Givosiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of aminolevulinic acid synthase 1 (ALAS1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference, resulting in a reduction of induced liver ALAS1 mRNA towards normal. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), the key causal factors of attacks and other disease manifestations of AHP.
In the placebo-controlled study in patients with AHP receiving givosiran 2.5 mg/kg once monthly (ENVISION), median reductions from baseline in urinary ALA and PBG of 83.7% and 75.1%, respectively, were observed 14 days after the first dose. Maximal reductions in ALA and PBG levels were achieved around month 3 with median reductions from baseline of 93.8% for ALA and 94.5% for PBG, and were sustained with repeated once monthly dosing.
Observed data and modelling demonstrated that once monthly dosing with 2.5 mg/kg givosiran resulted in a greater reduction and less fluctuation in ALA levels compared with doses less than 2.5 mg/kg or dosing once every 3 months.
Following subcutaneous administration, givosiran is rapidly absorbed with a time to maximum plasma concentration (tmax) of 0.5 to 2 hours. At the 2.5 mg/kg once monthly dose, the steady-state peak plasma concentrations of givosiran (Cmax) and area under the curve from time of dosing up to 24 hours after dosing (AUC24) were 321 ± 163 ng/mL and 4130 ± 1780 ng·h/mL, respectively, and corresponding values for the active metabolite were 123 ± 79.0 ng/mL and 1930 ± 1210 ng·h/mL, respectively.
Givosiran is greater than 90% bound to plasma proteins over the concentration range observed in humans at the 2.5 mg/kg once monthly dose. The population estimate for the steady state apparent volume of distribution (Vd/F) for givosiran and for the active metabolite was 10.4 L. Givosiran and its active metabolite distribute primarily to the liver after subcutaneous dosing.
Givosiran is metabolised by nucleases to oligonucleotides of shorter lengths. Active metabolite AS(N-1)3' givosiran (with equal potency as that of givosiran) was a major metabolite in plasma with 45 % exposure (AUC0-24) relative to givosiran at the 2.5 mg/kg once monthly dose. In vitro studies indicate that givosiran does not undergo metabolism by CYP450 enzymes.
Givosiran and its active metabolite are eliminated from plasma primarily by metabolism with an estimated terminal half-life of approximately 5 hours. The population estimate for apparent plasma clearance was 36.6 L/h for givosiran and 23.4 L/h for AS(N-1)3' givosiran. After subcutaneous dosing, up to 14 % and 13 % of the administered givosiran dose was recovered in urine as givosiran and its active metabolite, respectively, over 24 hours. The renal clearance ranged from 1.22 to 9.19 L/h for givosiran and 1.40 to 12.34 L/h for the active metabolite.
Givosiran and its active metabolite exhibited linear pharmacokinetics in plasma over the 0.35 to 2.5 mg/kg dose range. At doses greater than 2.5 mg/kg, plasma exposure increased slightly greater than dose-proportionally. Givosiran exhibited time-independent pharmacokinetics with chronic dosing at the recommended dose regimen of 2.5 mg/kg once monthly. There was no accumulation of givosiran or the active metabolite in plasma after repeated once monthly dosing.
Plasma concentrations of givosiran are not reflective of the extent or duration of pharmacodynamic activity. Since givosiran is a liver targeted therapy, concentrations in plasma decline rapidly due to uptake by the liver. In the liver, givosiran exhibits a long half-life leading to extended duration of pharmacodynamic effect maintained over the monthly dosing interval.
No studies have been conducted in patients aged >65 years. Age was not a significant covariate in the pharmacokinetics of givosiran.
In clinical studies there was no difference in the pharmacokinetics or pharmacodynamics of givosiran based on gender or race.
Adult patients with mild hepatic impairment (bilirubin ≤1×ULN and AST >1×ULN, or bilirubin >1×ULN to 1.5×ULN) had comparable plasma exposure of givosiran and its active metabolite and similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients with normal hepatic function. No studies have been conducted in patients with moderate or severe hepatic impairment.
Adult patients with mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²), moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73 m²) or severe renal impairment (eGFR ≥15 to <30 mL/min/1.73 m²) had comparable plasma exposure of givosiran and its active metabolite and similar pharmacodynamics (percent reduction in urinary ALA and PBG) as patients with normal renal function (eGFR ≥ to 90 mL/min/1.73 m²). No studies have been conducted in patients with end-stage renal disease or patients with dialysis.
Available data suggest that body weight but not age was a significant covariate in the pharmacokinetics of givosiran. At the 2.5 mg/kg dose, a similar exposure is expected in adolescents aged 12 years or older, as in adults with the same body weight.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development. In the repeat-dose toxicity studies conducted in rats and monkeys, the rat was identified as the most sensitive species to givosiran-related effects, with the liver being identified as the primary target organ of toxicity in both the rat and monkey. No adverse findings were associated with chronic, weekly administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 26.3-fold, respectively when compared to exposures achieved in patients receiving the maximum recommended human dose.
Givosiran did not exhibit a genotoxic potential in vitro and in vivo.
Animal studies have not been conducted to evaluate the carcinogenic potential of givosiran.
Embryo-foetal development studies have been performed in rats and rabbits during organogenesis. Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations. These findings are considered an indirect effect, secondary to maternal toxicity. No adverse developmental effects were observed in rats administered the maternally toxic dose of approximately 9 times the normalised maximum recommended human dose.
In a postnatal development study in rats, there was no effect on growth and development of the offspring.
No adverse effects were observed in the fertility of male and female rats when administered with givosiran.
© 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.
