Vorasidenib

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]

Vorasidenib

Clinical data
Trade names	Voranigo
AHFS/Drugs.com	Monograph
MedlinePlus	a624055
License data	US DailyMed: Vorasidenib
Pregnancy category	AU: D[1]
Routes of administration	By mouth
ATC code	L01XM04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1][2] CA: ℞-only[3][4] US: ℞-only[5]
Identifiers
IUPAC name 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	1644545-52-7
PubChem CID	117817422
IUPHAR/BPS	10663
DrugBank	DB17097
ChemSpider	64835242
UNII	789Q85GA8P
KEGG	D11834
ChEMBL	ChEMBL4279047
Chemical and physical data
Formula	C14H13ClF6N6
Molar mass	414.74 g·mol−1
3D model (JSmol)	Interactive image
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
InChI 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

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

Legal status

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]