How GIVLAARI® (givosiran) Works


GIVLAARI is a double-stranded small interfering RNA (siRNA) therapeutic specifically targeting ALAS1 mRNA, reducing ALAS1 mRNA levels and leading to reductions in urinary neurotoxic intermediates ALA and PBG.1,2

Watch how GIVLAARI works

See how GIVLAARI targets ALAS1 mRNA for degradation, leading to a reduction in levels of ALA and PBG.1,2

Patients with AHP have an enzyme deficiency in the heme biosynthesis pathway3

ALAS1 upregulation leads to the accumulation of neurotoxins that cause damage across the body4

Disease triggers, such as infections or certain medications, can induce ALAS1 and lead to overproduction of the neurotoxic intermediates ALA and PBG3,4

Icon showing induced ALAS1

ALA and PBG accumulate in the liver, and are further released into circulation, thereby causing neurotoxic effects4-6

Neuron with overproduced ALA and PBG

Neurotoxic effects can lead to acute attacks4

Neurotoxic effects lead to acute attacks



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

GIVLAARI specifically targets ALAS1, key to the pathophysiology of AHP1

Specifically targeting ALAS1 mRNA for degradation reduces the production of the neurotoxic intermediates ALA and PBG1,2

Mechanism of action for GIVLAARI® (givosiran)

Less ALA and PBG are released into circulation2,5

Neuron with less ALA and PBG

Reductions of ALA and PBG have been associated with fewer attacks2

Reductions of ALA and PBG have been associated with fewer AHP attacks



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

Neurotoxic intermediates ALA and PBG are factors associated
with AHP attacks and other disease manifestations.1,2

Treatment with GIVLAARI resulted in rapid and sustained reductions in ALA and PBG7,8

Urinary ALA levels7,8

Median level of urinary ALA of patients on GIVLAARI® (givosiran) compared to those on placebo through OLE period

Urinary PBG levels7,8

Median level of urinary PBG of patients on GIVLAARI® (givosiran) compared to those on placebo through OLE period

ALA, aminolevulinic acid; PBG, porphobilinogen.

Reductions through the ENVISION 6-month double blind period1,8

  • Reductions in urinary ALA and PBG were seen with GIVLAARI 2.5 mg/kg at Day 14, the first point measured
    • 14 days after the first dose of GIVLAARI, median reductions from baseline in urinary ALA and PBG were 84% and 75%, respectively
  • Maximal reductions in ALA and PBG levels were achieved around Month 3 with GIVLAARI 2.5 mg/kg, with median reductions from baseline of 94% for ALA  and 95% for PBG, and were sustained thereafter with repeated once-monthly dosing

Reductions in the ongoing ENVISION open-label extension (OLE) period7,8

  • In the first 6 months of the OLE period, 56 patients received GIVLAARI 2.5 mg/kg once monthly and 37 patients received GIVLAARI 1.25 mg/kg once monthly*
  • All endpoints were considered exploratory in the OLE period
  • Patients who continued treatment with GIVLAARI in the OLE period had sustained reductions of urinary ALA and PBG (86% and 88% median reductions from baseline, respectively) through month 18
  • In patients who crossed over from placebo to GIVLAARI in the OLE period (a total of 12 months of treatment with GIVLAARI), there was an 89% median reduction in ALA and an 86% median reduction in PBG from baseline at month 18

Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg have been pooled.8
Protocol amendment increased the dose for all patients to 2.5 mg/kg once monthly.7

Continued treatment with GIVLAARI resulted in
sustained reductions in ALA and PBG through Month 18.7

References: 1. GIVLAARI [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc. 2. Sardh E, Harper P, Balwani M, et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Eng J Med. 2019;380(6):549-558. 3. Balwani M, Wang B, Anderson K, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017; 66(4):1314-1322. 4. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924-937. 5. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377(9):862-872. 6. Bonkovsky HL, N Dixon, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019;128(3):213-218. 7. Kuter DJ, Keel S, Parker C, et al. Eighteen-month interim analysis of efficacy and safety of givosiran, an RNAi therapeutic for acute hepatic porphyria, in the ENVISION open-label extension. Presented at: American Society of Hematology (ASH) Congress; December 5-8, 2020; virtual. 8. Data on file, 2021. Alnylam Pharmaceuticals, Inc.




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%).


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

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