Zilganersen is an antisense oligonucleotide that causes degradation of glial fibrillary acidic protein (GFAP) pre-mRNA through binding to GFAP pre-mRNA, which results in a reduction of GFAP protein synthesis.
Plasma GFAP, an indirect measure of target engagement, was evaluated longitudinally in patients with Alexander disease. At week 61 (after 5 doses), the geometric mean ratio to baseline in plasma GFAP was 33.6% lower in patients on zilganersen compared to controls
Based on the chemical properties of zilganersen and the absence of cardiac electrophysiology findings in nonclinical studies, zilganersen is not expected to affect the QTc interval.
The pharmacokinetic properties of zilganersen were evaluated following intrathecal administration of multiple doses given as a 50mg bolus every 12 weeks in pediatric (≥2 years old) and adult patients with Alexander disease. Following 50 mg dosing in patients ≥2 years old, zilganersen was quantifiable in CSF 84 days after injection (trough). The steady state pharmacokinetics are presented as geometric mean (%CV). The steady-state CSF trough (Ctrough, CSF, ss) concentration was 1.21 ng/mL (40.8%). The steady-state maximum plasma concentration (Cmax,ss) was 908 ng/mL (74.3%), with a median time to maximum plasma concentration (Tmax,ss) of 4.03 hours (range: 1.00–23.7 hours). The steady-state trough plasma concentration (C~trough,plasma,ss~) was 0.252 ng/mL (147%), and the area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24h) was 7,716 ng·h/mL (97.4%).
No evidence of time-dependent plasma pharmacokinetics was observed between the first and sixth administration of zilganersen in patients >2 years of age.
In vitro, greater than 98% of zilganersen binds to human plasma proteins. Following intrathecal administration of zilganersen into the CSF, zilganersen distributes into the systemic circulation and tissues with the central compartment volume of 7.95 L and the peripheral compartment volume of 315 L.
The terminal elimination half-life in plasma is approximately 1 month.
Zilganersen undergoes endonuclease and exonuclease-mediated cleavage to shorter oligonucleotide metabolites; it is not a CYP substrate, and CYP450-mediated metabolism is not expected.
The primary route of elimination is likely by urinary excretion for zilganersen and its chain-shortened metabolites. The urinary excretion of unchanged zilganersen has not been characterized.
No clinically meaningful differences in the pharmacokinetics of zilganersen were observed based on age, body weight, sex, race, ethnicity, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²), or mild hepatic impairment (defined using NCI-ODWG Criteria: total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST).
Zilganersen has not been studied in patients aged ≥65 years, patients with moderate or severe renal impairment, end-stage renal disease, or moderate or severe hepatic impairment.
No clinical drug–drug interaction studies have been performed with zilganersen. In vitro, studies show that zilganersen is not a substrate or inhibitor of major drug transporters, does not interact with highly plasma protein bound medicines, and is not an inhibitor or inducer of cytochrome P450 (CYP) enzymes.
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