or 400 mg/kg) to male monkeys. Plasma exposure (AUC) at the highest doses tested in mouse and monkey are approximately 10 and 45 times that in humans at the recommended weekly intravenous dose of 30 mg/kg.

Kidney toxicity was observed in studies in male mice and rats; findings in urinary bladder were observed in male mice.

In male mice, golodirsen was administered weekly for 12 weeks by intravenous injection (0, 12, 120, or 960 mg/kg) or for 26 weeks by subcutaneous injection (0, 120, 300, or 600 mg/kg). In the 12-week study, microscopic findings in kidney (tubular dilatation, basophilic or eosinophilic casts, vacuolation), correlated with increases in serum markers of renal function (e.g., urea nitrogen, creatinine), were observed primarily at the highest dose tested; hypertrophy of the transitional epithelium of the ureter or urinary bladder was observed at all doses. In the 26-week study, renal tubular degeneration and degeneration of the transitional epithelium of the urinary bladder were observed at all doses.

In male rats, intravenous administration of golodirsen (0, 60, 100, 300, or 600 mg/kg) weekly for 13 weeks resulted in tubular degeneration at all but the lowest dose tested; at the high dose, the microscopic changes were accompanied by increases in serum urea nitrogen.

In male monkeys, intravenous administration of golodirsen (0, 80, 200, or 400 mg/kg) weekly for 39 weeks resulted in microscopic changes in kidney (basophilia, dilatation, or mononuclear cell infiltration) at all doses, which correlated with increases in serum markers of renal function (urea nitrogen, creatinine) at the highest dose tested.

The effect of VYONDYS 53 on dystrophin production was evaluated in one study in DMD patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping (Study 1; NCT02310906).

Study 1 Part 1 was a double-blind, placebo-controlled, dose-titration study in 12 DMD patients. Patients were randomized 2:1 to receive VYONDYS 53 or matching placebo. VYONDYS 53-treated patients received four escalating dose levels, ranging from 4 mg/kg/week (less than the recommended dosage) to 30 mg/kg/week by intravenous infusion for 2 weeks at each dose level.

Study 1 Part 2 was a 168-week, open-label study assessing the efficacy and safety of VYONDYS 53 at a dose of 30 mg/kg/week in the 12 patients enrolled in Part 1, plus 13 additional treatment-naive patients with DMD amenable to exon 53 skipping. At study entry (either in Part 1 or Part 2), patients had a median age of 8 years and were on a stable dose of corticosteroids for at least 6 months. Efficacy was assessed based on change from baseline in the dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 48 of Part 2. Muscle biopsies were obtained at baseline prior to treatment and at Week 48 of Part 2 in all VYONDYS 53-treated patients (n=25) and were analyzed for dystrophin protein level by Western blot. Mean dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal by Week 48 of Study 1 Part 2, with a mean change in dystrophin of 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%.

Individual patient dystrophin levels from Study 1 are shown in Table 2.

Table 2: Dystrophin Expression by Individual Patient From Study 1: