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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

See Long-term GIVLAARI Efficacy Data

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 upregulation of ALAS1 in the liver3

Image of liver showing increased ALAS1

Upregulation of ALAS1 leads to the accumulation of neurotoxic intermediates ALA and PBG in the liver4,5

Image of liver with icons of overproduced ALA and PBG

ALA and PBG are
released into circulation, thereby
causing neurotoxic effects4,5

Image of body with many ALA and PBG icons and hotspots in the head, torso, and arm

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

GIVLAARI targets ALAS1 mRNA for degradation in the liver1,3

Image of GIVLAARI® (givosiran) decreasing the amount of ALAS1 in the liver

ALAS1 mRNA degradation reduces the production of the neurotoxic intermediates ALA and PBG1,5

Image of liver with decreased ALAS1 and less ALA and PBG

Less ALA and PBG are released into circulation. Reductions of ALA and PBG have been associated with fewer AHP attacks1,2,5

Image of body with less ALA and PBG in the body and liver

ALA

PBG

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

Neurotoxic effects of ALA and PBG are factors associated
with AHP attacks and other disease manifestations6,7

Long-term GIVLAARI treatment reduced ALA and PBG by over 90%8

Urinary ALA levels8

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

Urinary PBG levels8

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

*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=delta-aminolevulinic acid, PBG=porphobilinogen.

Reductions through the ENVISION 6-month double-blind period1,9

  • Reductions in urinary ALA and PBG were seen with GIVLAARI 2.5 mg/kg at Day 14, the first time 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 ENVISION open-label extension (OLE) period10

  • In patients who continued treatment with GIVLAARI in the OLE period, reductions in urinary ALA and PBG were sustained through Month 36
    • 92.6% median reduction (Q1, Q3: 96.0%, 88.3%) and 95.9% median reduction (Q1, Q3: 99.2%, 90.7%) from baseline in urinary ALA and PBG, respectively
  • In patients who crossed over from placebo to GIVLAARI in the OLE period (a total of 30 months of treatment with GIVLAARI):
    • 92.0% median reduction (Q1, Q3: 94.9%, 86.9%) and 94.2% median reduction (Q1, Q3: 98.1%, 85.1%) from baseline in urinary ALA and PBG, respectively, were observed at Month 36

Elevated ALA and PBG are associated with AHP attacks6,7

NEXT: GIVLAARI Efficacy & Safety

References: 1. GIVLAARI [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc. 2. Sardh E, Harper P, Balwani M, et al. N Engl 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. Pischik E, Kauppinen R. Appl Clin Genet. 2015;8:201-214. 6. Szlendak U, Bykowska K, Lipniacka A. Adv Clin Exp Med. 2016;25(2):361-368. 7. Kuo H-C, Huang C-C, Chu C-C, et al. Eur Neurol. 2011;66(5):247-252. 8. Kuter DJ, Bonkovsky HL, Monroy S, et al. Presented at: American Society of Hematology (ASH) 2021 Annual Meeting; December 11-14, 2021. 9. Ventura P, Bonkovsky HL, Gouya L, et al. Liver Int. 2021;00:1-12. 10. 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.

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.