Identification

Summary

Vutrisiran is a transthyretin-directed small interfering RNA used to treat polyneuropathy associated with hereditary transthyretin-mediated amyloidosis.

Generic Name
Vutrisiran
DrugBank Accession Number
DB16699
Background

Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) that targets wild-type and mutant transthyretin (TTR) messenger RNA (mRNA).7 This siRNA therapeutic is indicated for the treatment of neuropathies associated with hereditary transthyretin-mediated amyloidosis (ATTR), a condition caused by mutations in the TTR gene.2 More than 130 TTR mutations have been identified so far,3 but the most common one is the replacement of valine with methionine at position 30 (Val30Met).2 The Val30Met variant is the most prevalent among hereditary ATTR patients with polyneuropathy, especially in Portugal, France, Sweden, and Japan.2

TTR mutations lead to the formation of misfolded TTR proteins, which form amyloid fibrils that deposit in different types of tissues. By targeting TTR mRNA, vutrisiran reduces the serum levels of TTR.6,7 Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a residue that enables the delivery of siRNA to hepatocytes.5,7 This delivery platform gives vutrisiran high potency and metabolic stability, and allows for subcutaneous injections to take place once every three months.8 Another siRNA indicated for the treatment of polyneuropathy associated with hereditary ATTR is patisiran.2 Vutrisiran was approved by the FDA in June 2022.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Synonyms
  • Votrisiran
  • Vutrisiran
External IDs
  • ALN-65492
  • ALN-TTRSC02

Pharmacology

Indication

Vutrisiran is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.7

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

The reduction of serum transthyretin (TTR) achieved with vutrisiran is dose-dependent and detected within days of dosing. Healthy subjects given a single subcutaneous dose of 25 mg of vutrisiran had a maximum TTR reduction of 80%.4 In patients with hereditary transthyretin-mediated amyloidosis (ATTR), vutrisiran reduced mean serum TTR by 83% at a steady state.7 At doses of 5–300 mg, the maximum TTR reduction was detected at 50–90 days and maintained for 90 days at doses of 25 mg or higher.4 The reduction in serum TTR achieved with vutrisiran is similar regardless of Val30Met genotype status, weight, sex, age, or race. Vutrisiran does not have a clinically significant effect on QT prolongation.7

Over 9 months of treatment, vutrisiran reduced serum vitamin A levels by 62%. Supplementation of vitamin A in patients treated with vutrisiran is recommended; however, doses higher than the recommended daily allowance should not be given. Patients with ocular symptoms suggestive of vitamin A deficiency, such as night blindness, should be referred to an ophthalmologist.7

Mechanism of action

Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) indicated for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (ATTR).7 Hereditary ATTR is caused by mutations in the transthyretin (TTR) gene that destabilize the TTR protein.1,2 TTR proteins are primarily expressed in the liver, acting as carriers of vitamin A. TTR exists as a tetramer (four monomers or subunits), and is composed of 127 amino acids.4 Mutations in the TTR gene lead to the dissociation of the TTR tetramer into monomers. TTR monomers misfold, aggregate and form amyloid fibrils that deposit in peripheral and autonomic nerves, heart, and other organs.1,2

Vutrisiran targets wild-type and mutant TTR messenger RNA (mRNA) and promotes its degradation. This decreases the serum levels of TTR protein and lowers the amount of amyloid fibril deposits in patients with hereditary ATTR.7 Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a molecule that binds to the asialoglycoprotein receptors (ASGPR) in hepatocytes. Therefore, the vutrisiran-GalNAc conjugate targets TTR mRNA in the liver.5,7

TargetActionsOrganism
ATransthyretin mRNA
suppressor
Humans
Absorption

In subjects receiving 5 to 300 mg of vutrisiran, Cmax increased in a dose-proportional manner, while the AUClast and AUCinf increased in a slightly more than dose-proportional manner.7 Of the 130 TTR mutations identified so far, more than 40 of them were detected in patients of Japanese descent.3 The pharmacokinetic parameters of vutrisiran were comparable in both Japanese and non-Japanese healthy subjects given 25 mg subcutaneously. Japanese subjects had an AUC0-last of 1.04 h∙µg/mL and a Cmax 0.120 µg/mL. Non-Japanese subjects had an AUC0-last of 0.854 h∙µg/mL and a Cmax 0.0875 µg/mL.4

The average Tmax of vutrisiran is 4 h, ranging from 0.17 to 12.0 h.7 Human bioavailability studies have not been performed; however, studies in rats have shown that N-acetylgalactosamine (GalNAc)-conjugated and unconjugated small interfering ribonucleic acids (siRNAs) given subcutaneously have 100% bioavailability.4 Plasma accumulation was not detected in hereditary transthyretin-mediated amyloidosis (ATTR) patients given 25 mg of vutrisiran every 3 months.7

Volume of distribution

Based on a population pharmacokinetic model estimation, the apparent volume of distribution of vutrisiran is 10.1 L.7

Protein binding

Vutrisiran is 80% bound to plasma proteins. Plasma protein binding was concentration-dependent and decreased as vutrisiran concentrations increased, going from 78% at 0.5 mcg/mL to 19% at 50 mcg/mL.7

Metabolism

As a small interfering ribonucleic acid (siRNA), vutrisiran is metabolized by endo- and exonucleases to produce short nucleotide fragments of varying sizes within the liver.7 In vitro studies suggest that vutrisiran is not a substrate or inhibitor of cytochrome P450 enzymes. Since vutrisiran does not induce CYP enzymes or activate drug transporters, drug-drug interactions are not expected.7

Route of elimination

Vutrisiran has a rapid elimination from systemic circulation. The mean renal clearance of vutrisiran goes from 4.5 to 5.7 L/hour, and the fraction of renal clearance to total clearance (CLR/[CL/F]) ranges from 15.5% to 27.5%, suggesting that renal excretion of vutrisiran is a minor route of elimination.4 At the recommended dose of 25 mg, approximately 19.4% of unchanged vutrisiran was eliminated in urine.7

Half-life

The median half-life of vutrisiran was 5.2 h (2.2 to 6.4 h range) in healthy subjects given a single dose of 25 mg.7

Clearance

The apparent clearance of vutrisiran was 21.4 L/h (19.8 to 30 L/h range) in healthy subjects given a single dose of 25 mg.7

Adverse Effects
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Toxicity

Toxicity information regarding vutrisiran is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as atrioventricular (AV) heart block and complete AV block.7 Symptomatic and supportive measures are recommended. In vitro assays of bacterial mutagenicity and chromosomal aberration in human blood peripheral lymphocytes, as well as in vivo assays of bone marrow micronucleus in rats, have shown that vutrisiran is non-mutagenic. In male and female rats, the subcutaneous administration of 0, 15, 30, or 70 mg/kg/week of vutrisiran during mating did not have an effect on reproductive performance. Similar results were obtained in female rats followed through gestation day 6.7 Carcinogenicity studies of vutrisiran have not been performed.7

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.
Not Available
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Vutrisiran sodium28O0WP6Z1PNot AvailableNot applicable
International/Other Brands
Amvuttra (Alnylam Pharmaceuticals, Inc.)

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
GB4I2JI8UI
CAS number
1867157-35-4

References

Synthesis Reference

Zimmermann, T., et al. (2017). Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases (WO 2017/023660 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/13/42/80/768cd7debf24f6/WO2017023660A1.pdf

General References
  1. Conceicao I, Gonzalez-Duarte A, Obici L, Schmidt HH, Simoneau D, Ong ML, Amass L: "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016 Mar;21(1):5-9. doi: 10.1111/jns.12153. [Article]
  2. Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB: Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. doi: 10.3109/07853890.2015.1068949. Epub 2015 Nov 27. [Article]
  3. Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y: Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018 Jan 17;13(1):6. doi: 10.1186/s13023-017-0726-x. [Article]
  4. Habtemariam BA, Karsten V, Attarwala H, Goel V, Melch M, Clausen VA, Garg P, Vaishnaw AK, Sweetser MT, Robbie GJ, Vest J: Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine-Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther. 2021 Feb;109(2):372-382. doi: 10.1002/cpt.1974. Epub 2020 Aug 13. [Article]
  5. Springer AD, Dowdy SF: GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Ther. 2018 Jun;28(3):109-118. doi: 10.1089/nat.2018.0736. Epub 2018 May 24. [Article]
  6. Alnylam: Vutrisiran Fact Sheet [Link]
  7. FDA Approved Drug Products: AMVUTTRA (vutrisiran) injection for subcutaneous use [Link]
  8. Business Wire: Alnylam Announces FDA Approval of AMVUTTRA™ (vutrisiran), an RNAi Therapeutic for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults [Link]
Wikipedia
Vutrisiran

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAmyloidosis, Hereditary / Transthyretin Amyloidosis1
3Active Not RecruitingTreatmentTransthyretin Amyloidosis (ATTR) With Cardiomyopathy1
1CompletedTreatmentTransthyretin Mediated Amyloidosis (ATTR)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Ligand
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Geselowitz DA, Neckers LM: Bovine serum albumin is a major oligonucleotide-binding protein found on the surface of cultured cells. Antisense Res Dev. 1995 Fall;5(3):213-7. doi: 10.1089/ard.1995.5.213. [Article]

Drug created at June 10, 2021 19:52 / Updated at June 15, 2022 17:32