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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.1,2

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 acute hepatic porphyria (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

PBG

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

Mechanism of action for GIVLAARI® (givosiran)

Less ALA and PBG are released into circulation1

Neuron with less ALA and PBG

Reductions of ALA and PBG have been associated with fewer attacks1

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

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 AHP attacks and other disease manifestations.1

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

Urinary ALA levels7

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

Urinary PBG levels7

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

*The determination of the ULN for ALA (1.5 mmol/mol of creatinine) was based on samples obtained from 150 healthy persons.

†Data for GIVLAARI 1.25 mg/kg and 2.5 mg/kg in the OLE period were pooled.

‡The determination of the ULN for PBG (0.14 mmol/mol of creatinine) was based on samples obtained from 150 healthy persons.

DB=double blind; OLE=open-label extension, ALA=aminolaevulinic acid, PBG=porphobilinogen.

Reductions through the ENVISION 6-month double-blind period1

  • 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) period1,7-9

  • In patients who continued treatment with GIVLAARI in the OLE period, reductions in urinary ALA and PBG were sustained through month 24
    • 89.5% median reduction (Q1, Q3: 94.0%, 80.4%) and 91.1% median reduction (Q1, Q3: 96.7%, 75.1%) from baseline in urinary ALA and PBG, respectively
  • There was an 89.3% median reduction (Q1, Q3: 94.2%, 81.3%) and 93.5% median reduction (Q1, Q3: 96.4%, 66.5%) from baseline in urinary ALA and PBG, respectively at month 24 in patients who crossed over from placebo to GIVLAARI in the OLE period (for a total of 18 months of treatment with GIVLAARI)
Continued treatment with GIVLAARI resulted in
sustained reductions in ALA and PBG through Month 24.7
NEXT: GIVLAARI Efficacy & Safety

References: 1. GIVLAARI [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc. 2. Sardh E, Harper P, Balwani M, et al. N Eng J Med. 2019;380(6):549-558. 3. Balwani M, Wang B, Anderson KE, et al; Porphyrias Consortium of the Rare Diseases Clinical Research Network. Hepatology. 2017;66:1314-1322. 4. Puy H, Gouya L, Deybach JC. Lancet. 2010;375:924-937. 5. Bissell DM, Anderson KE, Bonkovsky HL. N Engl J Med. 2017;377:862-872. 6. Bonkovsky HL, Dixon N, Rudnick S. Mol Genet Metab. 2019;128:213-218. 7. Ventura P, Bonkovsky HL, Gouya L, et al. Liver Int. 2021;00:1-12. 8. Balwani M, Sardh E, Ventura P, et al; ENVISION Investigators. N Engl J Med. 2020;382(24):2289-2301. 9. Data on file, Alnylam Pharmaceuticals, Inc; November 2021.
 

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.

Blood Homocysteine Increased

Increases in blood homocysteine levels have occurred in patients receiving GIVLAARI. In the ENVISION study, during the open label extension, adverse reactions of blood homocysteine increased were reported in 15 of 93 (16%) patients treated with GIVLAARI. Measure blood homocysteine levels prior to initiating treatment and monitor for changes during treatment with GIVLAARI. In patients with elevated blood homocysteine levels, assess folate, vitamins B12 and B6. Consider treatment with a supplement containing vitamin B6 (as monotherapy or a multivitamin preparation).

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.