Understanding Vorasidenib’s Mechanism of Action

Timothy F. Cloughesy, MD, director of UCLA’s neuro-oncology program and distinguished professor in neurology, discusses the mechanism of action of vorasidenib (Voranigo, formerly AG-881), the first oral, selective, highly brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes approved by the FDA for the treatment of patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation.

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0:09 | It started off when the Cancer Genome Atlas had just come out. We were evaluating, as a field, large-scale genomic evaluations of gliomas. Out of that evaluation came the identification of IDH mutations. Soon after that was understanding the biology of what that mutation did, how that mutation led to an oncogenic environment, and then the formation of these tumors in patients and developing into primary brain tumors.

1:00 | We then went on to identify the clinical characteristics associated with this mutation. We found these in specific types of disease that are usually a little lower grade, but still can be deadly, and identified both astrocytoma and oligodendroglioma subtypes out of that. In the end, this process led to disease-defining aspects of what was incorporated into the [World Health Organization (WHO)] criteria.

1:32 | Then, there is the opportunity of drugging this target. This was fascinating, the ability to make a potent selective inhibitor of the mutant enzyme and to have it be penetrant and to be highly tolerable was an important feat. That has not been done a lot in our field. As always, we had to go through a phase 1 study and try to identify the population that responds best. The most obvious population was those in the early disease where they were identified and are close to newly diagnosed, that there were slower growing changes. This provided an opportunity to think about how to develop a later stage study. But before doing that, there was an opportunity to give drugs to patients for a month, and then do surgery to understand exactly what kind of changes were occurring. I think that the totality of this development was unique for drug development and glioma, and I think it really sets a blueprint of how to consider moving forward.