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

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

Neurotoxic effects can lead to acute attacks4

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

Less ALA and PBG are released into circulation1

Reductions of ALA and PBG have been associated with fewer attacks1

ALA
PBG
ALA, delta-aminolevulinic acid; ALAS1, delta-aminolevulinic acid synthase 1; mRNA, messenger RNA; PBG, porphobilinogen.
with AHP attacks and other disease manifestations.1
Treatment with GIVLAARI resulted in rapid and sustained reductions in ALA and PBG7
Urinary ALA levels7
Urinary PBG levels7
*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)
sustained reductions in ALA and PBG through Month 24.7
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.