Imetelstat

{{Infobox drug

| image = Imetelstat sodium colored.svg

| width = 250

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| image2 = Imetelstat 3D.png

| width2 = 200

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| caption =

| pronounce =

| tradename = Rytelo

| Drugs.com = {{drugs.com|monograph|imetelstat-sodium}}

| MedlinePlus =

| DailyMedID = Imetelstat

| pregnancy_AU =

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| routes_of_administration = Intravenous

| class =

| ATC_prefix = L01

| ATC_suffix = XX80

| ATC_supplemental =

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| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Rytelo- imetelstat sodium injection, powder, lyophilized, for solution | website=DailyMed | date=11 June 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b0fab7ca-e578-43c5-9df6-bdaff4182257 | access-date=5 September 2024}}

| legal_EU = Rx-only

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| bioavailability =

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| index2_label = as salt

| CAS_number = 868169-64-6

| CAS_number2 = 1007380-31-5

| CAS_supplemental =

| PubChem = 72941969

| PubChem2 = 72941968

| IUPHAR_ligand =

| DrugBank = DB05036

| ChemSpiderID = 34983285

| ChemSpiderID2 = 34983286

| UNII = F60NE4XB53

| UNII2 = 2AW48LAZ4I

| KEGG = D09629

| KEGG2 = D09630

| ChEBI =

| ChEMBL = 2107856

| ChEMBL2 = 2108702

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = GRN163L

| IUPAC_name = N-[2-[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-[[[(2S,3S,5R)-3-amino-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(4-amino-2-oxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(2-amino-6-oxo-1H-purin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(6-aminopurin-9-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]amino]-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-hydroxy-phosphinothioyl]oxy-2-hydroxy-ethyl]heptadecanamide

| C = 148 | H = 211 | N = 68 | O = 53 | P = 13 | S = 13

| StdInChI = 1S/C148H211N68O53P13S13/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-97(218)160-34-69(217)38-255-282(242,295)256-51-95-74(25-102(261-95)207-37-68(4)136(221)191-148(207)229)195-274(234,287)249-45-89-78(29-106(264-89)212-61-175-115-124(155)165-56-170-129(115)212)199-277(237,290)252-48-92-81(32-109(267-92)215-64-178-118-132(215)183-143(158)187-139(118)224)202-280(240,293)254-50-94-82(33-110(269-94)216-65-179-119-133(216)184-144(159)188-140(119)225)203-281(241,294)253-49-93-79(30-107(268-93)213-62-176-116-130(213)181-141(156)185-137(116)222)200-278(238,291)246-42-86-72(23-100(260-86)205-35-66(2)134(219)189-146(205)227)193-272(232,285)245-41-85-73(24-101(259-85)206-36-67(3)135(220)190-147(206)228)194-273(233,286)248-44-88-77(28-105(263-88)211-60-174-114-123(154)164-55-169-128(114)211)198-276(236,289)251-47-91-80(31-108(266-91)214-63-177-117-131(214)182-142(157)186-138(117)223)201-279(239,292)250-46-90-76(27-104(265-90)210-59-173-113-122(153)163-54-168-127(113)210)197-275(235,288)244-40-84-71(22-99(258-84)204-20-19-96(150)180-145(204)226)192-271(231,284)247-43-87-75(26-103(262-87)209-58-172-112-121(152)162-53-167-126(112)209)196-270(230,283)243-39-83-70(149)21-98(257-83)208-57-171-111-120(151)161-52-166-125(111)208/h19-20,35-37,52-65,69-95,98-110,217H,5-18,21-34,38-51,149H2,1-4H3,(H,160,218)(H,242,295)(H2,150,180,226)(H2,151,161,166)(H2,152,162,167)(H2,153,163,168)(H2,154,164,169)(H2,155,165,170)(H,189,219,227)(H,190,220,228)(H,191,221,229)(H2,192,231,284)(H2,193,232,285)(H2,194,233,286)(H2,195,234,287)(H2,196,230,283)(H2,197,235,288)(H2,198,236,289)(H2,199,237,290)(H2,200,238,291)(H2,201,239,292)(H2,202,240,293)(H2,203,241,294)(H3,156,181,185,222)(H3,157,182,186,223)(H3,158,183,187,224)(H3,159,184,188,225)/t69?,70-,71-,72-,73-,74-,75-,76-,77-,78-,79-,80-,81-,82-,83+,84+,85+,86+,87+,88+,89+,90+,91+,92+,93+,94+,95+,98+,99+,100+,101+,102+,103+,104+,105+,106+,107+,108+,109+,110+,270?,271?,272?,273?,274?,275?,276?,277?,278?,279?,280?,281?,282?/m0/s1

| StdInChIKey = LVZYXEALRXBLJZ-ISQYCPACSA-N

| StdInChIKey2 = IEVORMRANFJJFR-NMZIRJKDSA-A

| SMILES = CCCCCCCCCCCCCCCC(=O)NCC(COP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N2C=C(C(=O)NC2=O)C)NP(=S)(O)OC[C@@H]3[C@H](C[C@@H](O3)N4C=NC5=C(N=CN=C54)N)NP(=S)(O)OC[C@@H]6[C@H](C[C@@H](O6)N7C=NC8=C7N=C(NC8=O)N)NP(=S)(O)OC[C@@H]9[C@H](C[C@@H](O9)N1C=NC2=C1N=C(NC2=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C1N=C(NC2=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=C(C(=O)NC1=O)C)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=C(C(=O)NC1=O)C)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C1N=C(NC2=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=CC(=NC1=O)N)NP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)NP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC2=C(N=CN=C21)N)N)S)O

| density =

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}}

Imetelstat, sold under the brand name Rytelo, is an anti-cancer medication used for the treatment of myelodysplastic syndromes with transfusion-dependent anemia. Imetelstat is an oligonucleotide telomerase inhibitor.{{cite journal | vauthors = Burchett KM, Yan Y, Ouellette MM | title = Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells | journal = PLOS ONE | volume = 9 | issue = 1 | pages = e85155 | year = 2014 | pmid = 24409321 | pmc = 3883701 | doi = 10.1371/journal.pone.0085155 | bibcode = 2014PLoSO...985155B | doi-access = free | title-link = doi }} By blocking telomerase activity, imetelstat causes telomere shortening, inhibits the proliferation of malignant stem and progenitor cells and induces cell death, ultimately leading to a reduction in malignant clones.

The most common adverse reactions include decreased platelets, decreased white blood cells, decreased neutrophils, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.

Imetelstat was approved for medical use in the United States in June 2024.{{cite web | title=FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia | website=U.S. Food and Drug Administration (FDA) | date=6 June 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent | access-date=7 June 2024 | archive-date=7 June 2024 | archive-url=https://web.archive.org/web/20240607065259/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent | url-status=live }} {{PD-notice}}{{cite web | title=Novel Drug Approvals for 2024 | website=U.S. Food and Drug Administration (FDA) | date=1 October 2024 | url=https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 | access-date=20 December 2024}}{{cite press release | title=Geron Announces FDA Approval of Rytelo (imetelstat), a First-in-Class Telomerase Inhibitor, for the Treatment of Adult Patients with Lower-Risk MDS with Transfusion-Dependent Anemia | publisher=Geron | via=Business Wire | date=7 June 2024 | url=https://www.businesswire.com/news/home/20240606850162/en/ | access-date=7 June 2024 | archive-date=7 June 2024 | archive-url=https://web.archive.org/web/20240607025144/https://www.businesswire.com/news/home/20240606850162/en/ | url-status=live }} The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.{{cite report | title=New Drug Therapy Approvals 2024 | website=U.S. Food and Drug Administration (FDA) | date=January 2025 | url=https://www.fda.gov/media/184967/download | format=PDF | access-date=21 January 2025 | archive-url=https://web.archive.org/web/20250121045744/https://www.fda.gov/media/184967/download | archive-date=21 January 2025 | url-status=live }}

Medical uses

Imetelstat is indicated for the treatment of adults with low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia requiring four or more red blood cell units over eight weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents.

History

Imetelstat is the first telomerase inhibitor to enter clinical trials.{{cite journal | vauthors = Relitti N, Saraswati AP, Federico S, Khan T, Brindisi M, Zisterer D, Brogi S, Gemma S, Butini S, Campiani G | title = Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials | journal = Current Topics in Medicinal Chemistry | volume = 20 | issue = 6 | pages = 433–457 | year = 2020 | pmid = 31894749 | doi = 10.2174/1568026620666200102104930 | s2cid = 209543655 }}

Chemically, imetelstat is a synthetic conjugate consisting of three parts: GRN163, a thio phosphoramide oligonucleotide, and a palmitoyl lipid group. GRN163 is the pharmacological component with telomerase inhibition based on experiments with poly-G oligonucleotides first conducted at the University of Nebraska Medical Center under contract with Lynx Therapeutics.{{cite journal | vauthors = Mata JE, Joshi SS, Palen B, Pirruccello SJ, et al. | title = A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cellsin Vitro and in Vivo | journal = Toxicology and Applied Pharmacology | volume = 144 | issue = 6 | pages = 189–197 | year = 1997 | doi = 10.1006/taap.1997.8103 | pmid = 9169084 | bibcode = 1997ToxAP.144..189M }} The palmitic acid moiety is conjugated via a phosphothioate linkage to the backbone of the antisense oligonucleotide.{{Medical citation needed|date=June 2024}} Telomere shortening and lower cell viability are observed after inhibition of telomerase activity in vitro.{{Medical citation needed|date=June 2024}} IC50 values ranged from 50 to 200nM for 10 different pancreatic cell lines.{{cite journal | vauthors = Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, Harley CB, Rudolph KL | title = Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma | journal = Hepatology | volume = 42 | issue = 5 | pages = 1127–36 | date = November 2005 | pmid = 16114043 | doi = 10.1002/hep.20822 | doi-access = free | title-link = doi }}

The efficacy of imetelstat was evaluated in IMerge (NCT02598661), a randomized (2:1), double-blind, placebo-controlled multicenter trial in 178 participants with myelodysplastic syndromes. Participants received an intravenous infusion of imetelstat 7.1 mg/kg or placebo in 28-day treatment cycles until disease progression or unacceptable toxicity. Randomization was stratified by prior red blood cell transfusion burden and by International Prognostic Scoring System (IPSS) risk group. All participants received supportive care, which included red blood cell transfusions.

Society and culture

= Legal status =

Imetelstat was approved for medical use in the United States in June 2024. The FDA granted the application for imetelstat orphan drug designation.{{cite web | title=Imetelstat Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=481315 | access-date=7 June 2024 | archive-date=7 June 2024 | archive-url=https://web.archive.org/web/20240607214400/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=481315 | url-status=live }}{{cite web | title=Imetelstat Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=501415 | access-date=7 June 2024 | archive-date=7 June 2024 | archive-url=https://web.archive.org/web/20240607214402/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=501415 | url-status=dead }}

In December 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Rytelo, intended for the treatment of adults with transfusion-dependent anemia due to very low, low or intermediate risk myelodysplastic syndromes. The applicant for this medicinal product is Geron Netherlands B.V.{{cite web | title=Rytelo EPAR | website=European Medicines Agency (EMA) | date=12 December 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/rytelo | access-date=16 December 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Imetelstat was authorized for medical use in the European Union in March 2025.

= Names =

Imetelstat is the international nonproprietary name.{{cite journal | vauthors = ((World Health Organization)) | year = 2010 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 63 | journal = WHO Drug Information | volume = 24 | issue = 1 | hdl = 10665/74530 | hdl-access = free | author-link = World Health Organization }}

References

External links

{{cite web | title=Imetelstat (Code C49084) | website=NCI Thesaurus | url=https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C49084 }}
{{cite web | title=Imetelstat Sodium (Code C84511) | website=NCI Thesaurus | url=https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C84511 }}
{{MeSH|67519562}}

Category:Antineoplastic drugs

Category:Orphan drugs