Patisiran
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Identification
- Summary
Patisiran is a transthyretin-directed small interfering RNA used to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis.
- Brand Names
- Onpattro
- Generic Name
- Patisiran
- DrugBank Accession Number
- DB14582
- Background
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.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Gene Therapies
Other gene therapies - Synonyms
- Patisiran
- External IDs
- ALN-18328
- ALN-TTR02
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
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Hereditary transthyretin-mediated amyloidosis •••••••••••• ••••• - Contraindications & Blackbox Warnings
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- 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.
Target Actions Organism ATransthyretin mRNA antisense oligonucleotideHumans - 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.
- Adverse Effects
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- 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.
- 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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Patisiran sodium WO0YM16LKG 1386913-72-9 Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Onpattro Solution 2 mg / mL Intravenous Alnylam Netherlands B.V. 2019-07-25 Not applicable Canada Onpattro Injection, lipid complex 2 mg/1mL Intravenous Alnylam Pharmaceuticals, Inc. 2018-08-13 Not applicable US Onpattro Injection, solution, concentrate 2 mg/ml Intravenous Alnylam Netherlands B.V. 2021-03-17 Not applicable EU
Categories
- ATC Codes
- N07XX12 — Patisiran
- Drug Categories
- Antisense Elements (Genetics)
- Compounds used in a research, industrial, or household setting
- Decreased RNA Integrity
- Increased Protein Breakdown
- Molecular Probes
- Nervous System
- Nucleic Acid Probes
- Nucleic Acids
- Nucleic Acids, Nucleotides, and Nucleosides
- Other Miscellaneous Therapeutic Agents
- RNA, Antisense
- RNA, Small Untranslated
- RNA, Untranslated
- Small Interfering RNA
- Transthyretin-directed RNA Interaction
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 50FKX8CB2Y
- CAS number
- 1420706-45-1
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- FDA Announcement: Patisiran [Link]
- FDA Approved Drug Products: ONPATTRO (patisiran) injection [Link]
- External Links
- FDA label
- Download (490 KB)
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 Amyloid Neuropathies / Amyloid Neuropathies, Familial / Amyloidosis, Hereditary, Transthyretin-Related / Familial Amyloid Polyneuropathy (FAP) / Hereditary Amyloidosis / TTR-mediated Amyloidosis 1 somestatus stop reason just information to hide Not Available Completed Not Available Hereditary Transthyretin-mediated (ATTRv) Amyloidosis / Polyneuropathies 1 somestatus stop reason just information to hide Not Available No Longer Available Not Available ATTR Amyloidosis With Cardiomyopathy / Transthyretin-mediated Amyloidosis With Cardiomyopathy 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Hereditary Amyloidosis / Transthyretin Amyloidosis 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Transthyretin Amyloidosis (ATTR) With Cardiomyopathy 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, lipid complex Intravenous 2 mg/1mL Injection, solution, concentrate Intravenous 2 mg/ml Injection, solution, concentrate Intravenous; Parenteral 2 MG/ML Solution Intravenous 2 mg / mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8802644 No 2014-08-12 2030-10-21 US US8778902 No 2014-07-15 2021-03-30 US US9234196 No 2016-01-12 2029-10-20 US US8822668 No 2014-09-02 2029-04-15 US US9364435 No 2016-06-14 2029-04-15 US US8158601 No 2012-04-17 2030-11-10 US US8741866 No 2014-06-03 2029-10-20 US US8168775 No 2012-05-01 2029-10-20 US US9193753 No 2015-11-24 2021-03-30 US US8334373 No 2012-12-18 2025-05-27 US US8058069 No 2011-11-15 2029-04-15 US US8492359 No 2013-07-23 2029-04-15 US US8642076 No 2014-02-04 2027-10-03 US US8362231 No 2013-01-29 2021-03-30 US US8895718 No 2014-11-25 2021-03-30 US US8552171 No 2013-10-08 2021-03-30 US US8372968 No 2013-02-12 2021-03-30 US US9943538 No 2018-04-17 2023-11-04 US US9943539 No 2018-04-17 2023-11-04 US US9567582 No 2017-02-14 2021-03-30 US US8895721 No 2014-11-25 2021-03-30 US US11079379 No 2021-08-03 2035-08-27 US US10240152 No 2019-03-26 2029-10-20 US US11141378 No 2021-10-12 2029-04-15 US
Properties
- State
- Not Available
- Experimental Properties
- Not Available
Targets
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Ligand
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Ligand
- General Function
- Functions as a 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 the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
Components:
Drug created at August 10, 2018 19:20 / Updated at January 10, 2024 06:22