Vorasidenib
TradenameVoranigo
Medlineplusa624055
DailymedidVorasidenib
Pregnancy auD
Pregnancy au comment[1]
Routes of administrationBy mouth
Atc prefixL01
Atc suffixXM04
Legal auS4
Legal au comment[1][2]
Legal caRx-only
Legal ca comment[3][4]
Legal usRx-only
Legal us comment[5]
Cas number1644545-52-7
Pubchem117817422
Iuphar ligand10663
DrugbankDB17097
Chemspiderid64835242
Unii789Q85GA8P
KeggD11834
Chembl4279047
Iupac name6-(6-Chloropyridin-2-yl)-2-N,4-N-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine
C14
H13
Cl1
F6
N6
Stdinchi1S/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
StdinchikeyQCZAWDGAVJMPTA-RNFRBKRXSA-N
SmilesC[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.[5][6] Vorasidenib is a dual mutant isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) inhibitor.[5][6] In people with astrocytoma or oligodendroglioma, IDH1 and IDH2 mutations lead to overproduction of the oncogenic metabolite 2-hydroxyglutarate (2-HG), which results in impaired cellular differentiation contributing to oncogenesis.[7] By inhibiting the IDH1 and IDH2 mutated proteins, vorasidenib inhibits the abnormal production of 2-HG thereby leading to differentiation of malignant cells and a reduction in their proliferation.[7]

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[6]

Vorasidenib was approved for medical use in the United States in August 2024.[6][8][9] 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.[6]

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.[6]

Side effects

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[6] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.[6]

Pharmacology

Agios Pharmaceuticals previously developed the mIDH1 inhibitor ivosidenib[10] and mIDH2 inhibitor enasidenib[11][12] 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.[13] Moreover, isoform switching between IDH1 and IDH2 has been observed as a mechanism of resistance to mIDH inhibitor therapy.[14] Vorasidenib was thus developed to improve blood-brain barrier penetration and inhibit both mIDH1/2.[13]

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.[6] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.[6] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.[6] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression.[6] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.[6]

Society and culture

Vorasidenib was approved for medical use in the United States in August 2024.[6][15] The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.[6]

In July 2025, 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 Voranigo, intended for the treatment of low grade astrocytoma or oligodendroglioma with an isocitrate dehydrogenase‑1 (IDH1) R132 or isocitrate dehydrogenase-2 (IDH2) R172 mutation in people aged twelve years of age and older weighing at least 40 kilograms (88 lb).[7] The applicant for this medicinal product is Les Laboratoires Servier.[7]

References

  1. ^ "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. ^ "Summary Basis of Decision for Voranigo". Drug and Health Products Portal. 5 December 2024. Retrieved 25 January 2025.
  4. ^ "Voranigo product information". Health Canada. 21 October 2024. Retrieved 27 December 2024.
  5. ^ "Voranigo- vorasidenib citrate tablet, film coated". DailyMed. 9 August 2024. Retrieved 15 August 2024.
  6. ^ "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 7 August 2024 at the Wayback Machine. Retrieved 7 August 2024.
  7. ^ "Voranigo EPAR". European Medicines Agency (EMA). 25 July 2025. Retrieved 27 July 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ^ "New Drug Therapy Approvals 2024" (PDF). U.S. Food and Drug Administration (FDA). January 2025. Archived 21 January 2025 at the Wayback Machine. Retrieved 21 January 2025.
  9. ^ "Servier's Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma". Servier Pharmaceuticals. 6 August 2024. Archived 7 August 2024 at the Wayback Machine. Retrieved 7 August 2024. – via PR Newswire.
  10. ^ 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 (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
  11. ^ Shih AH, Shank KR, Meydan C, Intlekofer AM, Ward P, Thompson CB, Melnick AM, Travins J, Straley K, Gliser C, Yen K (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
  12. ^ 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 (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
  13. ^ 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 (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
  14. ^ 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 (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
  15. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.

Further reading

  • Mellinghoff IK, Lu M, Wen PY, Taylor JW, Maher EA, Arrillaga-Romany I, Peters KB, Ellingson BM, Rosenblum MK, Chun S, Le K, Tassinari A, Choe S, Toubouti Y, Schoenfeld S, Pandya SS, Hassan I, Steelman L, Clarke JL, Cloughesy TF (March 2023). "Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial". Nature Medicine. 29 (3): 615–622. doi:10.1038/s41591-022-02141-2. PMC 10313524. PMID 36823302
  • Mellinghoff IK, Penas-Prado M, Peters KB, Burris HA, Maher EA, Janku F, Cote GM, de la Fuente MI, Clarke JL, Ellingson BM, Chun S, Young RJ, Liu H, Choe S, Lu M, Le K, Hassan I, Steelman L, Pandya SS, Cloughesy TF, Wen PY (August 2021). "Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial". Clinical Cancer Research. 27 (16): 4491–4499. doi:10.1158/1078-0432.CCR-21-0611. PMC 8364866. PMID 34078652
  • Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, Mendez J, Yust-Katz S, Welsh L, Mason WP, Ducray F, Umemura Y, Nabors B, Holdhoff M, Hottinger AF, Arakawa Y, Sepulveda JM, Wick W, Soffietti R, Perry JR, Giglio P, de la Fuente M, Maher EA, Schoenfeld S, Zhao D, Pandya SS, Steelman L, Hassan I, Wen PY, Cloughesy TF (August 2023). "Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma". The New England Journal of Medicine. 389 (7): 589–601. doi:10.1056/NEJMoa2304194. PMC 11445763. PMID 37272516
  • 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 (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