Patisiran

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Patisiran
Patisiran sodium.svg
Clinical data
Trade names Onpattro
Other namesALN-18328
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
Chemical and physical data
Formula C412H520N148O290P40
Molar mass 13424.388 g·mol−1

Patisiran, sold under the brand name Onpattro, is a medication used for the treatment of polyneuropathy in people with hereditary transthyretin-mediated amyloidosis, [7] a fatal rare disease that is estimated to affect 50,000 people worldwide. [8] [9]

Contents

It is the first small interfering RNA-based drug approved by the U.S. Food and Drug Administration (FDA) and the first drug approved by the FDA to treat this condition. [8] It is a gene silencing drug that interferes with the production of an abnormal form of transthyretin. [10] Patisiran utilizes a novel approach to target and reduce production of the TTR protein in the liver via the RNAi pathway. [11]

Patisiran was developed and is marketed by Alnylam. [12] The FDA considers it to be a first-in-class medication. [13]

History

Patisiran was granted orphan drug status, fast track designation, priority review and breakthrough therapy designation due to its novel mechanism and the rarity of the condition it treats. [14] [15] It was approved for medical use in the United States and in the European Union in August 2018. [16] [17] The per-patient cost is between US$451,430 and US$677,145 per year, depending on the number of vials needed. [18]

[19] [20]

Formulation

The siRNA active component of Patisiran is formulated into lipid nanoparticles, which protect the RNA and facilitate its delivery to target tissues. The lipid nanoparticle formulation includes buffer components, as well as the lipid components DLin-MC3-DMA, Distearoylphosphatidylcholine, cholesterol, and the PEGylated lipid DMG-PEG 2000. [21]

Society and culture

Economics

As of 2020, there were 1050 people globally receiving patisiran, generating $65.5M in net-revenues for Alnylam Pharmaceuticals. [22] [23]

Related Research Articles

<span class="mw-page-title-main">Amyloidosis</span> Metabolic disease involving abnormal deposited amyloid proteins

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.

<span class="mw-page-title-main">Small interfering RNA</span> Biomolecule

Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20–24 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation.

<span class="mw-page-title-main">Transthyretin</span> Serum protein related to amyloid diseases

Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: transports thyroxine and retinol. The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

Pegfilgrastim, sold under the brand name Neulasta among others, is a PEGylated form of the recombinant human granulocyte colony-stimulating factor (GCSF) analog filgrastim. It serves to stimulate the production of white blood cells (neutrophils). Pegfilgrastim was developed by Amgen.

<span class="mw-page-title-main">Diflunisal</span> NSAID analgesic and anti-inflammatory drug

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

<span class="mw-page-title-main">Familial amyloid polyneuropathy</span> Medical condition

Familial amyloid polyneuropathy, also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR, or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied. FAP can be ameliorated by liver transplantation.

The familial amyloid neuropathies are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.

<span class="mw-page-title-main">Solid lipid nanoparticle</span> Novel drug delivery system

Lipid nanoparticles (LNPs) are nanoparticles composed of lipids. They are a novel pharmaceutical drug delivery system, and a novel pharmaceutical formulation. LNPs as a drug delivery vehicle were first approved in 2018 for the siRNA drug Onpattro. LNPs became more widely known in late 2020, as some COVID-19 vaccines that use RNA vaccine technology coat the fragile mRNA strands with PEGylated lipid nanoparticles as their delivery vehicle.

<span class="mw-page-title-main">Tafamidis</span> Medication for transthyretin amyloidosis

Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis, transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart.

Alnylam Pharmaceuticals, Inc. is an American biopharmaceutical company focused on the discovery, development and commercialization of RNA interference (RNAi) therapeutics for genetically defined diseases. The company was founded in 2002 and is headquartered in Cambridge, Massachusetts. In 2016, Forbes included the company on its "100 Most Innovative Growth Companies" list.

<span class="mw-page-title-main">Arbutus Biopharma</span> Canadian Bio Tech Company

Arbutus Biopharma Corporation is a publicly traded Canadian biopharmaceutical company with an expertise in liposomal drug delivery and RNA interference, and is developing drugs for hepatitis B infection.

Burosumab, sold under the brand name Crysvita, is a human monoclonal antibody medication approved 2018 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia.

Inclisiran, sold under the brand name Leqvio, is a medication used for the treatment of high low-density lipoprotein (LDL) cholesterol and for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA (siRNA) that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein PCSK9.

<span class="mw-page-title-main">Phillip D. Zamore</span> American molecular biologist

Phillip D. Zamore is an American molecular biologist and developed the first in vitro system for studying the mechanism of RNA interference (RNAi). He is the Gretchen Stone Cook Professor of Biomedical Sciences and Professor of Biochemistry and Molecular Pharmacology at University of Massachusetts Chan Medical School, located in Worcester, Massachusetts. Zamore is the chair of the RNA Therapeutics Institute (RTI) at UMass Chan Medical School, established in 2009, and has been a Howard Hughes Medical Institute Investigator since 2008. 

Givosiran, sold under the brand name Givlaari, is a medication used for the treatment of adults with acute hepatic porphyria. Givosiran is a small interfering RNA (siRNA) directed towards delta-aminolevulinate synthase 1 (ALAS1), an important enzyme in the production of heme.

Inotersen, sold under the brand name Tegsedi, is a 2'-O-(2-methoxyethyl) (2'-MOE) antisense oligonucleotide medication used for the treatment of nerve damage in adults with hereditary transthyretin-mediated amyloidosis. The sequence is TCTTG GTTACATGAA ATCCC, where C is methylated C, and the first and third section are MOE-modified.

<span class="mw-page-title-main">Moderna COVID-19 vaccine</span> RNA COVID-19 vaccine

The Moderna COVID‑19 vaccine, sold under the brand name Spikevax, is a COVID-19 vaccine developed by American company Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA). Depending on the jurisdiction, it is authorized for use in people aged six months, twelve years, or eighteen years and older. It provides protection against COVID-19 which is caused by infection by the SARS-CoV-2 virus. It is designed to be administered as two or three 0.5 mL doses given by intramuscular injection at an interval of at least 28 days apart.

John Maraganore is an American scientist, entrepreneur, and life sciences industry leader.

Vutrisiran, previously known as (ALN-TTRSC02), sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years.

References

  1. 1 2 "Onpattro". Therapeutic Goods Administration (TGA). 2 December 2022. Archived from the original on 5 February 2023. Retrieved 28 April 2023.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ↑ "Onpattro patisiran 10 mg/5 mL concentrated injection for infusion vial (380813)". Therapeutic Goods Administration (TGA). 22 November 2022. Archived from the original on 18 December 2022. Retrieved 28 April 2023.
  4. ↑ "Onpattro (Alnylam Australia Pty Ltd)". Therapeutic Goods Administration (TGA). 5 December 2022. Archived from the original on 27 March 2023. Retrieved 28 April 2023.
  5. ↑ "Onpattro PI" (PDF). Archived from the original (PDF) on 30 May 2022.
  6. ↑ "Summary Basis of Decision (SBD) for Onpattro". Health Canada . 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  7. 1 2 "Onpattro- patisiran injection, lipid complex". DailyMed. U.S. National Library of Medicine. 10 May 2021. Archived from the original on 4 May 2022. Retrieved 9 June 2022.
  8. 1 2 Loftus P (10 August 2018). "New Kind of Drug, Silencing Genes, Gets FDA Approval" . The Wall Street Journal . Archived from the original on 10 August 2018. Retrieved 10 August 2018.
  9. ↑ Elafros MA, Kvalsund MP, Callaghan BC (June 2022). "The Global Burden of Polyneuropathy-In Need of an Accurate Assessment". JAMA Neurology. 79 (6): 537–538. doi:10.1001/jamaneurol.2022.0565. PMC   9197927 . PMID   35404377. S2CID   248083689.
  10. ↑ Kristen AV, Ajroud-Driss S, Conceição I, Gorevic P, Kyriakides T, Obici L (February 2019). "Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis". Neurodegenerative Disease Management. 9 (1): 5–23. doi: 10.2217/nmt-2018-0033 . PMID   30480471.
  11. ↑ "Onpattro (patisiran)". www.centerwatch.com. Archived from the original on 24 June 2021. Retrieved 18 June 2021.
  12. ↑ Reidy C (22 October 2012). "Alnylam, Genzyme Form Alliance". The Boston Globe. Archived from the original on 7 May 2021. Retrieved 5 May 2021.
  13. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020.
  14. ↑ "FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease" (Press release). U.S. Food and Drug Administration (FDA). 10 August 2018. Archived from the original on 7 September 2018. Retrieved 11 August 2018.
  15. ↑ Brooks M (10 August 2018). "FDA OKs Patisiran (Onpattro) for Polyneuropathy in hAATR". Medscape. WebMD. Archived from the original on 4 July 2019. Retrieved 10 August 2018.
  16. ↑ "Drug Approval Package: Onpattro (patisiran)". U.S. Food and Drug Administration (FDA). 7 September 2018. Archived from the original on 12 April 2021. Retrieved 2 September 2020.
  17. ↑ "Onpattro EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 8 November 2020. Retrieved 2 September 2020.
  18. ↑ "Executive Summary". Pharmacoeconomic Review Report: Patisiran (Onpattro) (Alnylam Netherlands B.V.): Indication: Treatment of polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. August 2019 – via National Center for Biotechnology Information.{{cite book}}: CS1 maint: location missing publisher (link)
  19. ↑ Lipschultz B, Cortez M (10 August 2018). "Rare-Disease Treatment From Alnylam to Cost $450,000 a Year". Bloomberg. Archived from the original on 14 November 2019. Retrieved 11 August 2018.
  20. ↑ "Onpattro Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 24 June 2021. Retrieved 23 June 2021.
  21. ↑ Akinc A, Maier MA, Manoharan M, Fitzgerald K, Jayaraman M, Barros S, et al. (December 2019). "The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs" (PDF). Nature Nanotechnology. 14 (12): 1084–1087. Bibcode:2019NatNa..14.1084A. doi:10.1038/s41565-019-0591-y. PMID   31802031. S2CID   208621038.
  22. ↑ "Patisiran and Vutrisiran, in development for the Treatment of Transthyretin-Mediated Amyloidosis" (PDF). Alnylam Pharmaceuticals. Archived (PDF) from the original on 9 October 2021.
  23. ↑ "Alnylam Pharmaceuticals Reports Fourth Quarter and Full Year 2020 Financial Results and Highlights Recent Period Activity" (Press release). Alnylam. 11 February 2021. Archived from the original on 24 June 2021. Retrieved 23 June 2021– via Business Wire.
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