Servier’s successful phase 3 trial of vorasidenib in patients with a slow-growing but usually fatal form of brain cancer demonstrates the power of good brain penetrance. The oral therapy vorasidenib inhibits both isocitrate dehydrogenases (IDH1 and IDH2) in their mutated forms, which disrupt cellular metabolism and drive oncogenesis in grade 2 IDH-mutated gliomas. Treatment with vorasidenib in the trial more than doubled progression-free survival (PFS) in post-operative patients with recurrent or residual IDH-mutated low-grade gliomas: those on the drug had a median PFS of 27.7 months, compared with 11.1 months for those on placebo. The drug, the first clinical breakthrough in the field for two decades, is likely to become a new standard of care.
Patients currently only have recourse to chemotherapy or radiotherapy after surgery. Vorasidenib will not be the first IDH inhibitor to reach patients, however. Servier already has a marketed IDH1 inhibitor in its portfolio: Tibsovo (ivosidenib), approved for acute myeloid leukemia (AML) and cholangiocarcinoma (bile duct cancer). Bristol Myers Squibb markets another, the IDH2 inhibitor Idhifa (enasidenib), approved in AML only. All three originated at Agios Pharma, but only vorasidenib is able to cross the blood–brain barrier. It owes this ability to two design features: its low polar surface area and its low number of hydrogen-bond donors, both of which contribute to its low polarity.
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