Vorasidenib

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Vorasidenib
Vorasidenib v2.svg
Clinical data
Trade names Voranigo
AHFS/Drugs.com Voranigo
License data
Pregnancy
category
Routes of
administration
By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
  • 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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C14H13ClF6N6
Molar mass 414.74 g·mol−1
3D model (JSmol)
  • 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=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

Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma. [3] [4] Vorasidenib is a dual mutant isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (mIDH1/2) inhibitor. [3] [4]

Contents

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures. [4]

Vorasidenib was approved for medical use in the United States in August 2024. [4] [5] 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. [4]

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. [4]

Side effects

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures. [4] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils. [4]

Pharmacology

Agios Pharmaceuticals previously developed the mIDH1 inhibitor ivosidenib [6] and mIDH2 inhibitor enasidenib [7] [8] 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. [9] Moreover, isoform switching between IDH1 and IDH2 has been observed as a mechanism of resistance to mIDH inhibitor therapy. [10] Vorasidenib was thus developed to improve blood-brain barrier penetration and inhibit both mIDH1/2. [9]

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. [4] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. [4] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test. [4] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. [4] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded. [4]

Society and culture

Vorasidenib was approved for medical use in the United States in August 2024. [4]

The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations. [4]

Related Research Articles

<span class="mw-page-title-main">Brain tumor</span> Neoplasm in the brain

A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondary tumors, which most commonly have spread from tumors located outside the brain, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the size of the tumor and the part of the brain that is involved. Where symptoms exist, they may include headaches, seizures, problems with vision, vomiting and mental changes. Other symptoms may include difficulty walking, speaking, with sensations, or unconsciousness.

<span class="mw-page-title-main">Glioma</span> Tumour of the glial cells of the brain or spine

A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are cancerous but some are extremely slow to develop. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.

<span class="mw-page-title-main">Oligodendroglioma</span> Medical condition

Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. They occur primarily in adults but are also found in children.

<span class="mw-page-title-main">Glioblastoma</span> Aggressive type of brain cancer

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.

<span class="mw-page-title-main">Isocitrate dehydrogenase</span> Class of enzymes

Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.

<span class="mw-page-title-main">Ollier disease</span> Medical condition

Ollier disease is a rare sporadic nonhereditary skeletal disorder in which typically benign cartilaginous tumors (enchondromas) develop near the growth plate cartilage. This is caused by cartilage rests that grow and reside within the metaphysis or diaphysis and eventually mineralize over time to form multiple enchondromas. Key signs of the disorder include asymmetry and shortening of the limb as well as an increased thickness of the bone margin. These symptoms are typically first visible during early childhood with the mean age of diagnosis being 13 years of age. Many patients with Ollier disease are prone to develop other malignancies including bone sarcomas that necessitate treatment and the removal of malignant bone neoplasm. Cases in patients with Ollier disease has shown a link to IDH1, IDH2, and PTH1R gene mutations. Currently, there are no forms of treatment for the underlying condition of Ollier disease but complications such as fractures, deformities, malignancies that arise from it can be treated through surgical procedures. The prevalence of this condition is estimated at around 1 in 100,000. It is unclear whether the men or women are more affected by this disorder due to conflicting case studies.

<span class="mw-page-title-main">IDH3A</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (IDH3α) is an enzyme that in humans is encoded by the IDH3A gene.

<span class="mw-page-title-main">IDH2</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NADP], mitochondrial is an enzyme that in humans is encoded by the IDH2 gene.

<span class="mw-page-title-main">IDH3G</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial is an enzyme that in humans is encoded by the IDH3G gene.

<span class="mw-page-title-main">IDH3B</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial is an enzyme that in humans is encoded by the IDH3B gene.

α-Hydroxyglutaric acid Chemical compound

α-Hydroxyglutaric acid is an alpha hydroxy acid form of glutaric acid.

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PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).

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Temozolomide, sold under the brand name Temodar among others, is an anticancer medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.

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Ponatinib, sold under the brand name Iclusig, is a medication used for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia. It was developed by Ariad Pharmaceuticals. It is a multi-targeted tyrosine-kinase inhibitor. Some forms of chronic myeloid leukemia, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.

<span class="mw-page-title-main">IDH1</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+. Five isocitrate dehydrogenases have been reported: three NAD+-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP+-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP+-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

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<span class="mw-page-title-main">Enasidenib</span> Chemical compound

Enasidenib, sold under the brand name Idhifa, is an anti-cancer medication used to treat relapsed or refractory acute myeloid leukemia. It is an inhibitor of isocitrate dehydrogenase 2 (IDH2).

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Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.

<span class="mw-page-title-main">Olutasidenib</span> Chemical compound

Olutasidenib, sold under the brand name Rezlidhia, is an anticancer medication used to treat relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor. It is taken by mouth.

References

  1. 1 2 "Voranigo (vorasidenib)". Therapeutic Goods Administration (TGA). 26 September 2024. Retrieved 12 October 2024.
  2. "Notice: Multiple additions to the Prescription Drug List (PDL) [2024-10-18]". Health Canada . 18 October 2024. Retrieved 25 October 2024.
  3. 1 2 3 "Voranigo- vorasidenib citrate tablet, film coated". DailyMed. 9 August 2024. Retrieved 15 August 2024.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation". U.S. Food and Drug Administration (FDA). 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. "Servier's Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma" (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 via PR Newswire.
  6. Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). "Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers". ACS Medicinal Chemistry Letters. 9 (4): 300–305. doi:10.1021/acsmedchemlett.7b00421. PMC   5900343 . PMID   29670690.
  7. Shih AH, Shank KR, Meydan C, Intlekofer AM, Ward P, Thompson CB, et al. (6 December 2014). "AG-221, a Small Molecule Mutant IDH2 Inhibitor, Remodels the Epigenetic State of IDH2-Mutant Cells and Induces Alterations in Self-Renewal/Differentiation in IDH2-Mutant AML Model in Vivo". Blood. 124 (21): 437. doi:10.1182/blood.V124.21.437.437. ISSN   0006-4971.
  8. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. (May 2017). "AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations". Cancer Discovery. 7 (5): 478–493. doi:10.1158/2159-8290.CD-16-1034. PMID   28193778.
  9. 1 2 Konteatis Z, Artin E, Nicolay B, Straley K, Padyana AK, Jin L, et al. (February 2020). "Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma". ACS Medicinal Chemistry Letters. 11 (2): 101–107. doi:10.1021/acsmedchemlett.9b00509. PMC   7025383 . PMID   32071674.
  10. Harding JJ, Lowery MA, Shih AH, Schvartzman JM, Hou S, Famulare C, et al. (December 2018). "Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition". Cancer Discovery. 8 (12): 1540–1547. doi:10.1158/2159-8290.CD-18-0877. PMC   6699636 . PMID   30355724.

Further reading