Vutrisiran, a chemically stabilized double-stranded small interfering ribonucleic acid (siRNA) that specifically targets variant and wild-type transthyretin (TTR) messenger RNA (mRNA), is covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes.
Through a natural process called RNA interference (RNAi), vutrisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in the reduction of variant and wild-type serum TTR protein levels.
Mean serum TTR was reduced as early as Day 22, with mean near to steady state TTR reduction of 73% by Week 6. With repeat dosing of 25 mg once every 3 months, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 88%, respectively. Similar TTR reductions were observed regardless of genotype (V30M or non-V30M), prior TTR stabiliser use, weight, sex, age, or race.
Serum TTR is a carrier of retinol binding protein 4, which is the principal carrier of vitamin A in the blood. Vutrisiran decreased vitamin A levels with mean steady state peak and trough reductions of 70% and 63%, respectively.
The pharmacokinetic properties of vutrisiran were characterised by measuring the plasma and urine concentrations of vutrisiran.
Following subcutaneous administration, vutrisiran is rapidly absorbed with a time to maximum plasma concentration (tmax) of 3.0 (range: 2.0 to 6.5) hours. At the recommended dosing regimen of 25 mg once every 3 months subcutaneously, the mean (% coefficient of variation [CV]) steady state peak concentrations (Cmax), and area under the concentration time curve from 0 to 24 hours (AUC0-24) were 0.12 μg/mL (64.3), and 0.80 μg·h/mL (35.0%), respectively. There was no accumulation of vutrisiran in plasma after repeated quarterly dosing.
Vutrisiran is greater than 80% bound to plasma proteins over the concentration range observed in humans at the dose of 25 mg once every 3 months subcutaneously. Vutrisiran plasma protein binding was concentration-dependent and decreased with increasing vutrisiran concentrations (from 78% at 0.5 µg/mL to 19% at 50 µg/mL). The population estimate for the apparent central compartment volume of distribution (Vd/F) of vutrisiran in humans was 10.2 L (% Relative standard error [RSE]=5.71%). Vutrisiran distributes primarily to the liver after subcutaneous dosing.
Vutrisiran is metabolised by endo- and exo-nucleases to short nucleotide fragments of varying sizes within the liver. There were no major circulating metabolites in humans. In vitro studies indicate that vutrisiran does not undergo metabolism by CYP450 enzymes.
Following a 25 mg single subcutaneous dose, the median apparent plasma clearance was 21.4 (range: 19.8, 30.0) L/h. The median terminal elimination half-life (t1/2) of vutrisiran was 5.23 (range: 2.24, 6.36) hours. After a single subcutaneous dose of 5 to 300 mg, the mean fraction of unchanged active substance eliminated in urine ranged from 15.4 to 25.4% and the mean renal clearance ranged from 4.45 to 5.74 L/h for vutrisiran.
Following single subcutaneous doses over the 5 to 300 mg dose range, vutrisiran Cmax was shown to be dose proportional while area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) and area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast) were slightly more than dose proportional.
Population pharmacokinetic/pharmacodynamic analyses in healthy subjects and patients with hATTR amyloidosis (n=202) showed a dose-dependent relationship between predicted vutrisiran liver concentrations and reductions in serum TTR. The model-predicted median steady state peak, trough, and average TTR reductions were 88%, 86%, and 87%, respectively, confirming minimal peak-totrough variability across the 3-month dosing interval. Covariate analysis indicated similar TTR reduction in patients with mild-to-moderate renal impairment or mild hepatic impairment, as well as by sex, race, prior use of TTR stabilisers, genotype (V30M or non-V30M), age and weight.
Clinical studies did not identify significant differences in steady state pharmacokinetic parameters or TTR reduction according to gender or race.
Elderly patients In the HELIOS-A study, 46 (38%) patients treated with vutrisiran were ≥65 years old and of these 7 (5.7%) patients were ≥75 years old. There were no significant differences in steady state pharmacokinetic parameters or TTR reduction between patients <65 years old and ≥65 years old.
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) on vutrisiran exposure or TTR reduction compared to patients with normal hepatic function. Vutrisiran has not been studied in patients with moderate or severe hepatic impairment.
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73 m²) on vutrisiran exposure or TTR reduction compared to subjects with normal renal function. Vutrisiran has not been studied in patients with severe renal impairment or end-stage renal disease.
Repeated once-monthly subcutaneous administration of vutrisiran at ≥30 mg/kg in monkeys produced the expected sustained reductions of circulating TTR (up to 99%) and vitamin A (up to 89%) without any apparent toxicological findings.
Following once monthly repeated dosing for up to 6 months in rats and 9 months in monkeys, the mild and consistent non-adverse histological changes in liver (hepatocytes, Kupffer cells), kidneys (renal tubules), lymph nodes and injection sites (macrophages) reflected the principal distribution and accumulation of vutrisiran. However, no toxicities were identified at up to more than 1000- and 3000- fold higher plasma AUC, when normalised to quarterly dosing and compared to the anticipated exposure at the maximum recommended human dose [MRHD].
Vutrisiran did not exert any genotoxic potential in vitro and in vivo. Carcinogenicity studies have not been completed.
Vutrisiran is not pharmacologically active in rats and rabbits, which limits the predictivity of these investigations. Nevertheless, a single dose of a rat-specific orthologue of vutrisiran did not impact on fertility and early embryonic development in a combined study in rats.
Weekly subcutaneous administrations of vutrisiran did not affect fertility and early embryonic development at more than 300-times the normalised MRHD In an embryo-foetal study with daily subcutaneous vutrisiran administration in pregnant rats, adverse effects on maternal body weight, food consumption, increased premature delivery and post-implantation loss were observed with a maternal NOAEL of 10 mg/kg/day that was more than 300-times the normalised MRHD of 0.005 mg/kg/day. Based on an adverse reduction in foetal body weights and increased skeletal variations at ≥10 mg/kg/day, the foetal NOAEL of vutrisiran was 3 mg/kg/day which is 97-times the normalised MRHD.
In an embryo-foetal development study in pregnant rabbits, no adverse effects on embryo-foetal development were observed at ≤30 mg/kg/day vutrisiran, which is more than 1900-times the normalised MRHD.
In a prenatal-postnatal development study, subcutaneous vutrisiran administration on every 6th day had no effect on growth and development of the offspring with a NOAEL of 20 mg/kg, which was more than 90-times the normalised MRHD.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
