Dordaviprone — Mechanism of Action and Clinical Evidence

In this episode, Dr. Chong asks Dr. Shonka to explain what dordaviprone is and how it works. Dr. Shonka describes dordaviprone (previously known as ONC201) as a blood–brain-barrier–penetrant, first-in-class imipridone with two mechanisms: antagonism of the dopamine D2 receptor (DR.D2), which activates the integrated stress response through the ATF4/CHOP pathway and drives apoptosis; and agonism of the mitochondrial protease ClpP, which disrupts oxidative phosphorylation and the electron transport chain. The H3 K27M-specific connection is restoration of repressive H3K27 trimethylation, reversing the epigenetic defect of these tumors, a mechanism distinct from temozolomide, which acts as an alkylator. Dr. Shonka then introduces the integrated 5-trial analysis supporting accelerated approval. Dr. Chong walks through the data: an overall response rate (ORR) of 22% (roughly 1 in 5 patients) in contrast-enhancing disease, with responses approaching 30% when non-enhancing tumor is also included; median duration of response of about 10.3 months; 73% of responders with a duration of response of 6 months or longer; and corticosteroid dose reduction in roughly half of treated patients, a clinically meaningful benefit beyond radiographic response. He notes the pediatric data remain limited (ONC014: 11 patients aged 11–19, with an ORR of 9.1%) but views the findings as likely generalizable to the H3 K27M-altered DMG population. He briefly recounts the “happy accident” origin: the Dr.ug was first studied in glioblastoma, where it largely failed, but a small group of responders were identified as H3 K27M-mutant, which redirected the program.

In the next episode, “Dordaviprone in Practice — Dosing, Safety, and Monitoring,” Dr. Shonka and Dr. Chong walk through the practical regimen and what to watch for.