ONPATTRO (patisiran) small interfering RNA for Treatment of Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

ONPATTRO (patisiran)  small interfering RNA for Treatment of Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

ONPATTRO contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid complex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3’ untranslated region (3’UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA). The molecular formula of patisiran sodium is C412 H480 N148 Na40 O290 P40 and the molecular weight is 14304 Da. 

Mechanism of Action 
Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. 

The pharmacodynamic effects of ONPATTRO were evaluated in hATTR amyloidosis patients treated with 0.3 mg/kg ONPATTRO via intravenous infusion once every 3 weeks. Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. The mean maximum reduction of serum TTR over 18 months was 88%. 

Following a single intravenous administration, systemic exposure to patisiran increases in a linear and dose-proportional manner over the range of 0.01 to 0.5 mg/kg. Greater than 95% of patisiran in the circulation is associated with the lipid complex. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks of treatment. The estimated mean ± SD steady state peak concentrations (Cmax), trough concentrations (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. In the placebo-controlled study, interpatient variability in patisiran exposure did not result in differences in clinical efficacy (mNIS+7 change from baseline) or safety (adverse events, serious adverse events).

Plasma protein binding of ONPATTRO is low, with ≤2.1% binding observed in vitro with human serum albumin and human α1-acid glycoprotein. ONPATTRO distributes primarily to the liver. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, the mean ± SD steady state volume of distribution of patisiran (Vss) was 0.26 ± 0.20 L/kg.

The terminal elimination half-life (mean ± SD) of patisiran is 3.2 ± 1.8 days. Patisiran is mainly cleared through metabolism, and the total body clearance (mean ± SD) at steady state (CLss) is 3.0 ± 2.5 mL/h/kg. 

Patisiran is metabolized by nucleases to nucleotides of various lengths. 

Less than 1% of the administered dose of patisiran is excreted unchanged into urine. 

Specific Populations 
Age, race (non-Caucasian vs. Caucasian), and sex had no impact on the steady state pharmacokinetics of patisiran or TTR reduction. 
Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73m2 ) or mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN) on patisiran exposure or TTR reduction. 

ONPATTRO has not been studied in patients with severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver transplant.

Drug Interaction Studies 
Patisiran is not a substrate of cytochrome P450 enzymes. In a population pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not impact the pharmacokinetic parameters of patisiran. ONPATTRO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes.

Initial U.S. Approval: 2018 

ONPATTRO contains a transthyretin-directed small interfering RNA and is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

  • For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg 
  • Premedicate with a corticosteroid, acetaminophen, and antihistamines 
  • Filter and dilute prior to administration
  • Infuse over approximately 80 minutes 

Lipid Complex Injection: 10 mg/5 mL (2 mg/mL) in a single-dose vial



Infusion-related reactions:
Monitor for signs and symptoms during infusion. Slow or interrupt the infusion if clinically indicated. Discontinue the infusion if a serious or life-threatening infusion-related reaction occurs.
Reduced serum vitamin A levels and recommended supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occurs.

The most frequently reported adverse reactions (that occurred in at least 10% of ONPATTRO-treated patients and at least 3% more frequently than on placebo) were upper respiratory tract infections and infusion-related reactions