Chemistry:Vorasidenib

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Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma.[1][2] Vorasidenib is a dual mutant isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) inhibitor.[1][2] 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.[3] 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.[3]

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[2]

Vorasidenib was approved for medical use in the United States in August 2024.[2][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.[2]

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.[2]

Side effects

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[2] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.[2]

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.[9]

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

Society and culture

Vorasidenib was approved for medical use in the United States in August 2024.[2][11] The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.[2]

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).[3] The applicant for this medicinal product is Les Laboratoires Servier.[3]

References

  1. ↑ 1.0 1.1 Cite error: Invalid <ref> tag; no text was provided for refs named Voranigo FDA label
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 "FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation". 6 August 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation.  Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ 3.0 3.1 3.2 3.3 "Voranigo EPAR". 25 July 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/voranigo.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ (PDF) New Drug Therapy Approvals 2024 (Report). January 2025. https://www.fda.gov/media/184967/download. Retrieved 21 January 2025. 
  5. ↑ "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.
  6. ↑ "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. doi:10.1021/acsmedchemlett.7b00421. PMID 29670690. 
  7. ↑ "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" (in en). Blood 124 (21): 437. December 2014. doi:10.1182/blood.V124.21.437.437. ISSN 0006-4971. https://ashpublications.org/blood/article/124/21/437/91960/AG221-a-Small-Molecule-Mutant-IDH2-Inhibitor. 
  8. ↑ "AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations". Cancer Discovery 7 (5): 478–493. May 2017. doi:10.1158/2159-8290.CD-16-1034. PMID 28193778. 
  9. ↑ 9.0 9.1 "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. doi:10.1021/acsmedchemlett.9b00509. PMID 32071674. 
  10. ↑ "Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition". Cancer Discovery 8 (12): 1540–1547. December 2018. doi:10.1158/2159-8290.CD-18-0877. PMID 30355724. 
  11. ↑ "Novel Drug Approvals for 2024". 1 October 2024. https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024. 

Further reading

  • 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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