Ivosidenib


Ivosidenib is an experimental drug for treatment of cancer. It is a small molecule inhibitor of isocitrate dehydrogenase-1, which is mutated in several forms of cancer. The drug is being developed by Agios Pharmaceuticals and is in phase III clinical trials. The U.S. Food and Drug Administration awarded orphan drug designation for acute myeloid leukemia and cholangiocarcinoma.
In 2018, ivosidenib was approved in the United States for relapsed or refractory acute myeloid leukemia with an IDH1 mutation and is presently in a phase III clinical trial for cholangiocarcinoma with an IDH1 mutation.
In 2019, ivosidenib was approved in the United States for newly diagnosed acute myeloid leukemia with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

Inhibitory behavior

In tumors from patients diagnosed with Glioma, Acute Myeloid Leukemia, Cholangiocarcinoma, and Chondrosarcoma, somatic mutations in the conserved active site of isocitrate dehydrogenase 1 and 2 are observed. With these new mutations, these enzymes exhibit new, neomorphic behavior, which results in the reduction of α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate. The new molecule competitively inhibits α-ketoglutarate–dependent enzymes, ultimately leading to epigenetic alterations and impaired hematopoietic differentiation. Mutations in the IDH1 enzyme mutations occur in approximately 6 to 10% of the patients with AML, and IDH2 mutations occur in approximately 9 to 13% of those with AML, with unknown statistics on other conditions listed.
Ivosidenib, in in vitro studies, showed non-competitive inhibitory behavior towards the alpha-ketoglutarate substrate and to the NADPH cofactor. This is what is believed to lead to Ivonsidenib being a rapid equilibrium inhibitor of the mIDH1-R132H homodimer, however NADPH is found to be pre-bound in recombinant enzyme preparations, which means this is not conclusive.
The drug is also believed to believed to be a slow-binding inhibitor of the IDH1-WT homodimer. Ivosidenib showed uncompetitive inhibition to the NADP cofactor, showing a hyperbolic curve for the rate constant of inhibition relative to concentration. Ivosidenib also showed no time-dependence in IC50 between 1 and 16 hours of incubation for either homodimer.

Patient Selection

Patients with AML should be tested for IDH1 mutations in the blood or bone marrow to see if they are suitable candidates for ivosidenib. Patients without the mutation should still be regularly tested to see if the mutation develops.

Adverse effects

In ivosidenib-treated patients, reported adverse effects have been febrile neutropenia, alanine aminotransferase increased, aspartate aminotransferase increased, colitis, hypertension, maculopapular rash. However, Ivosidenib was taken in conjunction with standard AML induction treatment, and side effects can not be directly related to the drug.