Imetelstat

Last updated

Imetelstat
Imetelstat sodium colored.svg
Imetelstat 3D.png
Clinical data
Trade names Rytelo
Other namesGRN163L
AHFS/Drugs.com Monograph
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
Formula C148H211N68O53P13S13
Molar mass 4610.18 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] [3] 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. [2]

Contents

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. [4]

Imetelstat was approved for medical use in the United States in June 2024. [4] [5] [6]

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. [1] [4]

History

Imetelstat is the first telomerase inhibitor to enter clinical trials. [7]

Chemically, imetelstat is a synthetic conjugate consisting of three parts: GRN163, a thio phosphoramide oligonucleotide, and a palmitoyl lipid group. [7] 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. [8] 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. [9]

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. [4] Participants received an intravenous infusion of imetelstat 7.1 mg/kg or placebo in 28-day treatment cycles until disease progression or unacceptable toxicity. [4] Randomization was stratified by prior red blood cell transfusion burden and by International Prognostic Scoring System (IPSS) risk group. [4] All participants received supportive care, which included red blood cell transfusions. [4]

Society and culture

Imetelstat was approved for medical use in the United States in June 2024. [4] The FDA granted the application for imetelstat orphan drug designation. [4] [10] [11]

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. [2] The applicant for this medicinal product is Geron Netherlands B.V. [2]

Names

Imetelstat is the international nonproprietary name. [12]

Related Research Articles

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Telomerase</span> Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

<span class="mw-page-title-main">Paroxysmal nocturnal hemoglobinuria</span> Blood disease in which red blood cells are attacked by the immune system

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venous blood clot formation. Research suggests that PNH thrombosis is caused by both the absence of GPI-anchored complement regulatory proteins on PNH platelets and the excessive consumption of nitric oxide (NO).

<span class="mw-page-title-main">Chromosome 5q deletion syndrome</span> Human disease

Chromosome 5q deletion syndrome is an acquired, hematological disorder characterized by loss of part of the long arm of human chromosome 5 in bone marrow myelocyte cells. This chromosome abnormality is most commonly associated with the myelodysplastic syndrome.

<span class="mw-page-title-main">Lenalidomide</span> Pair of enantiomers

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is a first line treatment, and is given with dexamethasone. It is taken by mouth.

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

Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.

<span class="mw-page-title-main">Geron Corporation</span> American biotechnology company

Geron Corporation is a biotechnology company located in Foster City, California which specializes in developing and commercializing therapeutic products for cancer that inhibit telomerase.

Eculizumab, sold under the brand name Soliris among others, is a recombinant humanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica. In people with paroxysmal nocturnal hemoglobinuria, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death. Eculizumab was the first medication approved for each of its uses, and its approval was granted based on small trials. It is given by intravenous infusion. It is a humanized monoclonal antibody functioning as a terminal complement inhibitor. It binds to the complement C5 protein and inhibits activation of the complement system, a part of the body's immune system. This binding prevents the breakdown of red blood cells in the bloodstream in people with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

Asunercept is a soluble CD95-Fc fusion protein which is in clinical development for the treatment of glioblastoma multiforme (GBM) and myelodysplastic syndromes (MDS). Asunercept has been granted orphan drug status for the treatment of GBM and MDS in the EU and the US. It has also received PRIME designation by the European Medicines Agency (EMA) for the treatment of GBM.

Luspatercept, sold under the brand name Reblozyl, is a medication used for the treatment of anemia in beta thalassemia and myelodysplastic syndromes.

<span class="mw-page-title-main">Ivosidenib</span> Anti-cancer medication

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.

Ravulizumab, sold under the brand name Ultomiris, is a humanized monoclonal antibody complement inhibitor medication designed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. It is designed to bind to and prevent the activation of Complement component 5 (C5).

Sutimlimab, sold under the brand name Enjaymo, is a monoclonal antibody that is used to treat adults with cold agglutinin disease (CAD). It is given by intravenous infusion. Sutimlimab prevents complement-enhanced activation of autoimmune human B cells in vitro.

<span class="mw-page-title-main">Transfusion-dependent anemia</span> Anemia which requires continuous blood transfusion

Transfusion-dependent anemia is a form of anemia characterized by the need for continuous blood transfusion. It is a condition that results from various diseases, and is associated with decreased survival rates. Regular transfusion is required to reduce the symptoms of anemia by increasing functional red blood cells and hemoglobin count. Symptoms may vary based on the severity of the condition and the most common symptom is fatigue.

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

Decitabine/cedazuridine, sold under the brand name Inqovi among others, is a fixed-dose combination anticancer medication used for the treatment of adults with myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). It is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor.

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

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer. Adagrasib is an inhibitor of G12C mutated KRAS GTPase. It is taken by mouth. It is being developed by Mirati Therapeutics.

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

Belzutifan, sold under the brand name Welireg, is an anti-cancer medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma. It is taken by mouth. Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.

Teclistamab, sold under the brand name Tecvayli, is a human bispecific monoclonal antibody used for the treatment of relapsed and refractory multiple myeloma. It is a bispecific antibody that targets the CD3 receptor expressed on the surface of T-cells and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells.

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

Olezarsen, sold under the brand name Tryngolza, is a medication used in the treatment of familial chylomicronemia syndrome. Olezarsen is an apolipoprotein C-III-directed antisense oligonucleotide. It is given by injection under the skin.

Maia Biotechnology is a public, Texas based, immune-oncology company.

References

  1. 1 2 3 4 "Rytelo- imetelstat sodium injection, powder, lyophilized, for solution". DailyMed. 11 June 2024. Retrieved 5 September 2024.
  2. 1 2 3 4 "Rytelo EPAR". European Medicines Agency (EMA). 12 December 2024. Retrieved 16 December 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ↑ 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.
  4. 1 2 3 4 5 6 7 8 9 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. ↑ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
  6. ↑ "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.
  7. 1 2 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ "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.
  11. ↑ "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.
  12. ↑ World Health Organization (2010). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 63". WHO Drug Information. 24 (1). hdl: 10665/74530 .
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