Vorasidenib (Voranigo): A Comprehensive Monograph on the First-in-Class Targeted Therapy for IDH-Mutant Glioma

Executive Summary

Vorasidenib, marketed under the brand name Voranigo, represents a landmark achievement in the field of neuro-oncology and a paradigm shift in the management of Grade 2 diffuse gliomas harboring mutations in the isocitrate dehydrogenase 1 or 2 genes (IDH1/2). As a first-in-class, orally available, brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes, vorasidenib directly targets the fundamental oncogenic driver of these tumors. The development of this agent was predicated on a deep understanding of the molecular pathogenesis of IDH-mutant gliomas, specifically the role of the oncometabolite D-2-hydroxyglutarate (2-HG) in disrupting epigenetic regulation and blocking cellular differentiation. Vorasidenib was rationally designed to overcome the critical limitation of previous IDH inhibitors—poor blood-brain barrier penetrance—thereby enabling effective therapeutic concentrations at the tumor site.

The clinical value of vorasidenib was unequivocally established in the pivotal Phase 3 INDIGO trial, a global, randomized, placebo-controlled study. The trial demonstrated statistically unprecedented and clinically transformative efficacy, more than doubling the median progression-free survival (PFS) from 11.1 months with placebo to 27.7 months with vorasidenib. Even more profoundly, it delayed the median time to next intervention (TTNI)—the need for subsequent cytotoxic radiation or chemotherapy—from 17.8 months to a duration not yet reached in the treatment arm, representing a 74% reduction in risk. These results were achieved with a manageable and favorable safety profile, with the most significant adverse event being reversible transaminase elevations, which can be effectively managed with routine monitoring.