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Identification
- Summary
Givosiran is a 5-aminolevulinic acid synthase-directed small interfering RNA (siRNA) used in the prophylaxis of acute hepatic porphyria.
- Brand Names
- Givlaari
- Generic Name
- Givosiran
- DrugBank Accession Number
- DB15066
- Background
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.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Gene Therapies
Antisense oligonucleotides - Synonyms
- Givosiran
- External IDs
- ALN-AS1
- WHO 10280
Pharmacology
- Indication
Givosiran is indicated for the treatment of adults with acute hepatic porphyria.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Acute hepatic porphyria (ahp) •••••••••••• ••••• ••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism AALAS1 mRNA cleavageHumans A5-aminolevulinate synthase, non-specific, mitochondrial inhibitorHumans - Absorption
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.
- Metabolism
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
- Clearance
The apparent clearance of givosiran is 35.1 L/hr.5
- Adverse Effects
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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
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Givosiran may decrease the excretion rate of Abacavir which could result in a higher serum level. Acebutolol The serum concentration of Acebutolol can be increased when it is combined with Givosiran. Aceclofenac The risk or severity of nephrotoxicity can be increased when Aceclofenac is combined with Givosiran. Acemetacin The risk or severity of nephrotoxicity can be increased when Acemetacin is combined with Givosiran. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Givosiran. - Food Interactions
- No interactions found.
Products
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Ingredient UNII CAS InChI Key Givosiran sodium 5XE21E41RT Not Available Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Givlaari Injection, solution 189 mg/1mL Subcutaneous Alnylam Pharmaceuticals, Inc. 2019-12-12 Not applicable US 
Givlaari Injection, solution 189 mg/mL Subcutaneous Alnylam Netherlands B.V. 2020-12-16 Not applicable EU 
Givlaari Solution 189 mg / mL Subcutaneous Alnylam Netherlands B.V. 2020-12-01 Not applicable Canada 
Categories
- ATC Codes
- A16AX16 — Givosiran
- Drug Categories
- Alimentary Tract and Metabolism
- Amino Sugars
- Aminolevulinate Synthase 1-directed RNA Interaction
- Aminolevulinate Synthase 1-Directed Small Interfering RNAs
- Antisense Oligonucleotides
- Carbohydrates
- Galactosamine
- Hepatotoxic Agents
- Hexosamines
- Nephrotoxic agents
- Oligonucleotides
- Other Miscellaneous Therapeutic Agents
- Porphyrias, Hepatic
- RNA, Antisense
- Small Interfering RNA
- Various Alimentary Tract and Metabolism Products
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- ROV204583W
- CAS number
- 1639325-43-1
References
- 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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- FDA Approved Drug Products: Givlaari subcutaneous injection [Link]
- Supplementary Appendix for Phase 1 trial of an RNA interference therapy for acute intermittent porphyria [File]
- Study Protocol for Phase 1 trial of an RNA interference therapy for acute intermittent porphyria [File]
- External Links
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Approved for Marketing Not Available Acute Hepatic Porphyria (AHP) 1 somestatus stop reason just information to hide 3 Completed Treatment Acute Hepatic Porphyria (AHP) / Acute Intermittent Porphyria (AIP) / Acute Porphyria / Delta-aminolevulinic acid dehydratase deficient porphyria / Hereditary Coproporphyria (HCP) / Variegate Porphyria 1 somestatus stop reason just information to hide 1 Completed Treatment Acute Hepatic Porphyria (AHP) / Acute Intermittent Porphyria (AIP) / Acute Porphyria 1 somestatus stop reason just information to hide 1 Completed Treatment Acute Intermittent Porphyria (AIP) 1 somestatus stop reason just information to hide 1, 2 Completed Treatment Acute Intermittent Porphyria (AIP) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Subcutaneous 189 mg/1mL Injection, solution Subcutaneous 189 MG/ML Solution Subcutaneous 189 mg / mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9631193 No 2017-04-25 2033-03-15 US US10131907 No 2018-11-20 2028-08-24 US US10125364 No 2018-11-13 2033-03-15 US US8106022 No 2012-01-31 2029-12-12 US US10119143 No 2018-11-06 2034-10-03 US US8546143 No 2013-10-01 2022-01-09 US US9133461 No 2015-09-15 2033-05-14 US US8828956 No 2014-09-09 2028-12-04 US US9708610 No 2017-07-18 2024-01-01 US US10273477 No 2019-04-30 2024-03-08 US US9708615 No 2017-07-18 2024-03-08 US US9150605 No 2015-10-06 2025-08-28 US US11028392 No 2021-06-08 2034-10-03 US US11530408 No 2004-05-18 2024-05-18 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products
- Specific Function
- 5-aminolevulinate synthase activity
- Gene Name
- ALAS1
- Uniprot ID
- P13196
- Uniprot Name
- 5-aminolevulinate synthase, non-specific, mitochondrial
- Molecular Weight
- 70580.325 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Drug created at May 20, 2019 14:46 / Updated at August 26, 2024 19:24