Vorasidenib Explained

Tradename:Voranigo
Dailymedid:Vorasidenib
Pregnancy Au:D
Routes Of Administration:By mouth
Atc Prefix:None
Legal Au:S4
Legal Au Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:[2]
Legal Us:Rx-only
Legal Us Comment:[3]
Cas Number:1644545-52-7
Pubchem:117817422
Iuphar Ligand:10663
Drugbank:DB17097
Chemspiderid:64835242
Unii:789Q85GA8P
Kegg:D11834
Chembl:4279047
Iupac Name:6-(6-Chloropyridin-2-yl)-2-N,4-N-bis[(2''R'')-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine
C:14
H:13
Cl:1
F:6
N:6
Stdinchi: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
Stdinchikey:QCZAWDGAVJMPTA-RNFRBKRXSA-N
Smiles:C[C@H](C(F)(F)F)NC1=NC(=NC(=N1)C2=NC(=CC=C2)Cl)N[C@H](C)C(F)(F)F

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

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

Vorasidenib was approved for medical use in the United States in August 2024.[4] [5] 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.

Medical uses

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.

Side effects

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

Pharmacology

Agios Pharmaceuticals previously developed the mIDH1 inhibitor ivosidenib[6] and mIDH2 inhibitor enasidenib[7] [8] 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.[9] Moreover, isoform switching between IDH1 and IDH2 has been observed as a mechanism of resistance to mIDH inhibitor therapy.[10] Vorasidenib was thus developed to improve blood-brain barrier penetration and inhibit both mIDH1/2.

History

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. Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test. Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.

Society and culture

Legal status

Vorasidenib was approved for medical use in the United States in August 2024.[11] The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.

Further reading

Notes and References

  1. Web site: Voranigo (vorasidenib) . Therapeutic Goods Administration (TGA) . 26 September 2024 . 12 October 2024.
  2. Web site: Notice: Multiple additions to the Prescription Drug List (PDL) [2024-10-18] ]. . 18 October 2024 . 25 October 2024.
  3. Web site: Voranigo- vorasidenib citrate tablet, film coated . DailyMed . 9 August 2024 . 15 August 2024.
  4. Web site: 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 . 7 August 2024 . 7 August 2024 . https://web.archive.org/web/20240807035511/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation . live .
  5. Servier's Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma . Servier Pharmaceuticals . PR Newswire . 6 August 2024 . 7 August 2024 . 7 August 2024 . https://web.archive.org/web/20240807072643/https://www.prnewswire.com/news-releases/serviers-voranigo-vorasidenib-tablets-receives-fda-approval-as-first-targeted-therapy-for-grade-2-idh-mutant-glioma-302215991.html . live .
  6. Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, Cianchetta G, Cai Z, Zhou D, Cui D, Chen P, Straley K, Tobin E, Wang F, David MD, Penard-Lacronique V, Quivoron C, Saada V, de Botton S, Gross S, Dang L, Yang H, Utley L, Chen Y, Kim H, Jin S, Gu Z, Yao G, Luo Z, Lv X, Fang C, Yan L, Olaharski A, Silverman L, Biller S, Su SM, Yen K . 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 . April 2018 . 29670690 . 5900343 . 10.1021/acsmedchemlett.7b00421 .
  7. Shih AH, Shank KR, Meydan C, Intlekofer AM, Ward P, Thompson CB, Melnick AM, Travins J, Straley K, Gliser C, Yen K . 2014-12-06 . 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 . en . 124 . 21 . 437 . 10.1182/blood.V124.21.437.437 . 0006-4971.
  8. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM . AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations . Cancer Discovery . 7 . 5 . 478–493 . May 2017 . 28193778 . 10.1158/2159-8290.CD-16-1034 .
  9. Konteatis Z, Artin E, Nicolay B, Straley K, Padyana AK, Jin L, Chen Y, Narayaraswamy R, Tong S, Wang F, Zhou D, Cui D, Cai Z, Luo Z, Fang C, Tang H, Lv X, Nagaraja R, Yang H, Su SM, Sui Z, Dang L, Yen K, Popovici-Muller J, Codega P, Campos C, Mellinghoff IK, Biller SA . 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 . February 2020 . 32071674 . 7025383 . 10.1021/acsmedchemlett.9b00509 .
  10. Harding JJ, Lowery MA, Shih AH, Schvartzman JM, Hou S, Famulare C, Patel M, Roshal M, Do RK, Zehir A, You D, Selcuklu SD, Viale A, Tallman MS, Hyman DM, Reznik E, Finley LW, Papaemmanuil E, Tosolini A, Frattini MG, MacBeth KJ, Liu G, Fan B, Choe S, Wu B, Janjigian YY, Mellinghoff IK, Diaz LA, Levine RL, Abou-Alfa GK, Stein EM, Intlekofer AM . Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition . Cancer Discovery . 8 . 12 . 1540–1547 . December 2018 . 30355724 . 6699636 . 10.1158/2159-8290.CD-18-0877 .
  11. Web site: Novel Drug Approvals for 2024 . U.S. Food and Drug Administration (FDA) . 1 October 2024 . 29 November 2024.

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