Chemical formula: C₄₁₂H₅₂₀N₁₄₈O₂₉₀P₄₀
Patisiran is a double-stranded small interfering ribonucleic acid (siRNA) that specifically targets a genetically conserved sequence in the 3' untranslated region of all mutant and wild-type TTR mRNA. Patisiran is formulated as lipid nanoparticles to deliver the siRNA to hepatocytes, the primary source of TTR protein in the circulation. Through a natural process called RNA interference (RNAi), patisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in a reduction of serum TTR protein.
Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose with 300 micrograms per kg patisiran. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. Serum TTR reduction was maintained with continued dosing.
Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months.
The pharmacokinetic properties of patisiran were characterised by measuring the plasma concentrations of patisiran and the lipid components DLin-MC3-DMA and PEG2000-C-DMG.
Greater than 95% of patisiran in the circulation is associated with lipid nanoparticles. At the dose regimen of 300 micrograms per kg every 3 weeks, steady state was reached by 24 weeks of treatment. The estimated patisiran mean ± SD steady-state peak concentration (Cmax), trough concentration (Ctrough), and area under the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg·h/mL, respectively. The accumulation of AUCτ was 3.2-fold at steady-state compared to the first dose.
The estimated DLin-MC3-DMA mean ± SD steady-state Cmax, Ctrough and AUCτ were 40.2 ± 11.5 µg/mL, 1.75 ± 0.698 µg/mL, and 1403 ± 105 µg·h/mL, respectively. The accumulation of AUCτ was 1.76-fold at steady-state compared to the first dose.
The estimated PEG2000-C-DMG mean ± SD steady-state Cmax, Ctrough and AUCτ were 4.22 ± 1.22 µg/mL, 0.0236 ± 0.0093 µg/mL, and 145 ± 64.7 µg·h/mL, respectively. There was no accumulation of AUCτ at steady-state compared to the first dose.
Plasma protein binding of patisiran is low, with ≤2.1% binding observed in vitro with human serum albumin and human α1-acid glycoprotein. At the dose regimen of 300 micrograms per kg every 3 weeks, the mean ± SD steady-state volume of distribution (Vss) of patisiran, DLin-MC3-DMA and PEG2000-C-DMG was 0.26 ± 0.20 L/kg, 0.47 ± 0.24 L/kg and 0.13 ± 0.05 L/kg, respectively.
Patisiran is metabolized by nucleases to nucleotides of various lengths. DLin-MC3-DMA is primarily metabolised to 4-dimethylaminobutyric acid (DMBA) by hydrolysis. There is little to no metabolism of PEG2000-C-DMG.
At the dose regimen of 300 micrograms per kg every 3 weeks, mean ± SD steady state plasma clearance (CLss) of patisiran was 3.0 ± 2.5 mL/h/kg. The mean ± SD terminal elimination half-life (t1/2β) of patisiran was 3.2 ± 1.8 days. Less than 1% of patisiran in the administered dose was recovered intact in urine.
The estimated DLin-MC3-DMA mean ± SD steady-state CLss was 2.1 ± 0.8 mL/h/kg. Approximately 5.5% of DLin-MC3-DMA was recovered after 96 hours as its metabolite (DMBA) in urine.
The estimated PEG2000-C-DMG mean ± SD steady-state CLss was 2.1 ± 0.6 mL/h/kg. In rats and monkeys, PEG2000-C-DMG is eliminated unchanged in the bile. PEG2000-C-DMG excretion in humans was not measured.
Exposure to patisiran and the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) increased proportionally with increase in dose over the range evaluated in clinical studies (10 to 500 micrograms per kg). Patisiran and the lipid components exhibit linear and time-independent pharmacokinetics with chronic dosing at the dose regimen of 300 micrograms per kg every 3 weeks.
Increasing the dose of patisiran resulted in greater TTR reduction, with maximal reductions plateauing at patisiran exposures obtained with 300 micrograms per kg every 3 weeks dosing.
The components of patisiran are not inhibitors or inducers of cytochrome P450 enzymes or transporters, except for CYP2B6. Patisiran is not a substrate of cytochrome P450 enzymes.
Clinical studies did not identify significant differences in steady state pharmacokinetic parameters or TTR reduction according to gender or race (non-Caucasian vs. Caucasian).
No data are available for patients weighing ≥110 kg.
In the placebo-controlled study, 62 (41.9%) patients treated with patisiran were ≥65 years of age and 9 (6.1%) patients were ≥75 years of age. There were no significant differences in steady state pharmacokinetic parameters or TTR reduction between patients <65 years of age and ≥65 years of age.
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN and any AST) on patisiran exposure or TTR reduction compared to patients with normal hepatic function. Patisiran has not been studied in patients with moderate or severe hepatic impairment.
In a clinical study in hATTR amyloidosis patients who had undergone prior liver transplant, steady state pharmacokinetic parameters and TTR reduction were comparable to those observed in patients without a liver transplant.
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73m²) on patisiran exposure or TTR reduction compared to subjects with normal renal function. Patisiran has not been studied in patients with severe renal impairment or end-stage renal disease.
Liver and spleen were the primary target organs of toxicity in both rats and monkeys. Intravenous administration of patisiran led to increases in serum liver markers (ALT, AST, ALP, and/or total bilirubin) and histopathology findings in the liver (hepatocellular/single cell necrosis, inflammation, pigment deposition, and/or monocytic infiltration) at doses >100 micrograms per kg every 4 weeks and >1.0 mg/kg every 3 weeks in rats and monkeys, respectively. In spleen, lymphoid atrophy/necrosis and histiocytosis in the white pulp was observed in rats and hypocellularity of the red pulp was observed in monkeys.
In general, all findings observed at the end of dosing in the rat and monkey toxicity studies had either a full recovery or were observed with reduced severity at the end of the 60-90 day recovery period, indicating at least partial reversibility.
Patisiran did not exhibit a genotoxic potential in vitro and in vivo and was not carcinogenic in transgenic rasH2 mice.
In rats, while there were parental decreases in serum TTR (≥90%), thyroxine (≥66%) and vitamin A (≥75%) levels using a rat specific surrogate to patisiran, no effects were found on male or female fertility, embryo-foetal development, or pre-/post-natal development.
In rabbits, patisiran generated spontaneous abortions, reduced embryo-foetal survival, and reduced foetal body weights at maternally toxic doses ≥1 mg/kg (HED 3.2 times the RHD). As patisiran is not pharmacologically active in rabbits, these effects are not due to reductions in TTR, thyroxine or vitamin A.
Intravenous administration of patisiran had no effect on male reproductive assessments in sexually mature cynomolgus monkeys.
In lactating rats, patisiran was not present in milk, although small amounts of the lipid components DLin-MC3-DMA and PEG2000-C-DMG were present in milk (up to 7% of concomitant maternal plasma concentrations). There were no adverse effects on the pups
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