How GIVLAARI® (givosiran) Works

What is GIVLAARI?

GIVLAARI is a double-stranded small interfering RNA (siRNA) therapeutic specifically targeting ALAS1 mRNA, reducing ALAS1 mRNA levels and leading to reductions in urinary ALA and PBG.1

Patients with AHP have an enzyme deficiency in the heme biosynthesis pathway2

ALAS1 upregulation leads to the accumulation of neurotoxins that cause damage across the body3

Disease triggers, such as infections or certain medications, can induce ALAS1 and lead to overproduction of the neurotoxic intermediates ALA and PBG2,3

Chart depicting AHP mechanism of disease

ALA and PBG accumulate in the liver, and are further released into circulation, thereby causing neurotoxic effects3-5

Neurotoxic effects lead to acute attacks3

ALA

PBG

 ALA, delta-aminolevulinic acid; ALAS1, delta-aminolevulinic acid synthase 1; mRNA, messenger RNA; PBG, porphobilinogen.

GIVLAARI targets ALAS1 mRNA for degradation1

Specifically targeting ALAS1 mRNA for degradation reduces the production of the neurotoxic intermediates ALA and PBG 1

Chart depicting mechanism of action for GIVLAARI® (givosiran)

Less ALA and PBG are released into circulation4,6

Reductions of ALA and PBG have been associated with fewer attacks6

ALA

PBG

 ALA, delta-aminolevulinic acid; ALAS1, delta-aminolevulinic acid synthase 1; mRNA, messenger RNA; PBG, porphobilinogen.

Neurotoxic intermediates ALA and PBG are factors associated with attacks and other disease manifestations of AHP.6

Treatment with GIVLAARI resulted in robust and sustained reductions in ALA and PBG1

Reductions in urinary ALA and PBG were seen with GIVLAARI at day 141

  • 14 days after the first dose of GIVLAARI, median reductions from baseline in urinary ALA and PBG were 84% and 75%, respectively
  • 94% and 95% median reductions from baseline in urinary ALA and PBG, respectively, were seen around Month 3 and sustained with once-monthly dosing of GIVLAARI 2.5 mg/kg    
Median level of urinary ALA compared to those on placebo
Median level of urinary ALA compared to those on placebo
Median level of urinary PBG compared to those on placebo
Median level of urinary PBG compared to those on placebo

ALA, aminolevulinic acid; PBG, porphobilinogen.

References: 1. GIVLAARI [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; 2019. 2. Balwani M et al; the Porphyrias Consortium of the Rare Diseases Clinical Research Network. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. 3. Puy H et al. Porphyrias. Lancet. 2010;375(9718):924-937. 4. Bissell DM et al. Porphyria. N Engl J Med. 2017;377(9):862-872. 5. Bonkovsky HL et al. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019. doi: 10.1016/j.ymgme.2019.03.002. 6. Sardh E et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380(6):549-558. 7. Data on file. Alnylam Pharmaceuticals, Inc.

 

IMPORTANT SAFETY INFORMATION

Contraindications

GIVLAARI® (givosiran) is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.

Anaphylactic Reaction

Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.

Hepatic Toxicity

Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.

Renal Toxicity

Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.

Injection Site Reactions

Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.

Drug Interactions

Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

Adverse Reactions

The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).

INDICATION

GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP).

For additional information about GIVLAARI, please see full Prescribing Information.