GIVLAARI (givosiran, siRNA) for treatment of Acute Hepatic Porphyria

GIVLAARI (givosiran) injection, for subcutaneous use

GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA (siRNA), covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable the delivery of the siRNA to hepatocytes.

CLINICAL PHARMACOLOGY

Mechanism of Action 
Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP. 

Pharmacodynamics The pharmacodynamic effects of GIVLAARI were evaluated in chronic high excreters treated with 0.035 to 2.5 mg/kg single dose and AHP patients treated with 2.5 to 5 mg/kg once monthly and 2.5 to 5 mg/kg once Reference ID: 4522564 quarterly dose via subcutaneous injection. Dose-dependent reduction in urinary ALAS1 mRNA, ALA and PBG levels was observed over the 0.035 to 5 mg/kg dose range (0.14 to 2-fold the approved recommended dosage). Median reductions from baseline in urinary ALA and PBG of 83.7% and 75.1%, respectively, were observed 14 days after the first dose of GIVLAARI 2.5 mg/kg once monthly in AHP patients. 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 thereafter with repeated once monthly dosing.

Cardiac Electrophysiology 
The effect of GIVLAARI on the QTc interval was evaluated in a double-blind, placebo-controlled study and the open-label extension in 94 patients. No large mean increase in QTc (i.e. >20 ms) was detected at the 2.5 mg/kg once monthly dose level. A dedicated thorough QT study has not been conducted with GIVLAARI. 

Pharmacokinetics
The pharmacokinetics of givosiran and its active metabolite [AS(N-1)3′givosiran] were evaluated following single and multiple dosing in chronic high excreter subjects and AHP patients (see Prescribing information for details)


Initial U.S. Approval: 2019

INDICATIONS AND USAGE
GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA indicated for the treatment of adults with acute hepatic porphyria (AHP).

DOSAGE AND ADMINISTRATION
The recommended dose of GIVLAARI is 2.5 mg/kg once monthly by subcutaneous injection. 

DOSAGE FORMS AND STRENGTHS 
Injection: 189 mg/mL in a single-dose vial. 

CONTRAINDICATIONS
Severe hypersensitivity to givosiran. 

WARNINGS AND PRECAUTIONS
  • Anaphylactic Reaction: Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms. If anaphylaxis occurs, discontinue GIVLAARI and administer appropriate medical treatment. 
  • Hepatic Toxicity: Measure liver function at baseline and periodically during treatment with GIVLAARI. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations.
  • Renal Toxicity: Monitor renal function during treatment with GIVLAARI as clinically indicated.
  • Injection Site Reactions: May occur, including recall reactions. Monitor for reactions and manage clinically as needed.

ADVERSE REACTIONS
The most common adverse reactions (≥20% of patients) included nausea and injection site reactions. 

DRUG INTERACTIONS
Sensitive CYP1A2 and CYP2D6 Substrates: Avoid concomitant use with CYP1A2 and CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. 



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