Accession Number
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides

Givosiran is a small interfering RNA (siRNA) directed towards 5-aminolevulinic acid synthase, a critical enzyme in the heme biosynthesis pathway.5 It is manufactured by Alnylam Pharmaceuticals and was first approved for use in the United States in November 2019 for the treatment of adults with acute hepatic porphyria, a genetic disorder in which the overproduction of toxic heme intermediates leads to neuro-, nephro-, and gastrotoxicity.5 Givosiran represents an important step forward in the treatment of acute hepatic porphyria as it is the first approved pharmacotherapy for the prevention of acute attacks - previous strategies involved non-therapeutic measures (e.g. trigger avoidance), intravenous hemin for the treatment of attacks, and liver transplantation in refractory cases.3 Givosiran is the second-ever FDA-approved member of the siRNA drug class (the first being patisiran), a new class of drugs promising an important and exciting step forward in the treatment of genetic disorders.

  • Givosiran
External IDs
ALN-AS1 / WHO 10280
Product Ingredients
IngredientUNIICASInChI Key
Givosiran sodium5XE21E41RTNot AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GivlaariInjection, solution189 mg/1mLSubcutaneousAlnylam Pharmaceuticals, Inc.2019-12-12Not applicableUs
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  • Product Code
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CAS number



Givosiran is indicated for the treatment of adults with acute hepatic porphyria.5

Associated Conditions

Givosiran decreases the rate at which toxic byproducts of heme synthesis are produced in the livers of patients with acute hepatic porphyria, thus preventing their accumulation and associated neuro-, nephro-, and gastrotoxicity.5,2 As givosiran works at the transcriptional level, it has a long duration of action and can be administered subcutaneously on a monthly basis. Although givosiran appears to be relatively well-tolerated, hepatic and renal toxicity were noted during clinical trials. Patients receiving therapy with givosiran should undergo routine laboratory monitoring of liver and kidney function.5

Mechanism of action

Acute hepatic porphyrias are a class of genetic disorders involving deficiencies in the pathway responsible for heme synthesis in liver hepatocytes.2 The rate-limiting step in heme synthesis is the first enzyme in the pathway, 5-aminolevulinic acid synthase (ALAS1), which is controlled via a negative feedback loop by the presence of heme end-product in the liver.2 Deficiencies in later enzymes in the pathway result in low circulating levels of heme, which in turn stimulates the up-regulation of ALAS1. The overexpression of ALAS1, in combination with downstream enzyme deficiencies, leads to the overproduction and accumulation of toxic heme intermediates which are ultimately responsible for the neurovisceral symptoms characteristic of acute hepatic porphyrias.5,2

Givosiran is a double-stranded small interfering RNA (siRNA) directed at ALAS1 mRNA in hepatocytes.5 It is covalently bound to a ligand containing three N-acetylgalactosamine (GalNAc) residues that facilitate uptake into hepatocytes via asialoglycoprotein receptors (ASPGRs), which are highly expressed on the cell surface of hepatocytes and are selective for glycoproteins containing GalNAc residues.7 Following endocytosis into hepatocytes, the antisense strand of givosiran is loaded into an enzyme complex called the RNA-induced silencing complex (RISC), which uses the antisense strand to seek out and selectively cleave the complementary mRNA sequence (in this case found between nucleotide 918 and 937 of the ALAS1 mRNA).7 Cleavage of the ALAS1 mRNA results in its degradation, preventing the synthesis of the ALAS1 enzyme and ultimately leading to reduced circulating levels of neurotoxic heme intermediates.

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The mean steady-state Cmax and AUC24 of givosiran are 321 ng/mL and 4130 ng·h/mL, respectively, and increase proportionally over the dosing range.5 The Tmax following subcutaneous injection is approximately 3 hours.5

Volume of distribution

The apparent central volume of distribution is 10.4 L.5 Both givosiran and AS(N-1)3' givosiran distribute primarily to the liver following subcutaneous administration.5

Protein binding

Plasma protein binding is inversely proportional to givosiran concentration, ranging from 92% at 1 μg/mL to 21% at 50 μg/mL.5 The specific plasma protein to which givosiran is bound is unclear.


Givosiran is metabolized to shorter oligonucleotides by nuclease enzymes. Its active metabolite, AS(N-1)3' givosiran, carries equal potency to the parent drug and its AUC0-24 comprises approximately 45% of the parent drug AUC at the recommended givosiran dosage.5 In vitro studies suggest that givosiran is not a substrate of the CYP enzyme system.5

Route of elimination

Approximately 5-14% of the dose recovered in urine is unchanged parent drug, and 4-13% is AS(N-1)3' givosiran.5

Half life

Both givosiran and its active metabolite, AS(N-1)3' givosiran, have an elimination half-life of 6 hours.5


The apparent clearance of givosiran is 35.1 L/hr.5


Little information is currently available regarding the toxicity of givosiran. Weekly subcutaneous dosing of up to 30 mg/kg in both female and male rats resulted in no apparent effects on fertility or reproductive function.5

Affected organisms
  • Humans and other mammals
Not Available
Pharmacogenomic Effects/ADRs
Not Available


Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Givosiran.
4-MethoxyamphetamineThe serum concentration of 4-Methoxyamphetamine can be increased when it is combined with Givosiran.
5-methoxy-N,N-dimethyltryptamineThe serum concentration of 5-methoxy-N,N-dimethyltryptamine can be increased when it is combined with Givosiran.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Givosiran.
8-azaguanineThe serum concentration of 8-azaguanine can be increased when it is combined with Givosiran.
8-chlorotheophyllineThe serum concentration of 8-chlorotheophylline can be increased when it is combined with Givosiran.
9-DeazaguanineThe serum concentration of 9-Deazaguanine can be increased when it is combined with Givosiran.
9-MethylguanineThe serum concentration of 9-Methylguanine can be increased when it is combined with Givosiran.
AbacavirGivosiran may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseGivosiran may decrease the excretion rate of Acarbose which could result in a higher serum level.
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Food Interactions
No interactions found.


Synthesis Reference

Brian Bettencourt, Kevin Fitzgerald, William Querbes, Robert J. Desnick, Makiko Yasuda, "Compositions and methods for inhibiting expression of the ALAS1 gene." US Patent US10119143B2, issued November, 2018.

General References
  1. Chan A, Liebow A, Yasuda M, Gan L, Racie T, Maier M, Kuchimanchi S, Foster D, Milstein S, Charisse K, Sehgal A, Manoharan M, Meyers R, Fitzgerald K, Simon A, Desnick RJ, Querbes W: Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification. Mol Ther Nucleic Acids. 2015 Nov 3;4:e263. doi: 10.1038/mtna.2015.36. [PubMed:26528940]
  2. Bonkovsky HL, Dixon N, Rudnick S: Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Mar 6. pii: S1096-7192(19)30084-8. doi: 10.1016/j.ymgme.2019.03.002. [PubMed:30987916]
  3. Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D, Penz C, Chan-Daniels A, He Q, Querbes W, Fitzgerald K, Kim JB, Garg P, Vaishnaw A, Simon AR, Anderson KE: Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med. 2019 Feb 7;380(6):549-558. doi: 10.1056/NEJMoa1807838. [PubMed:30726693]
  4. Fontanellas A, Avila MA, Anderson KE, Deybach JC: Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol. 2019 Aug;71(2):422-433. doi: 10.1016/j.jhep.2019.05.003. Epub 2019 May 16. [PubMed:31102718]
  5. FDA Approved Drug Products: Givlaari subcutaneous injection [Link]
  6. Supplementary Appendix for Phase 1 trial of an RNA interference therapy for acute intermittent porphyria [File]
  7. Study Protocol for Phase 1 trial of an RNA interference therapy for acute intermittent porphyria [File]
External Links

Clinical Trials

Clinical Trials
1CompletedTreatmentAcute Hepatic Porphyria (AHP) / Acute Intermittent Porphyria (AIP) / Porphyrias, Acute1
1CompletedTreatmentAcute Intermittent Porphyria (AIP)1
1, 2Active Not RecruitingTreatmentAcute Intermittent Porphyria (AIP)1
3Active Not RecruitingTreatmentAcute Hepatic Porphyria (AHP) / Acute Intermittent Porphyria (AIP) / ALA Dehydratase Deficient Porphyria (ADP) / Hereditary Coproporphyria (HCP) / Porphyrias, Acute / Variegate Porphyria1
Not AvailableAvailableNot AvailableAcute Hepatic Porphyria (AHP)1


Not Available
Not Available
Dosage forms
Injection, solutionSubcutaneous189 mg/1mL
Not Available
Patent NumberPediatric ExtensionApprovedExpires (estimated)
Additional Data Available
  • Filed On
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Experimental Properties
Not Available


Not classified


Pharmacological action
Region between nucleotide 918 and 937 of the ALAS1 mRNA; target for givosiran. The specific mRNA sequence targeted by givosiran is not explicitly given but can be inferred based on the structure of the molecule provided in the prescribing information and the study protocol from NCT02452372. The antisense strand of the double-stranded siRNA is the template used to seek out and cleave the ALAS1 mRNA, so its complementary sequence (provided here) should be the target mRNA sequence.
  1. FDA Approved Drug Products: Givlaari subcutaneous injection [Link]
  2. Study Protocol for Phase 1 trial of an RNA interference therapy for acute intermittent porphyria [File]

Drug created on May 20, 2019 08:46 / Updated on March 19, 2020 14:25

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