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ivosidenib + venetoclax + azacytidine + cytarabine

Development stage
Unknown
Lead developer
Agios Pharmaceuticals
Modality
Orthosteric Ligands → Classical Binding Small Molecules → Small Molecules, Metabolically Activated Prodrugs → Prodrugs/Conditional Activator Small Molecules → Small Molecules, Nucleic Acid-Directed Small Molecules → Small Molecules
Administration
Oral, Intravenous, Subcutaneous
01

Overview

This is a four-drug combination regimen consisting of ivosidenib, venetoclax, azacitidine, and cytarabine. - Ivosidenib is a targeted small molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1), used primarily in IDH1-mutated acute myeloid leukemia (AML). It blocks the production of the oncometabolite 2-hydroxyglutarate, thereby promoting differentiation of leukemic cells[2][4]. - Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor that induces apoptosis in cancer cells dependent on BCL-2 for survival[4]. - Azacitidine is a hypomethylating agent that incorporates into DNA and RNA, leading to DNA hypomethylation and direct cytotoxicity to abnormal hematopoietic cells[5][10]. - Cytarabine is an antimetabolite chemotherapeutic agent that inhibits DNA synthesis by acting as an analog of cytosine arabinoside[10]. This combination targets multiple pathways involved in leukemogenesis and resistance mechanisms. The regimen has been studied primarily for patients with IDH1-mutated myeloid malignancies such as AML or myelodysplastic syndromes (MDS), especially those not eligible for intensive induction chemotherapy. Early-phase studies suggest high rates of complete remission and measurable residual disease negativity with manageable toxicity profiles[2][3][8].

02

Targets

DNA polymerase familyIDH1 (Isocitrate dehydrogenase [NADP] cytoplasmic)DNMT (DNA methyltransferase)BCL-2 (BCL-2 family)

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