IDH inhibitor drugs are specialized medications that target specific genetic alterations in certain cancers. These precision medicine drugs focus on the unique molecular characteristics of a patient’s tumor, interfering with a mutated enzyme to disrupt cancer growth and progression.
Understanding IDH Mutations
Isocitrate dehydrogenase (IDH) is an enzyme involved in cellular metabolism, specifically the Krebs cycle. It converts isocitrate to alpha-ketoglutarate (α-KG), a molecule essential for cellular processes.
When IDH1 or IDH2 genes mutate, the enzyme’s function changes. The mutated IDH enzyme converts α-KG into 2-hydroxyglutarate (2-HG), an abnormal metabolite. Its accumulation interferes with normal cell processes, making 2-HG an “oncometabolite.”
High levels of 2-HG disrupt epigenetic regulation, leading to altered DNA methylation patterns and changes in gene expression. This prevents cancer cells from maturing, contributing to uncontrolled proliferation and blocked differentiation.
How IDH Inhibitors Work
IDH inhibitor drugs act as competitive inhibitors, binding to the mutated IDH enzyme’s active site. This prevents the enzyme from converting alpha-ketoglutarate into the oncometabolite 2-hydroxyglutarate, reducing 2-HG production.
Reducing 2-HG levels reverses epigenetic alterations caused by its accumulation. This restores normal cellular differentiation, prompting immature cancer cells to mature into healthy cells, which can slow or halt uncontrolled proliferation.
Unlike traditional chemotherapy, which often affects both healthy and cancerous cells, IDH inhibitors selectively target the specific molecular defect driving the cancer. This precision helps to minimize damage to healthy tissues, leading to a more favorable side effect profile.
Conditions Treated with IDH Inhibitors
IDH inhibitor drugs treat specific cancers with IDH1 or IDH2 gene mutations. Genetic testing is standard before treatment.
Acute myeloid leukemia (AML) is a primary cancer treated with IDH inhibitors. Approximately 6-10% of AML patients have an IDH1 mutation, and another 8-19% have an IDH2 mutation. These drugs are often used in patients with relapsed or refractory disease, or in newly diagnosed patients unable to tolerate intensive chemotherapy.
Gliomas, brain tumors, frequently exhibit IDH mutations, particularly IDH1 mutations in lower-grade gliomas and some secondary glioblastomas. About 70-80% of diffuse low-grade gliomas and secondary glioblastomas carry an IDH1 mutation. IDH inhibitors are being investigated and approved for use in these specific brain tumor types.
Additional cancers, such as cholangiocarcinoma (bile duct cancer) and some chondrosarcomas (bone cancers), can have IDH mutations. IDH inhibitors are approved for these indications.
Commonly Prescribed IDH Inhibitors
Several IDH inhibitor drugs have received regulatory approval and are generally administered orally, making them convenient for patients.
Ivosidenib, marketed as Tibsovo, is an IDH1 inhibitor approved for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation. It is used in newly diagnosed AML patients who cannot undergo intensive chemotherapy and in those with relapsed or refractory AML. Ivosidenib is also approved for previously treated cholangiocarcinoma with an IDH1 mutation.
Enasidenib, known as Idhifa, is an IDH2 inhibitor approved for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with a susceptible IDH2 mutation. This oral medication offers a targeted treatment option for patients whose AML has progressed.
Patient Experience and Considerations
Patients undergoing treatment with IDH inhibitors generally take these medications orally once daily. Regular monitoring by healthcare providers is important to assess treatment effectiveness and manage any potential side effects. Monitoring typically involves blood tests for blood counts, liver function, and 2-HG levels.
One notable side effect associated with IDH inhibitors, particularly in AML patients, is differentiation syndrome. This syndrome can manifest with symptoms such as fever, shortness of breath, and fluid retention. If differentiation syndrome occurs, it requires prompt medical attention and may necessitate temporary interruption of the IDH inhibitor and corticosteroids.
Other common side effects can include nausea, fatigue, diarrhea, and joint pain. These side effects are generally manageable with supportive care. Patients should report any new or worsening symptoms to their healthcare team promptly for appropriate management.
References
DiNardo, C. D., & Stone, R. M. (2015). Isocitrate dehydrogenase 1 and 2 mutations in acute myeloid leukemia. Cancer, 121(Suppl 1), 7-12.
MedlinePlus. (n.d.). Acute myeloid leukemia. Retrieved from https://medlineplus.gov/acutemyeloidleukemia.html
Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., … & Ellison, D. W. (2016). The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica, 131(6), 803-820.
FDA. (2021). FDA approves ivosidenib for cholangiocarcinoma. Retrieved from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-cholangiocarcinoma
Tibsovo (ivosidenib) prescribing information. (n.d.). Retrieved from various pharmaceutical company resources and prescribing information.
Idhifa (enasidenib) prescribing information. (n.d.). Retrieved from various pharmaceutical company resources and prescribing information.
Roboz, G. J., DiNardo, C. D., Stein, E. M., de Botton, S., Swords, R. T., Perl, A. E., … & Tallman, M. S. (2016). Ivosidenib (AG-120) induces remissions in relapsed/refractory AML with IDH1 mutation: results from a Phase 1 study. Blood, 128(22), 241.