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Voranigo (vorasidenib)
Australian Prescription Medicine Decision Summary
ARTGs
Device/Product name
Voranigo
Active Ingredient
vorasidenib
Date of decision
Published
Submission type
Type A - New chemical entity
Decision
Approved
What was the decision based on
The decision was based on:
-Quality (chemistry and manufacturing),
-Nonclinical (pharmacology and toxicology),
-Clinical (pharmacology, safety and efficacy) and
-Risk management plan information submitted by the sponsor.
The Sponsor demonstrated the efficacy of Voranigo in patients in a pivotal clinical study (Study AG881-C-004), "INDIGO", a phase 3, multi-centre, randomised, double-blind, placebo-controlled study of vorasidenib in subjects with residual or recurrent Grade 2 glioma with an isocitrate dehydrogenase (IDH)1 or IDH2 mutation. Vorasidenib is an inhibitor of the isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) proteins that carry certain mutations. As a result, a substance called 2-hydroxyglutarate (2-HG) is overproduced which contributes to the formation of cancer cells.
The primary study objective was to demonstrate the efficacy of vorasidenib based on radiographic progression-free survival compared with placebo in subjects with residual or recurrent Grade 2 oligodendroglioma and astrocytoma with an IDH1 or IDH2 mutation who have undergone surgery as their only treatment.
-Quality (chemistry and manufacturing),
-Nonclinical (pharmacology and toxicology),
-Clinical (pharmacology, safety and efficacy) and
-Risk management plan information submitted by the sponsor.
The Sponsor demonstrated the efficacy of Voranigo in patients in a pivotal clinical study (Study AG881-C-004), "INDIGO", a phase 3, multi-centre, randomised, double-blind, placebo-controlled study of vorasidenib in subjects with residual or recurrent Grade 2 glioma with an isocitrate dehydrogenase (IDH)1 or IDH2 mutation. Vorasidenib is an inhibitor of the isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) proteins that carry certain mutations. As a result, a substance called 2-hydroxyglutarate (2-HG) is overproduced which contributes to the formation of cancer cells.
The primary study objective was to demonstrate the efficacy of vorasidenib based on radiographic progression-free survival compared with placebo in subjects with residual or recurrent Grade 2 oligodendroglioma and astrocytoma with an IDH1 or IDH2 mutation who have undergone surgery as their only treatment.
What steps were involved in the decision process
Voranigo was granted priority review determination and orphan designation (for the orphan
indication of “Treatment of IDH-mutant diffuse glioma”) on the 6th of December 2023.
Submission dossier accepted and first round evaluation commenced | 29 February 2024 |
Evaluation completed | 17 June 2024 |
Delegate’s risk assessment and request for Advisory Committee advice | 3 July 2024 |
Advisory Committee meeting | 1 August 2024 |
Registration decision (Outcome) | 10 September 2024 |
Registration in the ARTG | 11 September 2024 |
Number of working days from submission dossier acceptance to registration decision | 136 |
Date of entry onto ARTG
Black triangle scheme
Yes, Voranigo is to be included in the Black Triangle Scheme. The PI and CMI for Voranigo must include the black triangle symbol ▼ for five years. The black triangle is a visual reminder to encourage health practitioners and patients to report a problem or side effect observed with this medicine.
Dose forms
Film-coated tablets
Strength
10 mg and 40 mg of vorasidenib
Other ingredients
− Microcrystalline cellulose
− Croscarmellose sodium
− Silicified microcrystalline cellulose
− Magnesium stearate
− Sodium lauryl sulfate
− Hypromellose
− Titanium dioxide
− Macrogol 400
− Lactose monohydrate
Printing Ink:
− OPACODE WB monogramming ink NS-78-17821 BLACK (Proprietary Ingredient No.: 12156)
Containers
White, high-density polyethylene (HDPE) bottle with polypropylene (PP) child resistant closure and
polyethylene (PE) faced induction heat seal liner. Each bottle contains 30 film-coated tablets and a silica gel
desiccant in HDPE canister(s).
polyethylene (PE) faced induction heat seal liner. Each bottle contains 30 film-coated tablets and a silica gel
desiccant in HDPE canister(s).
Pack sizes
1 bottle per pack
Routes of administration
Voranigo is for oral use.
Dosage
The recommended dose of Voranigo in adults and adolescents 12 years of age and older:
• 40 mg taken orally once daily for patients weighing at least 40 kg
• 20 mg taken orally once daily for patients weighing less than 40 kg
Pregnancy category
Category D
There are no data from the use of vorasidenib in pregnant women.
Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with Voranigo.
Voranigo is not recommended during pregnancy and in women of childbearing potential not using contraception. Pregnant women, women of childbearing potential or male patients with female partners of childbearing potential should be advised on the potential risk to a fetus.
Vorasidenib caused embryofetal toxicity in pregnant rats and rabbits. Higher incidences of resorptions and delayed ossification were observed in rats and rabbits at 10 and 6 mg/kg/day, respectively, resulting in systemic exposures ≥27- and 5-fold higher than the clinical exposure based on AUC. Visceral malformations (malpositioned kidney and testes) were seen in rats at 75 mg/kg/day (100-fold higher than the clinical exposure at the daily recommended dose). It is not known whether vorasidenib could cause fetal harm when administered to a pregnant woman.
Women of childbearing potential and males with female partners of childbearing potential should use effective non-hormonal contraception during treatment with VORANIGO and for at least 3 months after the last dose. Since the effect of vorasidenib on the metabolism and efficacy of systemically acting hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy.
There are no data from the use of vorasidenib in pregnant women.
Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with Voranigo.
Voranigo is not recommended during pregnancy and in women of childbearing potential not using contraception. Pregnant women, women of childbearing potential or male patients with female partners of childbearing potential should be advised on the potential risk to a fetus.
Vorasidenib caused embryofetal toxicity in pregnant rats and rabbits. Higher incidences of resorptions and delayed ossification were observed in rats and rabbits at 10 and 6 mg/kg/day, respectively, resulting in systemic exposures ≥27- and 5-fold higher than the clinical exposure based on AUC. Visceral malformations (malpositioned kidney and testes) were seen in rats at 75 mg/kg/day (100-fold higher than the clinical exposure at the daily recommended dose). It is not known whether vorasidenib could cause fetal harm when administered to a pregnant woman.
Women of childbearing potential and males with female partners of childbearing potential should use effective non-hormonal contraception during treatment with VORANIGO and for at least 3 months after the last dose. Since the effect of vorasidenib on the metabolism and efficacy of systemically acting hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy.
What was approved
Voranigo was approved to treat Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation or isocitrate dehydrogenase-2 (IDH2) mutation in adults and paediatric patients 12 years and older, who are not in need of immediate chemotherapy or radiotherapy following surgical intervention.
What is this medicine and how does it work
Vorasidenib is a brain-penetrant, small molecule, dual inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 enzymes. In patients with astrocytoma or oligodendroglioma, IDH1 and IDH2 mutations lead to overproduction of the oncogenic metabolite 2-hydroxyglutarate (2-HG), resulting in impaired cellular differentiation and increased cellular proliferation contributing to oncogenesis. Direct inhibition of the gain-of-function activity of the IDH1- and IDH2-mutated proteins by vorasidenib is intended to inhibit the abnormal production of 2-HG and impact clinical outcomes through the differentiation of malignant cells and reduction of cellular proliferation.
What post-market commitments will the sponsor undertake
Voranigo (Vorasidenib citrate) is to be included in the Black Triangle Scheme. The PI and CMI for Voranigo must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date of first supply of the product.
The Voranigo EU-Risk Management Plan (RMP) (version 0.1, dated 19 December 2023, data lock point 6 September 2022), with Australian Specific Annex (version 0.2, dated 4 April 2024), included with submission PM-2023-06126-1-4, and any subsequent revisions, as agreed with the TGA will be implemented in Australia. An obligatory component of risk management plans is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Conduct and submit to the TGA for evaluation:
- An in vivo micronucleus assay in rat bone marrow following oral dosing with AGI-69460 to assess genotoxicity.
- A study to assess the carcinogenicity of vorasidenib and AGI-69460 in Wistar rats.
- A study to assess the carcinogenicity of vorasidenib and AGI-69460 in transgenic RasH2 mice.
More information
The latest Product Information (PI) and Consumer Medicine Information (CMI) can be found by searching the Australian Register of Therapeutic Goods (ARTG).
Australian Public Assessment Reports (AusPARs) can be found by searching our AusPAR dataset.
The latest news and updates regarding therapeutic goods regulation can be found on our news page.