Inotersen

Last updated

Inotersen
Inotersen.svg
Clinical data
Trade names Tegsedi
Other namesGSK-2998728, ISIS-420915
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Subcutaneous
Drug class Antisense oligonucleotides
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
KEGG
Chemical and physical data
Formula C230H318N69O121P19S19
Molar mass 7183.08 g·mol−1
3D model (JSmol)
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  • Key:KLEGMTRDCCDFJK-XDQSQZFTSA-N

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. [6] [7] The sequence is TCTTG GTTACATGAA ATCCC, where C is methylated C, and the first and third section (bases 1-5 and 16–20, separated from the middle section by spaces) are MOE-modified. [8]

Contents

The most common side effects are injection site reactions (redness, swelling, bleeding, pain, rash, and itching at the injection site), nausea, headache, tiredness, low platelet counts, and fever. [6]

Inotersen can cause serious side effects, including low platelet counts and kidney inflammation. [6] Because of these serious side effects, Inotersen is available in the United States only through a restricted program called the Tegsedi Risk Evaluation and Mitigation (REMS) Program. [6]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [9]

History

Inotersen was approved for medical use in the European Union in July 2018. [5]

The U.S. Food and Drug Administration (FDA) approved inotersen in October 2018. [6] The application for inotersen was granted orphan drug designation. [10]

The FDA approved inotersen based on evidence from one clinical trial (Trial 1/NCT01737398) that included 172 patients with hereditary transthyretin-mediated amyloidosis. [6] The trial was conducted at 24 sites in Australia, Europe, South America, and the United States. [6]

The benefits and side effects of inotersen were evaluated in one clinical trial that enrolled patients with hereditary transthyretin-mediated amyloidosis. [6] Patients were randomly assigned to receive inotersen or placebo by subcutaneous injection given once a week for 65 weeks. [6] During the first week of treatment, patients received three doses of treatment, followed by once weekly subcutaneous injections for 64 weeks. [6] Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. [6]

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.

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.

<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.

<span class="mw-page-title-main">Treprostinil</span> Chemical compound

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<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.

Caplacizumab is a bivalent single-domain antibody (VHH) designed for the treatment of thrombotic thrombocytopenic purpura (TTP) and thrombosis.

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">Ionis Pharmaceuticals</span> Biotechnology company

Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has three commercially approved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen) and has four drugs in pivotal studies: tominersen for Huntington's disease, tofersen for SOD1-ALS, AKCEA-APO(a)-LRx for cardiovascular disease, and AKCEA-TTR-LRx for all forms of TTR amyloidosis.

<span class="mw-page-title-main">Nusinersen</span> Medication used for spinal muscular atrophy

Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder.

<span class="mw-page-title-main">Patisiran</span> Pharmaceutical drug

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

<span class="mw-page-title-main">Golodirsen</span> Drug of DMD

Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry.

Trastuzumab/hyaluronidase, sold under the brand name Herceptin SC among others, is a fixed-dose combination medication for the treatment of HER2-overexpressing breast cancer in adults. It is a combination of trastuzumab and hyaluronidase.

<span class="mw-page-title-main">Viltolarsen</span> Pharmaceutical drug

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera. It is an interferon. It is given by injection.

<span class="mw-page-title-main">Casimersen</span> Medication

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.

Gapmers are short DNA antisense oligonucleotide structures with RNA-like segments on both sides of the sequence. These linear pieces of genetic information are designed to hybridize to a target piece of RNA and silence the gene through the induction of RNase H cleavage. Binding of the gapmer to the target has a higher affinity due to the modified RNA flanking regions, as well as resistance to degradation by nucleases. Gapmers are currently being developed as therapeutics for a variety of cancers, viruses, and other chronic genetic disorders.

Vutrisiran, 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.

<span class="mw-page-title-main">Eplontersen</span> Medication

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References

  1. ↑ "PrTEGSEDI inotersen injection" (PDF). Product Monograph Including Patient Medication Information. Akcea Therapeutics, Inc. – via The Drug and Health Product Register, Government of Canada.
  2. ↑ "Tegsedi 284 mg solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 15 October 2019. Retrieved 3 October 2020.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. ↑ "Tegsedi- inotersen injection, solution". DailyMed. 2 September 2020. Retrieved 3 October 2020.
  5. 1 2 "Tegsedi EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 3 October 2020.
  6. 1 2 3 4 5 6 7 8 9 10 11 "Drug Trial Snapshot: Tegsedi". U.S. Food and Drug Administration (FDA). 23 July 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ Benson MD, Dasgupta NR, Monia BP (February 2019). "Inotersen (transthyretin-specific antisense oligonucleotide) for treatment of transthyretin amyloidosis". Neurodegenerative Disease Management. 9 (1): 25–30. doi:10.2217/nmt-2018-0037. PMID   30561247. S2CID   56178847.
  8. ↑ Yu RZ, Collins JW, Hall S, Ackermann EJ, Geary RS, Monia BP, et al. (June 2020). "Population Pharmacokinetic-Pharmacodynamic Modeling of Inotersen, an Antisense Oligonucleotide for Treatment of Patients with Hereditary Transthyretin Amyloidosis". Nucleic Acid Therapeutics. 30 (3): 153–163. doi:10.1089/nat.2019.0822. PMC   7249474 . PMID   32286934.
  9. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  10. ↑ "Inotersen Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 July 2012. Archived from the original on 19 December 2019. Retrieved 18 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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