Pharmacological Profile and Mechanism of Action

Ivosidenib is a targeted small-molecule inhibitor of mutant isocitrate dehydrogenase-1 (IDH1), an enzyme implicated in oncogenic metabolism. By selectively binding to mutant IDH1 variants (e.g., R132H/C/G/L/S), it suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), thereby restoring cellular differentiation and reducing leukemic or tumor cell proliferation. This mechanism is validated across hematologic malignancies and solid tumors, with clinical efficacy demonstrated in IDH1-mutated AML, MDS, and cholangiocarcinoma.

Clinical Efficacy and Safety Overview

TIBSOVO has shown significant clinical benefit in pivotal trials (e.g., AG120-C-009, AG120-C-001), including improved event-free survival (HR: 0.35) and overall survival (HR: 0.44) in newly diagnosed AML when combined with azacitidine. As monotherapy, it induces durable complete remissions (CR: 24.7% in relapsed/refractory AML) and objective responses in cholangiocarcinoma. Administered orally at 500 mg once daily, it requires vigilant monitoring for differentiation syndrome (15–25% incidence), QTc prolongation (14% with QTcF >500 ms), and Guillain-Barré syndrome (0.8%). Common adverse reactions include cytopenias, gastrointestinal disturbances, and electrolyte imbalances. Dose modifications are mandated for toxicity management, particularly with concomitant CYP3A4 inhibitors or QTc-prolonging agents.