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Vorasidenib

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Vorasidenib
Clinical data
Trade namesVoranigo
AHFS/Drugs.comVoranigo
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
  • 6-(6-Chloropyridin-2-yl)-2-N,4-N-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC14H13ClF6N6
Molar mass414.74 g·mol−1
3D model (JSmol)
  • C[C@H](C(F)(F)F)NC1=NC(=NC(=N1)C2=NC(=CC=C2)Cl)N[C@H](C)C(F)(F)F
  • InChI=1S/C14H13ClF6N6/c1-6(13(16,17)18)22-11-25-10(8-4-3-5-9(15)24-8)26-12(27-11)23-7(2)14(19,20)21/h3-7H,1-2H3,(H2,22,23,25,26,27)/t6-,7-/m1/s1
  • Key:QCZAWDGAVJMPTA-RNFRBKRXSA-N

Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma.[4][5] Vorasidenib is a dual mutant isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (mIDH1/2) inhibitor.[4][5]

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[5]

Vorasidenib was approved for medical use in the United States in August 2024.[5][6] It is the first approval by the US Food and Drug Administration (FDA) of a systemic therapy for people with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation.[5]

Medical uses

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Vorasidenib is indicated for the treatment of people aged twelve years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.[5]

Side effects

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The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[5] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.[5]

Pharmacology

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Agios Pharmaceuticals previously developed the mIDH1 inhibitor ivosidenib[7] and mIDH2 inhibitor enasidenib[8][9] for treatment of acute myeloid leukemia (AML) with susceptible IDH1 or IDH2 mutations, respectively. However, ivosidenib and enasidenib have low brain exposure, precluding their use in gliomas.[10] Moreover, isoform switching between IDH1 and IDH2 has been observed as a mechanism of resistance to mIDH inhibitor therapy.[11] Vorasidenib was thus developed to improve blood-brain barrier penetration and inhibit both mIDH1/2.[10]

History

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Efficacy was evaluated in 331 participants with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation following surgery enrolled in INDIGO (NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial.[5] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.[5] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.[5] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression.[5] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.[5]

Society and culture

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Vorasidenib was approved for medical use in the United States in August 2024.[5][12] The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.[5]

References

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  1. ^ a b "Voranigo (vorasidenib)". Therapeutic Goods Administration (TGA). 26 September 2024. Retrieved 12 October 2024.
  2. ^ "Voranigo (Servier Laboratories (Aust) Pty Ltd)". Therapeutic Goods Administration (TGA). 9 December 2024. Retrieved 19 December 2024.
  3. ^ "Notice: Multiple additions to the Prescription Drug List (PDL) [2024-10-18]". Health Canada. 18 October 2024. Retrieved 25 October 2024.
  4. ^ a b c "Voranigo- vorasidenib citrate tablet, film coated". DailyMed. 9 August 2024. Retrieved 15 August 2024.
  5. ^ a b c d e f g h i j k l m n o "FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation". U.S. Food and Drug Administration (FDA). 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ^ "Servier's Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma" (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 – via PR Newswire.
  7. ^ Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). "Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers". ACS Medicinal Chemistry Letters. 9 (4): 300–305. doi:10.1021/acsmedchemlett.7b00421. PMC 5900343. PMID 29670690.
  8. ^ Shih AH, Shank KR, Meydan C, Intlekofer AM, Ward P, Thompson CB, et al. (6 December 2014). "AG-221, a Small Molecule Mutant IDH2 Inhibitor, Remodels the Epigenetic State of IDH2-Mutant Cells and Induces Alterations in Self-Renewal/Differentiation in IDH2-Mutant AML Model in Vivo". Blood. 124 (21): 437. doi:10.1182/blood.V124.21.437.437. ISSN 0006-4971.
  9. ^ Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. (May 2017). "AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations". Cancer Discovery. 7 (5): 478–493. doi:10.1158/2159-8290.CD-16-1034. PMID 28193778.
  10. ^ a b Konteatis Z, Artin E, Nicolay B, Straley K, Padyana AK, Jin L, et al. (February 2020). "Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma". ACS Medicinal Chemistry Letters. 11 (2): 101–107. doi:10.1021/acsmedchemlett.9b00509. PMC 7025383. PMID 32071674.
  11. ^ Harding JJ, Lowery MA, Shih AH, Schvartzman JM, Hou S, Famulare C, et al. (December 2018). "Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition". Cancer Discovery. 8 (12): 1540–1547. doi:10.1158/2159-8290.CD-18-0877. PMC 6699636. PMID 30355724.
  12. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.

Further reading

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  • Clinical trial number NCT04164901 for "Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)" at ClinicalTrials.gov
  • Clinical trial number NCT02481154 for "Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation" at ClinicalTrials.gov
  • Clinical trial number NCT03343197 for "Study of AG-120 and AG-881 in Subjects With Low Grade Glioma" at ClinicalTrials.gov
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