What Is Vorasidenib (Voranigo)? FDA Approval, Licensing and Reimbursement in Turkey

• Brand Name: Voranigo
• Active Ingredient: Vorasidenib
• Route of Administration: Oral – taken once daily in tablet form.
• Class: Antineoplastic drug
• Category: Isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor
• Manufacturer: Servier Pharmaceuticals LLC, Boston, MA
• Distribution in Turkey: Supplied and sent to patients by the Turkish Pharmacists' Association (TEB).
• Approved Cancers: Grade 2 IDH-mutant glioma – approved particularly for grade 2 astrocytoma and oligodendroglioma carrying IDH1 or IDH2 mutations.

What Is Voranigo?

Voranigo, containing vorasidenib, is an IDH1 and IDH2 inhibitor used to treat grade 2 gliomas that develop in the central nervous system from glial cells, the brain's supporting cells.

Gliomas, the most common central nervous system tumors in adults, can disrupt brain function and cause various symptoms. They are generally highly recurrent and progressive. Mutations in the IDH1 and IDH2 enzymes prevent normal cell differentiation, which may cause uncontrolled growth and tumor formation. By reducing the activity of mutant IDH1 and IDH2 enzymes, vorasidenib lowers the production of 2-hydroxyglutarate (2-HG) and helps control tumor growth.

Mechanism of Action

Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes are found in various cancers, including acute myeloid leukemia (AML) and gliomas. These mutant enzymes produce the oncogenic metabolite D-2-hydroxyglutarate (2-HG). By inhibiting α-ketoglutarate-dependent enzymes, 2-HG contributes to cancer development and tumor growth. This causes epigenetic abnormalities such as DNA hypermethylation and also affects the immune system.

Vorasidenib is a small-molecule inhibitor targeting the IDH1 and IDH2 enzymes. In laboratory studies, it inhibited both wild-type and mutant IDH1 (particularly R132H), as well as wild-type and mutant IDH2. In cell-based and in vivo tumor models expressing mutant IDH1 or IDH2 proteins, vorasidenib reduced 2-HG production and partially restored cellular differentiation.

FDA Approval History

• August 6, 2024: The FDA approved Voranigo for grade 2 glioma carrying IDH1 or IDH2 mutations. It was approved for use after surgery in patients aged 12 and older.

Under this FDA approval, the indication for vorasidenib is as follows:

Indicated for the treatment of grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation in adults and pediatric patients aged 12 and older following surgery, including biopsy, subtotal resection or total resection.

The main result of the phase 3 INDIGO trial that led to FDA approval of vorasidenib is shown below: 

In Summary, the INDIGO Trial Showed:

• IDH1/2-mutant gliomas cannot be cured completely and continually grow and spread in the brain, even after maximal resection.
• Postoperative treatment is limited to radiotherapy and chemotherapy, which carry risks of neurocognitive impairment and debilitating side effects.
• Vorasidenib is an oral inhibitor of mutant IDH1/2 enzymes with demonstrated brain penetration.
• According to the results of a global, multicenter phase 3 trial (INDIGO), vorasidenib:
  • Significantly improves imaging-based progression-free survival and time to the next intervention.
  • Reduces tumor volume.
  • Preserves patient-reported quality of life and maintains seizure control.
  • Has a manageable safety profile.
• Vorasidenib is the first targeted therapy for IDH1/2-mutant diffuse glioma patients, particularly those with treatment-resistant disease who do not urgently need radiotherapy or chemotherapy.

Licensing and Reimbursement in Turkey

Voranigo is currently not licensed by Turkey's Ministry of Health.

However, when it is needed as a treatment option for a patient, the patient may apply to the Turkish Pharmacists' Association (TEB) with a prescription and report from a medical oncologist. The drug may then be imported for that patient.

Mechanisms of Resistance

Research into resistance to this drug is ongoing. However, mechanisms of resistance to similar IDH inhibitors used in acute myeloid leukemia (AML) may also apply to vorasidenib.

Resistance to vorasidenib may develop through secondary mutations in IDH enzymes, isoform switching, activation of alternative signaling pathways, epigenetic changes and tumor microenvironment factors as possible mechanisms.

Pharmacologic Properties

Absorption

Vorasidenib is well absorbed after oral administration. With daily use, it reaches steady state within 28 days. Bioavailability is 34%, and its concentration in the body increases after a high-fat, high-calorie meal.

Distribution

The steady-state volume of distribution of vorasidenib is approximately 3,930 L. It can cross the blood–brain barrier and reach brain tissue. The brain tumor-to-plasma concentration ratio is 1.6, indicating its potential to provide effective treatment for brain tumors such as gliomas. Plasma protein binding is 97% and is concentration-independent.

Metabolism

Vorasidenib is metabolized mainly by CYP1A2 in the liver, with smaller contributions from enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. Its metabolic pathways have not been fully characterized, and up to 30% may be metabolized through non-CYP pathways.

Excretion

After a single oral dose, 85% of vorasidenib is excreted in feces (56% of this unchanged), while 4.5% is excreted in urine.

Half-Life and Clearance

The average terminal half-life of vorasidenib at steady state is 10 days, and steady-state oral clearance is approximately 14 L/hour.

Dose Range

Adult Dose: 40 mg orally once daily

Pediatric Patients (Age 12 and Older):

• 40 kg or more: 40 mg/day
• Below 40 kg: 20 mg/day

Treatment continues until disease progression or unacceptable toxicity.

Drug Interactions

Several important interactions require attention when it is used with other drugs:

• CYP1A2 Inhibitors: Vorasidenib is metabolized primarily by CYP1A2. Strong and moderate CYP1A2 inhibitors, such as ciprofloxacin , may increase vorasidenib plasma levels and the risk of side effects. Concomitant use with these inhibitors should therefore be avoided.
• CYP1A2 Inducers: Moderate CYP1A2 inducers and tobacco use may reduce vorasidenib's efficacy. It is therefore recommended to avoid smoking and avoid concomitant use of these inducers.
• CYP3A Substrates: Vorasidenib may reduce plasma concentrations of certain CYP3A substrates. This is particularly important for drugs with a narrow therapeutic range. Concomitant use with such drugs should be avoided.
• Hormonal Contraceptives: Vorasidenib may reduce the effectiveness of hormonal contraception. Additional or alternative contraception should therefore be used during treatment and for at least 3 months afterward.
• Herbal products such as St. John's Wort may also interact with vorasidenib. It is therefore important to consult your doctor before taking herbal supplements.

Precautions

1. Liver Function: Vorasidenib is metabolized in the liver and may increase liver enzymes. Regular liver function tests should therefore be performed.
2. CYP1A2 Inhibitors and Inducers: It interacts with drugs that affect CYP1A2. Strong inhibitors, such as ciprofloxacin, may increase vorasidenib levels, while inducers, such as smoking, may reduce its efficacy.
3. Hormonal Contraceptives: Vorasidenib may reduce the effectiveness of contraceptive drugs. Additional or alternative contraception should be used during treatment.
4. Side Effects: Watch for common side effects such as headache, fatigue and nausea. Seek medical advice if serious adverse effects occur.
5. Pregnancy and Breastfeeding: Vorasidenib is not recommended during pregnancy or breastfeeding because it may harm the fetus or infant.
6. Regular Monitoring: Patients should remain under medical supervision throughout treatment and undergo the specified tests regularly.

Side Effects

Most Common Side Effects (≥15%)

• Fatigue
• Headache
• COVID-19
• Musculoskeletal pain
• Diarrhea
• Nausea
• Seizure

Serious Adverse Effects

• Hepatotoxicity: Elevated liver enzymes (ALT, AST, GGT)
• Risk of Fetal Harm: Contraindicated during pregnancy.