Jump to content

Imetelstat: Difference between revisions

Add links
From Wikipedia, the free encyclopedia
Browse history interactively
← Previous edit
Content deleted Content added
VisualWikitext
Actura (talk | contribs)
63 edits
added research evidence for MDS indication
infobox
 
(19 intermediate revisions by 5 users not shown)
Line 1: Line 1:
{{Short description|Experimental cancer drug}}
{{Short description|Medication}}
{{Use American English|date=June 2024}}
{{Use dmy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
{{Infobox drug
| drug_name =
| image = Imetelstat sodium colored.svg
| INN =
| width = 250
| type =<!-- empty -->
| alt =
| image = Imetelstat.svg
| width = 200
| image2 = Imetelstat 3D.png
| image2 = Imetelstat 3D.png
| width2 = 200
| width2 = 200
| alt =
| alt2 =
| caption =
| caption =

<!-- Clinical data -->
<!-- Clinical data -->
| pronounce =
| pronounce =
| tradename =
| tradename = Rytelo
| Drugs.com =
| Drugs.com = {{drugs.com|monograph|imetelstat-sodium}}
| MedlinePlus =
| MedlinePlus =
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| DailyMedID = Imetelstat
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment =
| pregnancy_AU_comment =
| pregnancy_US = <!-- A/B/C/D/X/N -->
| pregnancy_category=
| pregnancy_category=
| routes_of_administration =
| routes_of_administration = [[Intravenous]]
| ATCvet =
| class =
| ATC_prefix = L01
| ATC_prefix = L01
| ATC_suffix = XX80
| ATC_suffix = XX80
| ATC_supplemental =
<!-- Legal data -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
<!-- Legal status -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_DE = <!-- Anlage I, II, III -->
| legal_NZ = <!-- Class A, B, C -->
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_US = <!-- OTC/Rx-only/Schedule I, II, III, IV, V -->
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_status = Experimental
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Rytelo FDA label">{{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}}</ref>
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
<!-- Pharmacokinetic data -->
| bioavailability =
| bioavailability =
| protein_bound =
| protein_bound =
| metabolism =
| metabolism =
| metabolites =
| metabolites =
| onset =
| onset =
| elimination_half-life =
| elimination_half-life =
| duration_of_action=
| duration_of_action =
| excretion =
| excretion =

<!-- Identifiers -->
<!-- Identifiers -->
| index2_label = as salt
| synonyms = GRN163L
| IUPAC_name = <nowiki>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</nowiki>
| CAS_number = 868169-64-6
| CAS_number = 868169-64-6
| CAS_number2 = 1007380-31-5
| ChemSpiderID = 34983285
| CAS_supplemental =
| PubChem = 71587831
| PubChem = 72941969
| PubChem2 = 72941968
| IUPHAR_ligand =
| DrugBank = DB05036
| DrugBank = DB05036
| ChemSpiderID = 34983285
| UNII = F60NE4XB53
| ChemSpiderID2 = 34983286
| 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
| UNII = F60NE4XB53
| StdInChIKey=LVZYXEALRXBLJZ-ISQYCPACSA-N
| UNII2 = 2AW48LAZ4I
| 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
| KEGG = D09629
| KEGG2 = D09630
| ChEBI =
| ChEMBL = 2107856
| ChEMBL2 = 2108702
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = GRN163L

<!-- Chemical and physical data -->
<!-- Chemical and physical data -->
| IUPAC_name = <nowiki>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</nowiki>
| chemical_formula = C<sub>148</sub>H<sub>210</sub>N<sub>68</sub>O<sub>53</sub>P<sub>13</sub>S<sub>13</sub>
| C = 148 | H = 211 | N = 68 | O = 53 | P = 13 | S = 13
| molecular_weight = 4610
| 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 =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
}}


'''Imetelstat''' (development code '''GRN163L''') is an experimental [[anticancer drug]].<ref>{{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 }}</ref> The first [[telomerase]] [[enzyme inhibitor|inhibitor]] to enter [[clinical trial]]s,<ref name=Relitti>{{cite journal | vauthors = Relitti N, Saraswati AP, Federico S, Khan T, Brindisi M, Zisterer D, Brogi S, Gemma S, Butini S, Campiani G | display-authors = 6 | 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 }}</ref> As of early 2023, it was in [[Phases of clinical research#Phase II|Phase 2]]/[[Phases of clinical research#Phase III|3]] trials for various cancer types.{{which|date=September 2021}}<ref name=Relitti/>
'''Imetelstat''', sold under the brand name '''Rytelo''', is an [[anti-cancer medication]] used for the treatment of [[myelodysplastic syndrome]]s with [[transfusion-dependent anemia]].<ref name="Rytelo FDA label" /> Imetelstat is an [[oligonucleotide]] telomerase inhibitor.<ref name="Rytelo FDA label" /><ref>{{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 }}</ref>


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.<ref name="FDA 20240606" />
Chemically, imetelstat is a synthetic [[conjugated system|conjugate]] consisting of three parts: [[GRN163]], a [[thio-|thio]] [[phosphoramide]] [[oligonucleotide]], and a [[palmitic acid|palmitoyl lipid group]].<ref name=Relitti/> GRN163 is the pharmacological component with telomerase inhibition. The palmitic acid moiety is conjugated via a [[thiophosphate|phosphothioate]] linkage to the backbone of the antisense oligonucleotide. Telomere shortening and lower cell viability are observed after inhibition of telomerase activity in vitro. IC50 values ranged from 50 to 200nM for 10 different pancreatic cell lines. <ref>{{cite journal | vauthors = Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, Harley CB, Rudolph KL | display-authors = 6 | 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 }}</ref>


Imetelstat was approved for medical use in the United States in June 2024.<ref name="FDA 20240606">{{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}}</ref><ref>{{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 }}</ref>
Imetelstat is being developed by Geron Corporation to treat patients with low- or intermediate-risk [[Myelodysplastic syndrome|myelodysplastic syndromes]] (MDS) who are reliant on red blood cell transfusions. In 2023, Geron submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for imetelstat based on results from the phase 2/3 IMerge clinical trial (NCT02598661).<ref>{{Cite web |date=2023-06-21 |title=FDA Receives New Drug Application for Imetelstat in MDS |url=https://www.cancernetwork.com/view/fda-receives-new-drug-application-for-imetelstat-in-mds |access-date=2024-05-20 |website=Cancer Network |language=en}}</ref> The IMerge trial evaluated imetelstat against placebo in 178 transfusion-dependent MDS patients who were refractory or ineligible for erythropoiesis-stimulating agents (ESAs). Results demonstrated significantly higher rates of 8-week transfusion independence with imetelstat than placebo (p<0.001), with a median duration of independence of approximately 1 year. Imetelstat also significantly increased hemoglobin levels over time compared to placebo (p<0.001). The safety profile was consistent with previous trials. If approved, imetelstat could address significant unmet needs for lower-risk MDS patients often experiencing chronic transfusion-dependent anemia.

== 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.<ref name="Rytelo FDA label" /><ref name="FDA 20240606" />

== History ==
Imetelstat is the first [[telomerase]] [[enzyme inhibitor|inhibitor]] to enter [[clinical trial]]s.<ref name=Relitti>{{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 }}</ref>

Chemically, imetelstat is a synthetic [[conjugated system|conjugate]] consisting of three parts: GRN163, a [[thio-|thio]] [[phosphoramide]] [[oligonucleotide]], and a [[palmitic acid|palmitoyl lipid group]].<ref name=Relitti/> 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.<ref name=Mata.>{{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 }}</ref> The palmitic acid moiety is conjugated via a [[thiophosphate|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.<ref>{{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 }}</ref>

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.<ref name="FDA 20240606" /> Participants received an intravenous infusion of imetelstat 7.1 mg/kg or placebo in 28-day treatment cycles until disease progression or unacceptable toxicity.<ref name="FDA 20240606" /> Randomization was stratified by prior red blood cell transfusion burden and by International Prognostic Scoring System (IPSS) risk group.<ref name="FDA 20240606" /> All participants received supportive care, which included red blood cell transfusions.<ref name="FDA 20240606" />

== Society and culture ==
=== Legal status ===
Imetelstat was approved for medical use in the United States in June 2024.<ref name="FDA 20240606" /> The FDA granted the application for imetelstat [[orphan drug]] designation.<ref name="FDA 20240606" /><ref>{{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 }}</ref><ref>{{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=live }}</ref>

=== Names ===
Imetelstat is the [[international nonproprietary name]].<ref>{{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 }}</ref>


== References ==
== References ==
{{reflist}}
{{reflist}}


== External links ==
[[Category:Experimental cancer drugs]]
* {{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 }}</ref>
* {{MeSH|67519562}}

{{Chemotherapeutic agents}}
{{Portal bar | Medicine}}
{{Authority control}}

[[Category:Antineoplastic drugs]]
[[Category:Orphan drugs]]

Latest revision as of 05:23, 6 October 2024

Imetelstat
Clinical data
Trade namesRytelo
Other namesGRN163L
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
  • 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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC148H211N68O53P13S13
Molar mass4610.18 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key:LVZYXEALRXBLJZ-ISQYCPACSA-N
  • Key:IEVORMRANFJJFR-NMZIRJKDSA-A

Imetelstat, sold under the brand name Rytelo, is an anti-cancer medication used for the treatment of myelodysplastic syndromes with transfusion-dependent anemia.[1] Imetelstat is an oligonucleotide telomerase inhibitor.[1][2]

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.[3]

Imetelstat was approved for medical use in the United States in June 2024.[3][4]

Medical uses

[edit]

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.[1][3]

History

[edit]

Imetelstat is the first telomerase inhibitor to enter clinical trials.[5]

Chemically, imetelstat is a synthetic conjugate consisting of three parts: GRN163, a thio phosphoramide oligonucleotide, and a palmitoyl lipid group.[5] 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.[6] The palmitic acid moiety is conjugated via a phosphothioate linkage to the backbone of the antisense oligonucleotide.[medical citation needed] Telomere shortening and lower cell viability are observed after inhibition of telomerase activity in vitro.[medical citation needed] IC50 values ranged from 50 to 200nM for 10 different pancreatic cell lines.[7]

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.[3] Participants received an intravenous infusion of imetelstat 7.1 mg/kg or placebo in 28-day treatment cycles until disease progression or unacceptable toxicity.[3] Randomization was stratified by prior red blood cell transfusion burden and by International Prognostic Scoring System (IPSS) risk group.[3] All participants received supportive care, which included red blood cell transfusions.[3]

Society and culture

[edit]
[edit]

Imetelstat was approved for medical use in the United States in June 2024.[3] The FDA granted the application for imetelstat orphan drug designation.[3][8][9]

Names

[edit]

Imetelstat is the international nonproprietary name.[10]

References

[edit]
  1. ^ a b c d "Rytelo- imetelstat sodium injection, powder, lyophilized, for solution". DailyMed. 11 June 2024. Retrieved 5 September 2024.
  2. ^ Burchett KM, Yan Y, Ouellette MM (2014). "Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells". PLOS ONE. 9 (1): e85155. Bibcode:2014PLoSO...985155B. doi:10.1371/journal.pone.0085155. PMC 3883701. PMID 24409321.
  3. ^ a b c d e f g h i "FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia". U.S. Food and Drug Administration (FDA). 6 June 2024. Archived from the original on 7 June 2024. Retrieved 7 June 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  4. ^ "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" (Press release). Geron. 7 June 2024. Archived from the original on 7 June 2024. Retrieved 7 June 2024 – via Business Wire.
  5. ^ a b Relitti N, Saraswati AP, Federico S, Khan T, Brindisi M, Zisterer D, et al. (2020). "Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials". Current Topics in Medicinal Chemistry. 20 (6): 433–457. doi:10.2174/1568026620666200102104930. PMID 31894749. S2CID 209543655.
  6. ^ Mata JE, Joshi SS, Palen B, Pirruccello SJ, et al. (1997). "A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cellsin Vitro and in Vivo". Toxicology and Applied Pharmacology. 144 (6): 189–197. Bibcode:1997ToxAP.144..189M. doi:10.1006/taap.1997.8103. PMID 9169084.
  7. ^ Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, et al. (November 2005). "Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma". Hepatology. 42 (5): 1127–36. doi:10.1002/hep.20822. PMID 16114043.
  8. ^ "Imetelstat Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on 7 June 2024. Retrieved 7 June 2024.
  9. ^ "Imetelstat Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on 7 June 2024. Retrieved 7 June 2024.
  10. ^ World Health Organization (2010). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 63". WHO Drug Information. 24 (1). hdl:10665/74530.
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Imetelstat&oldid=1249667866"