Plozasiran

Plozasiran is a siRNA conjugated with GalNAc that degrades the apoC-III mRNA through the RNA interference mechanism resulting in reduced levels of hepatic and serum apoC-III protein. Reduction of apoC-III protein leads to increased clearance of serum triglycerides.

In Trial 1, following the recommended dose of 25 mg administered every 3 months in patients with FCS, plozasiran reduced median fasting serum apoC-III protein. The placebo-corrected median percent change in fasting serum apoC-III protein from baseline was -90% at 1 month, -93% at 3 months, -82% at 6 months, -91% at 10 months, and -87% at 12 months.

Cardiac Electrophysiology:

At a dose 4 times the recommended dose of 25 mg administered every 3 months, clinically significant QTc interval prolongation was not observed.

Plozasiran exhibited linear and time-invariant pharmacokinetics following subcutaneous injections within the dose range of 10 mg to 100 mg. The following pharmacokinetic parameters were observed in healthy adults after receiving a 25 mg dose of plozasiran.

Absorption

Plozasiran peak plasma concentration (C_max) is 68.5 ng/mL. The median time to reach C_max (T_max) is 6 hours.

Distribution

Plozasiran is 78% protein bound in vitro at the clinically relevant plasma concentrations. Following subcutaneous multiple administration of 25 mg plozasiran, the apparent volume of distribution is approximately 146 L. Plozasiran is distributed in plasma and extracellular body water before its uptake by hepatocytes to decrease apoC-III mRNA expression and reduce serum triglycerides.

Elimination

The terminal elimination half-life of plozasiran in plasma is approximately 3 to 4 hours. The mean apparent systemic clearance is 33.8 L/hour.

Metabolism

Plozasiran is primarily metabolized by nucleases to shorter oligonucleotides of varying lengths.

Excretion

Approximately 16 to 19% of plozasiran dose is excreted in urine.

Specific Populations

No clinically significant differences in plozasiran pharmacokinetics based on age, sex, race, mild and moderate renal impairment (eGFR ≥30 to <90 mL/min), or mild hepatic impairment (total bilirubin ≤1 times ULN and AST >1 times ULN, or total bilirubin >1.0 to 1.5 times ULN and any AST) were found in the population pharmacokinetic analysis. The impact of severe renal impairment, end-stage renal impairment, or moderate to severe hepatic impairment is not known.

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

CYP450 Enzymes:

Plozasiran is not a substrate, inhibitor, or inducer of CYP450 enzymes at clinically relevant concentrations.

Transporter Systems:

Plozasiran is not a substrate or an inhibitor of P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.