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mIDH glioma mechanism of disease and VORANIGO® mechanism of action

The role of mIDH in glioma

2-hydroxyglutarate (2-HG) levels are elevated in mIDH astrocytoma and oligodendroglioma.

Mutations to IDH1/2 genes produce mutated IDH1/2 enzymes, which are key players in the Krebs cycle¹
These mutated enzymes lead to the overproduction of 2-HG, which disrupts normal cellular processes, contributing to impaired cellular differentiation and subsequent oncogenesis¹

Oncogenesis in mIDH glioma and the inhibition of mIDH1/2 with VORANIGO^1-3

^*mIDH glioma cells include astrocytes and oligodendrocytes that are mutated in adult-type diffuse glioma.

VORANIGO mechanism of action

VORANIGO was developed to dually target the IDH1/2 enzymes in gliomas.

VORANIGO inhibits mIDH1 and mIDH2 enzymes to decrease the production of 2-HG and partially restore cellular differentiation²
VORANIGO crosses the blood-brain barrier and demonstrated brain tumor penetration^2,4

Explore VORANIGO efficacy in patients with mIDH glioma in the INDIGO trial

mIDH1/2, mutant isocitrate dehydrogenase-1 or mutant isocitrate dehydrogenase-2.

References: 1. Peters KB. Targeting mutant IDH to treat low-grade glioma. touchREVIEWS in Oncology & Haematology. 2023;19(2):7-11. https://doi.org/10.17925/OHR.2023.19.2.3 2. Voranigo. Package insert. Servier Pharmaceuticals LLC; 2024. 3. Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013;13(5):345. doi:10.1007/s11910-013-0345-4 4. Kulkarni AD, Patel HM, Surana SJ, Belgamwar VS, Pardeshi CV. Brain-blood ratio: implications in brain drug delivery. Expert Opin Drug Deliv. 2016;13(1):85-92. doi:10.1517/17425247.2016.1092519

INDICATION

VORANIGO (40 mg tablets) is indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation following surgery including biopsy, sub-total resection, or gross total resection.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hepatotoxicity: VORANIGO can cause hepatic transaminase elevations, which can lead to hepatic failure, hepatic necrosis, and autoimmune hepatitis. Monitor liver laboratory tests (AST, ALT, GGT, total bilirubin, and alkaline phosphatase) prior to the start of VORANIGO, every 2 weeks during the first 2 months of treatment, then monthly for the first 2 years of treatment, and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue VORANIGO based on severity.

Embryo-Fetal Toxicity: Based on findings from animal studies, VORANIGO can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with VORANIGO and for 3 months after the last dose, since VORANIGO can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VORANIGO and for 3 months after the last dose.

ADVERSE REACTIONS

The most common (≥15%) adverse reactions included fatigue, headache, COVID-19, musculoskeletal pain, diarrhea, nausea, and seizure. Grade 3 or 4 (≥2%) laboratory abnormalities were ALT increased, AST increased, GGT increased, and neutrophils decreased.

DRUG INTERACTIONS

Avoid concomitant use of VORANIGO with strong and moderate CYP1A2 inhibitors. Avoid concomitant use with moderate CYP1A2 inducers and smoking tobacco. Avoid concomitant use with CYP3A substrates, where a minimal concentration change can reduce efficacy. If concomitant use of hormonal contraception cannot be avoided, use nonhormonal contraception methods.

LACTATION

Advise women not to breastfeed during VORANIGO treatment and for 2 months after the last dose.

IMPAIRED FERTILITY

VORANIGO may impair fertility of females and males of reproductive potential.

Please see Full Prescribing Information.