GIVLAARI Solution for injection Ref.[9931] Active ingredients: Givosiran

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 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.

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 as summarized in Table 2.

Table 2. Pharmacokinetic Parameters of Givosiran and Its Active Metabolite

* Based on population PK model estimation.
^† Givosiran plasma protein binding was concentration-dependent and decreased with increasing givosiran concentrations (from 92% at 1 μg/mL to 21% at 50 μg/mL).
^‡ Based on in vitro study result.
^§ After single and multiple subcutaneous doses of givosiran 2.5 mg/kg and 5 mg/kg.

Specific Populations

No clinically meaningful differences in givosiran pharmacokinetics or pharmacodynamics (percent reduction in urinary ALA and PBG) were observed based on age (19 to 65 years), sex, race/ethnicity, mild, moderate or severe renal impairment (eGFR ≥15 to <89 mL/min/1.73m ² estimated by the Modification of Diet in Renal Disease [MDRD] formula), and mild hepatic impairment (bilirubin ≤1×ULN and AST >1×ULN, or bilirubin >1×ULN to 1.5×ULN).The effect of end-stage renal disease (eGFR <15 mL/min/1.73m ²), and moderate to severe hepatic impairment on givosiran pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

Effect of givosiran on CYP1A2 Substrates: Concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg increased caffeine (sensitive CYP1A2 substrate) AUC by 3.1-fold and C_max by 1.3-fold [see Drug Interactions (7.1)].

Effect of givosiran on CYP2D6 Substrates: Concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg increased dextromethorphan (sensitive CYP2D6 substrate) AUC by 2.4-fold and C_max by 2.0-fold [see Drug Interactions (7.1)].

Effect of givosiran on other CYP450 Substrates: Concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg increased losartan (CYP2C9 substrate) AUC by 1.1-fold with no change in C_max; increased omeprazole (sensitive CYP2C19 substrate) AUC by 1.6-fold and C_max by 1.1-fold; increased midazolam (sensitive CYP3A4 substrate) AUC by 1.5-fold and C_max by 1.2-fold. These changes in exposure were not considered clinically relevant.

In Vitro Studies

Effect of givosiran on CYP450 Enzymes: In vitro studies indicate that givosiran does not directly inhibit or induce CYP enzymes; however, because of its pharmacological effects on the hepatic heme biosynthesis pathway, givosiran has the potential to reduce the activity of CYP enzymes in the liver.

Carcinogenicity studies have not been conducted with givosiran.

Givosiran was not genotoxic in the in vitro bacterial reverse mutation (Ames) assays, an in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes or the in vivo micronucleus assay in rats.

In fertility and early embryonic development studies, givosiran administered subcutaneously once weekly at doses up to 30 mg/kg in male and female rats prior to and during mating, and continuing in females throughout organogenesis, resulted in no adverse effects on fertility or reproductive function in male or female animals.

The efficacy of GIVLAARI in patients with acute hepatic porphyria was evaluated in the ENVISION trial (NCT03338816), a randomized, double-blind, placebo-controlled, multinational study.

ENVISION enrolled 94 patients with acute hepatic porphyria (AHP) (89 patients with AIP, 2 patients with variegate porphyria [VP], 1 patient with hereditary coproporphyria [HCP], and 2 patients with no identified mutation). Eligible patients were randomized 1:1 to receive once monthly subcutaneous injections of GIVLAARI 2.5 mg/kg or placebo during the 6-month double-blind period. In this study, inclusion criteria specified a minimum of 2 porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home in the 6 months prior to study entry. Hemin use during the study was permitted for the treatment of acute porphyria attacks.

The median age of patients studied was 37.5 years (range 19 to 65 years), 89% of patients were female, and 78% were white. GIVLAARI and placebo arms were balanced with respect to historical porphyria attack rate, hemin prophylaxis prior to study entry, use of opioid medications, and patient-reported measures of pain symptoms between attacks.

Efficacy in the 6-month double-blind period was measured by the rate of porphyria attacks that required hospitalizations, urgent healthcare visit, or intravenous hemin administration at home.

Efficacy results for GIVLAARI are provided in Table 3. On average, AHP patients on GIVLAARI experienced 70% (95% CI: 60%, 80%) fewer porphyria attacks compared to placebo.

Table 3. Rate of Porphyria Attacks^* and Days of Hemin Use in Patients with AHP Over the 6-Month Double-blind Period of ENVISION:

* Attacks that require hospitalization, urgent healthcare visits, or intravenous hemin administration at home.
^† Adjusted for prior hemin prophylaxis status and historical attack rates. A ratio <1 represents a favorable outcome for GIVLAARI.
^‡ p < 0.0001
^§ p = 0.0002

GIVLAARI also resulted in a reduction in hemin use, urinary ALA, and urinary PBG.