Casimersen is designed to bind to exon 45 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon 45 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 45 skipping.
In the interim analysis of muscle biopsy tissue obtained at baseline and at Week 48 from patients in Study 1, patients who received casimersen (n=27) demonstrated a significant increase in skipping of exon 45 (p<0.001) compared to baseline, demonstrated by reverse transcription digital droplet polymerase chain reaction (RT-ddPCR). Patients who received placebo (n=16) did not demonstrate a significant increase in exon 45 skipping (p=0.808). The level of exon skipping is positively correlated with dystrophin protein expression.
In Study 1, dystrophin levels as assessed by the Sarepta Western blot assay increased from 0.93% (SD 1.67) of normal at baseline to 1.74% (SD 1.97) of normal after 48 weeks of treatment with casimersen. The mean change from baseline in dystrophin after 48 weeks of treatment with casimersen was 0.81% (SD 0.70) of normal levels (p<0.001). This increase in dystrophin protein expression after treatment with casimersen positively correlated with the level of exon skipping. The mean change from baseline in dystrophin after 48 weeks of treatment with placebo was 0.22% (SD 0.49). Patients who received casimersen showed a significantly greater increase in dystrophin protein levels from baseline to Week 48 compared to those who received placebo (mean difference of 0.59%; p=0.004). Dystrophin levels assessed by Western blot can be meaningfully influenced by differences in sample processing, analytical technique, reference materials, and quantitation methodologies. Therefore, comparing dystrophin results from different assay protocols will require a standardized reference material and additional bridging studies.
Correct localization of dystrophin to the sarcolemma in patients treated with casimersen was demonstrated by immunofluorescence staining.
The pharmacokinetics of casimersen was evaluated in DMD patients following administration of intravenous (IV) doses ranging from 4 mg/kg/week to 30 mg/kg/week (i.e., recommended dosage). Following a single IV dose of casimersen, Cmax was reached at the end of infusion. Casimersen exposure increased in a proportional manner with dose increment. No accumulation of casimersen was observed in plasma following once weekly dosing. Inter-subject variability (as %CV) for casimersen Cmax and AUC ranged from 12% to 34% and 16% to 34%, respectively.
Binding of casimersen to human plasma protein was not concentration-dependent and ranged from 8.4% to 31.6%. The mean apparent volume of distribution at steady state (Vss) was 367 mL/kg (%CV = 28.9) following a 30 mg/kg dose of casimersen administered intravenously.
The plasma clearance (CL) of casimersen was 180 mL/hr/kg at the 30 mg/kg dose. The elimination half-life (t1/2) was 3.5 hours (SD 0.4 hours).
Casimersen is metabolically stable in human hepatic microsomal incubations. No metabolites were detected in plasma or urine.
Casimersen is mostly excreted unchanged in the urine. In a clinical study with radiolabeled casimersen, more than 90% of the drug was excreted in urine, with negligible fecal excretion.
The pharmacokinetics of casimersen have been evaluated in male DMD patients 9 to 20 years of age. There is no experience with the use of casimersen in DMD patients 65 years of age or older. Casimersen has not been studied in female patients. The potential impact of race on the pharmacokinetics of casimersen is unknown.
The effect of renal impairment on the pharmacokinetics of casimersen was evaluated in non-DMD subjects aged 35 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=9, eGFR ≥90 mL/min/1.73 m²). Subjects received a single 30 mg/kg intravenous dose of casimersen.
In subjects with Stage 2 or Stage 3 CKD, exposure (AUC) increased approximately 1.2-fold and 1.8-fold, respectively, compared with subjects with normal renal function. The Cmax in subjects with Stage 2 CKD was similar to Cmax in subjects with normal renal function; in subjects with Stage 3 CKD, there was a 1.2-fold increase in Cmax compared with subjects with normal renal function. The effect of Stage 4 or Stage 5 CKD on casimersen 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.
Casimersen has not been studied in patients with hepatic impairment. However, casimersen does not undergo hepatic metabolism, and the systemic clearance of casimersen is not expected to be affected by hepatic impairment.
Based on in vitro data, casimersen has a low potential for clinically relevant drug-drug interactions with major CYP enzymes and transporters.
Casimersen did not inhibit CYP1A2, CYP2B6, CYP2C8, or CYP2D6 in vitro. Casimersen was a potential inhibitor of CYP3A4/5, CYP2C9, and CYP2C19 in vitro; however, considering its short plasma half-life and lack of plasma accumulation with the weekly dosing regimen, clinical drug interaction with substrates for these enzymes is unlikely. Casimersen did not induce CYP1A2, CYP2B6, or CYP3A4 either at the mRNA or protein (activity) level. Casimersen was not metabolized by human hepatic microsomes and was not a substrate or strong inhibitor of the key human drug transporters tested (OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, and MRP2).
Kidney toxicity was observed in studies in male mice and rats.
In male mice, casimersen was administered weekly for 12 weeks (0, 12, 120, or 960 mg/kg) or 22 weeks (0, 300, 960, or 2000 mg/kg) by intravenous injection or for 26 weeks by subcutaneous injection (0, 300, 600, or 960 mg/kg). In the 12-week study, microscopic findings in kidney (cytoplasmic basophilia and microvacuolation) were observed at the highest dose tested. In the 22- and 26-week studies, renal tubular degeneration was observed at all doses. A no-effect dose for adverse effects on kidney was not identified. Plasma exposure (AUC) at the lowest dose tested in the 26-week study (300 mg/kg) was approximately 2 times that in humans at the recommended human dose (RHD) of 30 mg/kg/week.
In male rats, intravenous administration of casimersen (0, 250, 500, 1000, or 2000 mg/kg) weekly for 13 weeks resulted in renal tubular degeneration at all doses tested; at the highest dose, the microscopic changes were accompanied by increases in blood urea nitrogen. A no-effect dose for adverse effects on kidney was not identified. Plasma exposure (AUC) at the lowest dose tested were approximately 4 times that in humans at the RHD.
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