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Imetelstat

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Overview

Description
A medication used to treat blood cancers in certain anemic patients.
Structure
Description
A medication used to treat blood cancers in certain anemic patients.
DrugBank ID
DB14909
Type
Small Molecule
US Approved
YES
Other Approved
NO
Patents
4
Indicated Conditions
1
Clinical Trials
Phase 0
0
Phase 1
10
Phase 2
12
Phase 3
2
Phase 4
0
Mechanism of Action

Identification

Summary

Imetelstat is a human telomerase inhibitor used to treat myelodysplastic syndromes in patients with transfusion-dependent anemia.

Brand Names
Rytelo
Generic Name
Imetelstat
DrugBank Accession Number
DB14909
Background

Imetelstat is a first-in-class 18-amino acid oligonucleotide that directly and competitively inhibits human telomerase.1 It is used to treat anemia in patients with myelodysplastic syndromes (MDS), a group of hematologic disorders characterized by ineffective hematopoiesis, peripheral cytopenia, abnormal marrow cell morphology and a risk for transformation to acute myeloid leukemia.2 Standard therapy for anemia in patients with MDS involves the use of erythropoiesis-stimulating agents (e.g. erythropoietin), but primary resistance to these agents is frequent - the median response duration is 18 to 24 months, with most responders (70%) relapsing due to loss of sensitivity of erythroid progenitors to ESAs.2

Imetelstat received FDA approval in June 2024 for use in certain patients with MDS who have transfusion-dependent anemia and are unable to use ESAs.3,4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Similar Structures
Weight
Average: 4610.18
Monoisotopic: 4606.886420162
Chemical Formula
C148H211N68O53P13S13
Synonyms
  • Imetelstat
External IDs
  • GRN-163L
  • GRN163L
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Pharmacology

Indication

Imetelstat is indicated for the treatment of adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring four or more red blood cell units over eight weeks who have not responded to, are no longer responsive to, or are ineligible for erythropoiesis-stimulating agents (ESA).3

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofLow- or intermediate-1-risk myelodysplastic syndrome (mds)••••••••••••••••••••••••••••••••• •••••••••••••••
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Pharmacodynamics

Non-clinical studies have shown that treatment with imetelstat leads to a reduction in telomere length, reduction of malignant stem and progenitor cell proliferation, and the induction of apoptotic cell death.3

Mechanism of action

Imetelstat exerts its therapeutic effects by binding to the RNA template component of telomerase, directly inhibiting its activity.3 This inhibition leads to the progressive shortening of telomeres in cancerous cells, ultimately resulting in cell death. The selectivity of imetelstat for malignant cells is due to a relatively higher telomerase activity in myelodysplastic syndrome and malignant stem and progenitor cells compared to normal cells.

TargetActionsOrganism
ATelomerase reverse transcriptase
inhibitor
Humans
AHuman telomerase RNA component
binder
Humans
Absorption

Imetelstat is effectively 100% bioavailable given its intravenous administration. The geometric mean maximum plasma concentration (Cmax) is 18.3 µM and the AUC from 0 to 28 days (AUC0-28 is 114.2 h*µM.3 It does not accumulate between treatment cycles.

Volume of distribution

The geometric mean volume of distribution of imetelstat following a single intravenous dose of 7.1 mg/kg administered over 2 hours in patients with myelodysplastic syndromes is approximately 14.1 liters.3

Protein binding

In vitro, human plasma protein binding is >94%.3 The specific protein(s) to which imetelstat binds are unclear.

Metabolism

Imetelstat is likely metabolized by non-specific nucleases to smaller nucleotides.3

Route of elimination

Not Available

Half-life

The geometric mean apparent plasma half-life of imetelstat is approximately 4.9 hours when given at the approved recommended dosage.3

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available
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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.
DrugInteraction
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interactions in your software
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Imetelstat.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Imetelstat is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Imetelstat is combined with Articaine.
AsunaprevirThe serum concentration of Asunaprevir can be increased when it is combined with Imetelstat.
AtogepantThe serum concentration of Atogepant can be increased when it is combined with Imetelstat.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Imetelstat sodium2AW48LAZ4I1007380-31-5IEVORMRANFJJFR-UHFFFAOYSA-A
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RyteloInjection, powder, lyophilized, for solution188 mg/1IntravenousGeron Corporation2024-06-06Not applicableUS flag
RyteloInjection, powder, lyophilized, for solution47 mg/1IntravenousGeron Corporation2024-06-06Not applicableUS flag

Categories

ATC Codes
L01XX80 — Imetelstat
Drug Categories
Classification
Not classified
Affected organisms
  • Humans

Chemical Identifiers

UNII
F60NE4XB53
CAS number
868169-64-6
InChI Key
LVZYXEALRXBLJZ-UHFFFAOYSA-N
InChI
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)
IUPAC Name
[(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)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-[({[(2S,3S,5R)-3-[({[(2S,3S,5R)-3-amino-5-(6-amino-9H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(6-amino-9H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(6-amino-9H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(6-amino-9H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(6-amino-9H-purin-9-yl)oxolan-2-yl]methoxy}(sulfanyl)phosphoryl)amino]-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-2-yl]methyl 3-hexadecanamido-2-hydroxypropyl sulfanylphosphonate
SMILES
CCCCCCCCCCCCCCCC(=O)NCC(O)COP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1NP(S)(=O)OCC1OC(CC1N)N1C=NC2=C1N=CN=C2N)N1C=NC2=C1N=CN=C2N)N1C=CC(N)=NC1=O)N1C=NC2=C1N=CN=C2N)N1C=NC2=C1N=C(N)NC2=O)N1C=NC2=C1N=CN=C2N)N1C=C(C)C(=O)NC1=O)N1C=C(C)C(=O)NC1=O)N1C=NC2=C1N=C(N)NC2=O)N1C=NC2=C1N=C(N)NC2=O)N1C=NC2=C1N=C(N)NC2=O)N1C=NC2=C1N=CN=C2N)N1C=C(C)C(=O)NC1=O

References

General References
  1. Lucero J, Al-Harbi S, Yee KWL: Management of Patients with Lower-Risk Myelodysplastic Neoplasms (MDS). Curr Oncol. 2023 Jun 27;30(7):6177-6196. doi: 10.3390/curroncol30070459. [Article]
  2. Kubasch AS, Platzbecker U: Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes. Int J Mol Sci. 2019 Aug 7;20(16). pii: ijms20163853. doi: 10.3390/ijms20163853. [Article]
  3. FDA Approved Drug Products: Rytelo (imetelstat) injection for intravenous use [Link]
  4. Geron Corporation Press Release: 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 [Link]
RxNav
2685236
Wikipedia
Geron_Corporation

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not AvailableApproved for MarketingNot AvailableMyelodysplastic Syndrome1somestatusstop reasonjust information to hide
3RecruitingTreatmentMyelofibrosis1somestatusstop reasonjust information to hide
2CompletedTreatmentEssential Thrombocythemia (ET) / Polycythemia Vera (PV)1somestatusstop reasonjust information to hide
2CompletedTreatmentLocally Recurrent and Metastatic Breast Cancer1somestatusstop reasonjust information to hide
2CompletedTreatmentMultiple Myeloma (MM)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous188 mg/1
Injection, powder, lyophilized, for solutionIntravenous47 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9388416No2004-09-092024-09-09US flag
US9388415No2004-09-092024-09-09US flag
US9375485No2013-03-152033-03-15US flag
US7494982No2005-12-272025-12-27US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityHighly solublehttps://pi.geron.com/products/US/pi/rytelo_pi.pdf
Predicted Properties
PropertyValueSource
logP-3.2Chemaxon
pKa (Strongest Acidic)0.29Chemaxon
Physiological Charge-12Chemaxon
Hydrogen Acceptor Count74Chemaxon
Hydrogen Donor Count45Chemaxon
Polar Surface Area1587.05 Å2Chemaxon
Rotatable Bond Count95Chemaxon
Refractivity1045.35 m3·mol-1Chemaxon
Polarizability442.86 Å3Chemaxon
Number of Rings35Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Telomerase reverse transcriptase
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis
Specific Function
DNA binding
Gene Name
TERT
Uniprot ID
O14746
Uniprot Name
Telomerase reverse transcriptase
Molecular Weight
126995.435 Da
References
  1. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Details2. Human telomerase RNA component
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Binder
References
  1. FDA Approved Drug Products: Rytelo (imetelstat) injection for intravenous use [Link]

Transporters

Details1. Solute carrier organic anion transporter family member 1B1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function
bile acid transmembrane transporter activity
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Rytelo (imetelstat) injection for intravenous use [Link]
Details2. Solute carrier organic anion transporter family member 1B3
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function
bile acid transmembrane transporter activity
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: Rytelo (imetelstat) injection for intravenous use [Link]

Drug created at May 20, 2019 14:34 / Updated at November 09, 2024 06:20