Plozasiran is a small interfering RNA (siRNA, double-stranded oligonucleotide) conjugated with N-acetylgalactosamine to facilitate delivery to and uptake by hepatocytes. In hepatocytes, plozasiran selectively degrades the mRNA for apolipoprotein C3 (APOC3) through the RNA interference mechanism resulting in reduced levels of hepatic and serum APOC3 protein. This, in turn, enhances the activity of lipoprotein lipase and hepatocyte uptake of TG-rich lipoprotein remnants leading to decreases in serum TG.
In the PALISADE study, 25 mg plozasiran administered every 3 months in patients with FCS decreased APOC3, TG, non-high density lipoprotein cholesterol (non-HDL-C), and very low-density lipoprotein cholesterol (VLDL-C) and increased HDL-C and LDL-C. LDL-C levels remained within the normal range for most patients. The median reductions in fasting serum APOC3 protein and TG at month 1 were 95% and 85%, respectively, suggesting pharmacodynamic steady-state is achieved following the first dose.
PALISADE is a randomised, double-blind, placebo-controlled clinical study in 75 adult patients with FCS maintained on a low-fat diet.
Doses of 100 mg plozasiran (4 times the recommended dose) did not prolong the QT interval to any clinically relevant extent.
Following a single subcutaneous injection of 25 mg plozasiran, the peak plasma concentration (Cmax) was 68.5 ng/mL. The median time to reach Cmax (Tmax) was 6 hours.
Plozasiran has not been administered intravenously in any clinical studies, therefore, absolute bioavailability data in humans are not available. Following subcutaneous administration in cynomolgus monkeys, the absolute bioavailability of plozasiran was estimated to be 40%.
Following repeated subcutaneous injections of 25 mg plozasiran, it is distributed in plasma and extracellular body water with apparent volume of distribution (Vz/F) of 146 L in the terminal-phase of elimination. Once in systemic circulation, plozasiran is primarily distributed to the liver. In plasma, plozasiran has an unbound fraction of 22%.
In vitro studies suggest that plozasiran is not a substrate, inhibitor, or inducer of transporters. Therefore, plozasiran is not expected to cause or be affected by interactions mediated through transporters.
Plozasiran is primarily metabolised by nucleases in the liver to shorter oligonucleotides of varying lengths. In vitro studies suggest that plozasiran is not a substrate of cytochrome P450 (CYP450) enzymes.
In vitro studies suggest that plozasiran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Therefore, plozasiran is not expected to cause or be affected by interactions mediated through CYP450 enzymes.
The terminal elimination half-life of plozasiran in plasma is approximately 3–4 hours. The mean apparent systemic clearance is 33.8 L/hour. Approximately 16–19% of plozasiran dose is excreted in the urine.
Plozasiran exhibited time-invariant pharmacokinetics following repeated subcutaneous injections. Following multiple dose administrations, plasma levels of plozasiran (Cmax, AUC0-t and AUC0-inf) increased proportionally with dose within the dose range of 10–50 mg.
Plozasiran is active inside hepatocytes with prolonged pharmacodynamic activity that is disconnected from its pharmacokinetic profile in the plasma compartment. The long duration of action is beyond the plasma elimination half-life of 3–4 hours. Pharmacodynamic response is likely saturated at the recommended dose of 25 mg plozasiran every 3 months.
In the PALISADE study, none of the 50 FCS patients treated with plozasiran over a period of 12 months developed treatment-induced or treatment-boosted anti-drug antibodies (ADA). There was no evidence to indicate that plozasiran pharmacokinetics changed over time following multiple administrations of plozasiran.
No clinically significant differences in plozasiran pharmacokinetics based on age were found in a population pharmacokinetic analysis conducted with data from adult healthy subjects and patients (N=146); age 65–74 years (N=16); age 75–85 years (N=4).
No clinically significant differences in plozasiran pharmacokinetics based on mild (eGFR ≥60 to ˂90 mL/min) or moderate (eGFR ≥30 to ˂60 mL/min) renal impairment were found in a population pharmacokinetic analysis that included data from 23 and 4 patients with mild and moderate degrees of renal impairment, respectively. Plozasiran has not been studied in patients with severe renal impairment or end-stage renal disease (eGFR ˂30 mL/min).
No clinically significant differences in plozasiran pharmacokinetics were found in a population pharmacokinetic analysis from 4 patients with elevation of AST > ULN and total bilirubin ≤ ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST. Plozasiran has not been studied in patients with moderate or severe hepatic impairment.
Plozasiran plasma exposures (Cmax and AUC) are typically lower in patients with higher body weight or BMI without reduced treatment efficacy, and therefore no dose adjustment is recommended for heavier patients.
No clinically significant differences in plozasiran pharmacokinetics based on gender and race or ethnicity were found in a population pharmacokinetic analysis that included data from 65 (44.5%) females and 81 (55.5%) males with diverse race or ethnicity (67.1% White, 11.0% Black, 9.6% Asian, 2.1% Native Hawaiian or Pacific Islander, and 10.3% multiracial or unknown).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
In a pre- and post-natal development study, there was an increase in the number of stillborn pups and a subsequent reduction in live birth index at the high dose, with a body surface area (BSA) adjusted safety margin of 3.1- and 31-fold at the preweaning and maternal/postnatal no observed adverse effect level (NOAEL).
There is no information on the excretion of plozasiran or its metabolites in animal milk.
In a 2-year rat carcinogenicity study, benign hepatocellular adenomas and a low incidence of carcinomas were noted at the high dose. Safety margins at the NOAEL are 10- and 16-fold based on BSA, and 60- and 53-fold based on AUC for males and females, respectively. Although the relevance for humans is unknown, the risk is likely low due to the high safety margins.
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