Vorasidenib

Vorasidenib is an inhibitor of the mutated forms of the enzymes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2). In astrocytoma and oligodendroglioma, IDH1 or IDH2 mutations make the tumour cells overproduce the oncogenic metabolite 2-hydroxyglutarate (2-HG), which impairs cell differentiation and contributes to tumour growth. Vorasidenib reduces that production. Its use rests on INDIGO, a randomised (1:1), double-blind, placebo-controlled phase 3 study in 331 adults and adolescents aged 12 years and older (weighing at least 40 kg) with grade 2 astrocytoma or oligodendroglioma and an IDH1 R132 or IDH2 R172 mutation, whose only treatment so far had been surgery. In that study vorasidenib prolonged progression-free survival and delayed the time to the next anticancer intervention compared with placebo.

Mechanism of Action

• Target: vorasidenib inhibits the mutant IDH1 (R132) and IDH2 (R172) enzymes. In vitro it also inhibited the wild-type and mutant variants of both enzymes, including IDH1 R132H.
• Oncometabolite: the mutant enzymes produce D-2-hydroxyglutarate (2-HG), which blocks α-ketoglutarate-dependent enzymes and causes epigenetic changes such as widespread DNA hypermethylation. Inhibiting the mutant enzymes reduces 2-HG production, which allows malignant cells to differentiate and reduces their proliferation.
• Pharmacodynamic effect: a therapeutic daily dose lowered the 2-HG concentration in the tumours of patients with IDH1- or IDH2-mutated glioma.
• Brain exposure: vorasidenib crosses the blood–brain barrier; the brain tumour-to-plasma concentration ratio is 1.6.

Pharmacokinetics

• Absorption: after a single 40 mg dose the median time to peak concentration is 2 hours, with a geometric mean Cmax of 75.4 ng/mL and AUC of 2,860 ng·h/mL. At steady state, Cmax is 133 ng/mL and AUC 1,988 ng·h/mL, with accumulation of about 3.8-fold (Cmax) and 4.4-fold (AUC); steady state is reached after 2 to 3 weeks of once-daily dosing. Most patients show a second, lower peak within 24 hours. Absolute bioavailability has not been measured directly; absorption is estimated to be moderate to high.
• Food effect: a high-fat meal raised Cmax 3.1-fold and AUC 1.4-fold, and a low-fat meal raised them 2.3-fold and 1.4-fold. For this reason the tablets are taken without food (none for 2 hours before and 1 hour after).
• Distribution: apparent volume of distribution about 3,930 L; plasma protein binding about 97% for vorasidenib and 87% for its metabolite AGI-69460, mainly to albumin. The blood-to-plasma ratio is 0.87.
• Metabolism: mainly by CYP1A2, with negligible to minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5; non-CYP pathways may account for up to 30% of hepatic metabolic clearance. AGI-69460 is a downstream active metabolite whose levels peak much later (about 336 hours after a single dose). In vitro, vorasidenib is a strong inducer through activation of the pregnane X receptor (PXR) and an inhibitor of the breast cancer resistance protein (BCRP).
• Elimination: mean terminal half-life at steady state about 10 days. After a single radiolabelled dose, 85% of the radioactivity was recovered in faeces (56% as unchanged vorasidenib) and 4.5% in urine.
• Special populations: pharmacokinetics are similar in patients with low-grade glioma and in healthy subjects. No dose adjustment is needed for patients aged 65 or over, or for mild or moderate hepatic impairment or an estimated glomerular filtration rate (eGFR) above 40 mL/min/1.73 m². The medicine has not been studied in severe hepatic impairment or in eGFR of 40 or below.

Vorasidenib is used as monotherapy.

• Grade 2 astrocytoma or oligodendroglioma with an IDH mutation: predominantly non-enhancing grade 2 astrocytoma or oligodendroglioma with an IDH1 R132 or IDH2 R172 mutation, in adults and adolescents aged 12 years and older weighing at least 40 kg.
• Prior treatment and timing: patients who have had surgical intervention only and are not in immediate need of radiotherapy or chemotherapy.
• Mutation test required: the IDH1 R132 or IDH2 R172 mutation must be confirmed before treatment with a CE-marked in vitro diagnostic test for this purpose or, if none is available, an alternative validated test.

• Hypersensitivity to vorasidenib or to any of the excipients.

The frequencies come from the INDIGO study (167 patients treated with vorasidenib) and from post-marketing experience. The most common reactions, including laboratory abnormalities, were raised ALT (59.3%), raised AST (45.5%), raised gamma-glutamyl transferase (GGT, 37.7%), fatigue (36.5%) and diarrhoea (24.6%). The most common grade 3 or higher reactions were raised ALT (9.6%), raised AST (4.2%) and raised GGT (3.0%).

Very common (≥1/10): decreased platelet count, dizziness, diarrhoea, abdominal pain, increased ALT, increased AST, increased GGT, fatigue.

Common (≥1/100 to <1/10): hyperglycaemia, decreased appetite, hypophosphataemia, dyspnoea, gastro-oesophageal reflux disease, increased alkaline phosphatase, increased blood bilirubin.

Uncommon (≥1/1,000 to <1/100): hepatic failure, autoimmune hepatitis, hepatic necrosis.

Not known: drug-induced liver injury and acute hepatitis (identified after authorisation).

Liver injury is the important serious reaction. Hepatic failure, autoimmune hepatitis and raised ALT were each reported as a serious reaction in 0.6% of patients. In INDIGO, ALT rose above 3 times the upper limit of normal (ULN) in 18.6% of patients and AST in 8.4%; in 1.2% ALT or AST above 3 × ULN occurred together with total bilirubin above 2 × ULN. The increases were transient and improved or resolved with dose modification or permanent discontinuation; the median time to first onset was 85 days for AST and 57 days for ALT.

Adverse reactions led to dose interruption in 18.6% of patients (mainly raised ALT 14.4% and raised AST 6.0%) and to dose reduction in 9.6% (mainly raised ALT 7.8%). Treatment was stopped permanently for grade 3 or higher raised ALT in 3.0% of patients and for autoimmune hepatitis in 0.6%.

Vorasidenib is metabolised mainly by CYP1A2. Based on in vitro data it is also a strong inducer through PXR activation, so it may lower the exposure to many co-administered medicines that are metabolised or transported by PXR-regulated enzymes and transporters.

• Strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin): may raise vorasidenib levels. With ciprofloxacin 500 mg twice daily for 14 days, the Cmax of a 20 mg vorasidenib dose rose by 29% and the AUC by 153%. Avoid strong CYP1A2 inhibitors and consider alternatives.
• Moderate CYP1A2 inducers (phenytoin, rifampicin): may lower vorasidenib levels. Consider alternatives that are not moderate CYP1A2 inducers.
• Gastric acid reducing agents (omeprazole): no clinically significant effect on vorasidenib pharmacokinetics.
• CYP substrates with a narrow therapeutic index (substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4): their plasma levels may fall. The SmPC names, among others, amitriptyline, alfentanil, carbamazepine, ciclosporin, dosulepin, everolimus, fentanyl, fosphenytoin, ifosfamide, imipramine, phenobarbital, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, tamoxifen, trimipramine, valproic acid and warfarin. Avoid using such medicines in patients taking vorasidenib.
• Sensitive CYP substrates without a narrow therapeutic index (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4): their levels may also fall. The SmPC names, among others, bupropion, buspirone, celecoxib, darunavir, ibrutinib, midazolam, repaglinide, saquinavir, tipranavir and triazolam. Consider alternatives that are not sensitive substrates.
• BCRP substrates (for example rosuvastatin): vorasidenib inhibits BCRP in vitro, so use such medicines with caution.
• Hormonal contraceptives: vorasidenib may lower their concentrations, so a barrier method of contraception is recommended during treatment and for at least 2 months after the last dose.
• Food: take on an empty stomach, with no food for at least 2 hours before and 1 hour after the dose.

Treatment should be started and supervised by a physician experienced in the use of anti-cancer medicinal products. Before treatment, the IDH1 R132 or IDH2 R172 mutation must be confirmed with a CE-marked in vitro diagnostic test or, if none is available, an alternative validated test. The tablets are taken once daily at about the same time each day, swallowed whole with a glass of water, and must not be split, crushed or chewed. Patients should not eat for at least 2 hours before and 1 hour after taking them.

Recommended Dose

• 40 mg once daily in adults and adolescents aged 12 years and older who weigh at least 40 kg.
• No dose recommendation can be made for patients weighing under 40 kg, because there are no clinical data.
• Treatment continues as long as clinical benefit is observed or until the patient can no longer tolerate it.

Monitoring

Complete blood counts and blood chemistry, including liver enzymes, are assessed before starting, every 2 weeks during the first 2 months, then monthly for the first 2 years of treatment, and as clinically indicated afterwards. Some patients may need more frequent and continued monitoring.

Dose Reductions

• Starting dose 40 mg once daily (one 40 mg tablet).
• First reduction 20 mg once daily (two 10 mg tablets).
• Second reduction 10 mg once daily (one 10 mg tablet).

Dose Modifications for Adverse Reactions

Severity is graded by the NCI Common Terminology Criteria for Adverse Events, version 5.0.

• Raised ALT or AST, grade 1 (above ULN up to 3 × ULN, without bilirubin above 2 × ULN): continue at the current dose and monitor liver enzymes weekly until recovery to below grade 1.
• Grade 2 (above 3 up to 5 × ULN, without bilirubin above 2 × ULN):
  • First occurrence: withhold vorasidenib and monitor liver enzymes twice a week until recovery to grade 1 or baseline. If recovery takes 28 days or less, resume at the same dose; if it takes longer, resume at the reduced dose.
  • Recurrence: withhold, monitor twice a week until recovery to grade 1 or baseline, and resume at the reduced dose.
• Grade 3 (above 5 up to 20 × ULN, without bilirubin above 2 × ULN):
  • First occurrence: withhold and monitor twice a week until recovery to grade 1 or baseline. If recovery takes 28 days or less, resume at the reduced dose; if it does not, stop permanently.
  • Recurrence: stop permanently and monitor twice a week until recovery to grade 1 or baseline.
• Grade 2 or 3 with bilirubin above 2 × ULN (ALT or AST above 3 up to 20 × ULN, with no clear alternative explanation): stop permanently and monitor twice a week until recovery to grade 1 or baseline. If another cause is identified, resuming at a reduced dose can be considered once the values return to grade 1 or baseline.
• Grade 4 (ALT or AST above 20 × ULN): stop permanently and monitor twice a week until recovery to grade 1 or baseline.
• Other adverse reactions, grade 3: first occurrence, withhold until recovery to grade 1 or baseline, then resume at the reduced dose; recurrence, stop permanently.
• Other adverse reactions, grade 4: stop permanently.

Special Populations

• Elderly: no dose adjustment at 65 years or over.
• Renal impairment: no starting dose adjustment when the eGFR is above 40 mL/min/1.73 m². Vorasidenib has not been studied at an eGFR of 40 or below or in patients on dialysis, and should not be used in them.
• Hepatic impairment: no starting dose adjustment in mild or moderate impairment (Child-Pugh A or B). It has not been studied in severe impairment (Child-Pugh C); use with caution and monitor closely.
• Children and adolescents: the indication starts at 12 years. No clinical data are available in patients aged 12 to under 18 years, and no dose can be recommended below 40 kg.

Missed or Vomited Dose

A missed dose, or one not taken at the usual time, is taken as soon as possible within 6 hours; the next dose is taken at the regular time. If more than 6 hours have passed, the dose is skipped. If a dose is vomited, no replacement tablets are taken; the tablets are taken as usual the next day.

Liver Injury

Drug-induced liver injury, including serious cases of hepatic failure, hepatic necrosis and acute hepatitis, has been reported in the pivotal study and after marketing. ALT, AST, GGT and total bilirubin must be measured before treatment, every 2 weeks during the first 2 months, then monthly for the first 2 years, and as clinically indicated afterwards. Weekly monitoring should be considered for ALT or AST elevations of up to 3 × ULN. Treatment is withheld, reduced or stopped permanently according to severity (see Administration and Dosage).

Carcinogenicity Risk

Animal findings, notably in the liver, may suggest a potential carcinogenic risk. Carcinogenicity studies have not yet been done and long-term clinical safety data are insufficient, so a carcinogenic risk in humans cannot be excluded.

Contraception and Pregnancy Testing

• Women of childbearing potential: vorasidenib could cause foetal harm. A pregnancy test is recommended before starting, and effective contraception should be used during treatment and for at least 2 months after the last dose. Because vorasidenib may lower the concentrations of hormonal contraceptives, a barrier method should be added. Women planning to conceive should seek reproductive counselling.
• Male patients: men with female partners of childbearing potential should use effective contraception during treatment and for at least 2 months after the last dose, and should seek advice on sperm cryopreservation before treatment.

Hepatic and Renal Impairment

The safety and efficacy of vorasidenib have not been established in severe hepatic impairment (Child-Pugh C); it should be used with caution and these patients monitored closely. It should not be used in patients with an eGFR of 40 mL/min/1.73 m² or below or on dialysis.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no or limited data in pregnant women, and animal studies showed embryo-foetal toxicity. Vorasidenib should not be used during pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether vorasidenib or its metabolites pass into human milk. Breastfeeding should be stopped during treatment and for at least 2 months after the last dose.
• Fertility: there are no human data. Findings in the reproductive organs of female and male animals were seen in repeat-dose toxicity studies, and their clinical relevance is unknown. Patients planning to conceive should seek reproductive counselling.

Lactose and Sodium

The tablets contain lactose (0.60 mg in the 10 mg tablet, 2.39 mg in the 40 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Vorasidenib has no or negligible influence on the ability to drive and use machines.

Voranigo tablets do not require any special storage conditions. They are supplied in a white HDPE bottle with a child-resistant polypropylene closure and an induction-sealed liner; the bottle also holds three silica gel desiccants in HDPE canisters. The pack size is 30 film-coated tablets. As with all medicines, keep out of the sight and reach of children.

48 months. Do not use after the expiry date on the bottle.

Prescription only (Rx), on restricted medical prescription (Annex II B) from a physician experienced in the use of anti-cancer medicinal products, after the IDH1 R132 or IDH2 R172 mutation has been confirmed. Vorasidenib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.