Identification

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Name
Patisiran
Accession Number
DB14582
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Other gene therapies
Description

Parisiran is a first in class short interfering RNA for the treatment of patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis 4. It is marketed as Onpattro which is formulated as patisiran within a liposome envelope for better delivery to the liver, where transthyretin is produced. The approval for Onpattro was granted to Alnylam Pharmaceuticals, Inc. in August of 2018. Onpattro has been granted Fast Track, Priority Review and Breakthrough Therapy, and Orphan Drug designations.

Synonyms
Not Available
External IDs
ALN-18328 / ALN-TTR02
Product Ingredients
IngredientUNIICASInChI Key
Patisiran sodiumWO0YM16LKG1386913-72-9Not applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OnpattroInjection, lipid complex2 mg/1mLIntravenousAlnylam Pharmaceuticals, Inc.2018-08-13Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
50FKX8CB2Y
CAS number
1420706-45-1

Pharmacology

Indication

Patisirant is indicated for the treatment of hereditary transthyretin-mediated amyloidosis in adults Label.

It is administered with pre-medication to reduce complications Label. These include an intravenous corticosteroid equivalent to 10 mg of dexamethasone, 500 mg of oral acetaminophen, an intravenous histamine H1 blocker equivalent to 50 mg of diphenhydramine, and an intravenous histamine H2 blocker equivalent to 50 mg of ranitidine

Associated Conditions
Pharmacodynamics

Transthyretin normally plays a role in the transport of vitamin A in conjunction with retinol binding protein 1. Mutant transthyretin of the ATTR genotype is capable of forming amyloid fibrils and creating protein deposits in a condition known as transthyretin-mediated amyloidosis.

Patisiran reduces the amount of wild-type and mutant transthyretin mRNA available for translation through RNA interference 2,3,Label. This has the effect of decreasing circulating transthyretin protein and reducing the amyloid deposits associated with transthyretin-mediated amyloidosis.

Mechanism of action

Patisirant is a double-stranded short interfering RNA (siRNA) targeting mRNA encoding both wild-type and mutant transthyretin 3,Label. Patisiran enters the cell an is processed by the Dicer enzyme. This processing involved cleaving overhanging nucleotides on the edges of the RNA. Once processed the siRNA can bind to the RNA-induced silencing complex (RISC). RISC separates the strands of the RNA sequence. One strand is released and one remains bound. The bound strand then acts as a targeting sequence for a complimentary mRNA sequence. In this case, the bound strand of patisiran binds to the complimentary transthyretin mRNA and aligns the RISC complex with it. The transthyretin mRNA is then cleaved and rendered non-functional. One targeting sequence may be used to destroy many copies of complimentary mRNA.

TargetActionsOrganism
ATransthyretin mRNA
suppressor
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

Patisiran follows a linear dose-proportional absorption curve Label. Over 95% of administered drug remains with the liposomal complex which distributes primarily to the liver. With chronic dosing at 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks. The accumulation factor of the AUC is 3.2 with chronic dosing.

Volume of distribution

The steady state volume of distribution of patisiran is 0.26 ± 0.20 L/kg observed with chronic dosing at 0.3 mg/kg every 3 weeks Label.

Protein binding

Less than 2.1% of patisiran is bound to serum albumin and α1-acid glycoprotein Label.

Metabolism

Patisiran is metabolized to individual nucleotides and oligonucleotides of varying lengths by nucleases similarly to endogenous RNA Label

Route of elimination

Less than 1% is excreted through the urine. The bulk of the drug is broken down by nucleases Label. No dosage adjustment is required in patients with mild hepatic impairment or mild to moderate renal impairment. No data exists for patients with severe to end-stage renal impairment or moderate to severe hepatic impairment.

Half life

Patisiran has a terminal elimination half-life of 3.2 ± 1.8 days Label.

Clearance

The total body clearance of patisiran is 3.0 ± 2.5 mL/h/kg Label.

Toxicity

Patisiran produced no signs of embryo-fetal toxicity at dosages of up to 1.5 mg/kg in rats Label. In rabbits given dosages of 0, 0.3, 1, and 2 mg/kg embryo-fetal and maternal toxicity were seen at mid and high dosages. No data exists in human subjects regarding risk during pregnancy.

Patisirant does not appear to be present in breast milk, however the lipid components of the liposomal dosage form are present Label.

Patisirant is immunogenic with specific antibodies appearing in 3.6% of treated patients Label. While there is no evidence of these antibodies reducing the efficacy of the drug, there is a risk of experiencing immunologic complications associated with the use of biologics.

Patisirant is known to reduce available vitamin A. Patients using the drug are at increased risk of vitamin A deficiency Label.

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Butler JS, Chan A, Costelha S, Fishman S, Willoughby JL, Borland TD, Milstein S, Foster DJ, Goncalves P, Chen Q, Qin J, Bettencourt BR, Sah DW, Alvarez R, Rajeev KG, Manoharan M, Fitzgerald K, Meyers RE, Nochur SV, Saraiva MJ, Zimmermann TS: Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid. 2016 Jun;23(2):109-18. doi: 10.3109/13506129.2016.1160882. Epub 2016 Mar 31. [PubMed:27033334]
  2. Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Plante-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB: Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153. [PubMed:29972753]
  3. Dana H, Chalbatani GM, Mahmoodzadeh H, Karimloo R, Rezaiean O, Moradzadeh A, Mehmandoost N, Moazzen F, Mazraeh A, Marmari V, Ebrahimi M, Rashno MM, Abadi SJ, Gharagouzlo E: Molecular Mechanisms and Biological Functions of siRNA. Int J Biomed Sci. 2017 Jun;13(2):48-57. [PubMed:28824341]
  4. FDA Announcement: Patisiran [Link]
External Links
Wikipedia
Patisiran
ATC Codes
N07XX12 — Patisiran
FDA label
Download (490 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentTTR-mediated Amyloidosis1
1CompletedTreatmentTransthyretin (TTR)-Mediated Amyloidosis1
2CompletedTreatmentTTR-mediated Amyloidosis2
3CompletedTreatmentAmyloid Neuropathies / Amyloid Neuropathies, Familial / Amyloidosis, Hereditary / Amyloidosis, Hereditary, Transthyretin-Related / Familial Amyloid Polyneuropathies / TTR-mediated Amyloidosis1
3Enrolling by InvitationTreatmentAmyloidosis1
3RecruitingTreatmentAmyloidosis, Familial / Transthyretin Amyloidosis1
3RecruitingTreatmentAmyloidosis, Hereditary / Transthyretin Amyloidosis1
Not AvailableApproved for MarketingNot AvailableAmyloid Neuropathies / Amyloid Neuropathies, Familial / Amyloidosis, Hereditary / Amyloidosis, Hereditary, Transthyretin-Related / Familial Amyloid Polyneuropathies / TTR-mediated Amyloidosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, lipid complexIntravenous2 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8802644No2014-08-122030-10-21Us
US8778902No2014-07-152021-03-30Us
US9234196No2016-01-122029-10-20Us
US8822668No2014-09-022029-04-15Us
US9364435No2016-06-142029-04-15Us
US8158601No2012-04-172030-11-10Us
US8741866No2014-06-032029-10-20Us
US8168775No2012-05-012029-10-20Us
US9193753No2015-11-242021-03-30Us
US8334373No2012-12-182025-05-27Us
US8058069No2011-11-152029-04-15Us
US8492359No2013-07-232029-04-15Us
US8642076No2014-02-042027-10-03Us
US8362231No2013-01-292021-03-30Us
US8895718No2014-11-252021-03-30Us
US8552171No2013-10-082021-03-30Us
US8372968No2013-02-122021-03-30Us
US9943538No2018-04-172023-11-04Us
US9943539No2018-04-172023-11-04Us
US9567582No2017-02-142021-03-30Us
US8895721No2014-11-252021-03-30Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Not Available
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

1. Transthyretin mRNA
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Suppressor

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
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Ligand
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:

Drug created on August 10, 2018 13:20 / Updated on May 01, 2019 13:34