ONC201 (dordaviprone) in Pediatric Diffuse Midline Glioma (H3K27-altered): Evidence of Benefit, Limitations, and the Path Forward
Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is among the most devastating pediatric brain tumors. Most cases harbor the hallmark histone H3 K27-alteration (commonly H3K27M), which rewires epigenetic programs and drives aggressive, infiltrative growth in the brainstem and other midline structures. Historically, focal radiation yields temporary neurologic improvement but nearly universal relapse. Durable disease control with systemic therapy has remained elusive. ONC201 (dordaviprone), the first-in-class imipridone and a pharmacologic activator of the mitochondrial protease ClpP that triggers the integrated stress response, has been extensively explored preclinically and clinically in DMG. As of August 2025, the U.S. FDA has approved dordaviprone (brand name MODEYSO) for adults and pediatric patients aged 1 year and older with H3 K27M-mutant DMG and progressive disease, with Jazz Pharmaceuticals as the NDA holder (NDA 219876), based on safety and efficacy data in this molecularly defined population. Compassionate-use series and translational monitoring studies suggest that a subset of patients experience clinical or radiographic stabilization, often accompanied by favorable biomarker dynamics, though broad, durable remissions remain uncommon in monotherapy settings. This review synthesizes mechanistic and clinical evidence to answer a critical question from families and clinicians: do ONC201 or related ClpP-activating agents materially help children with DMG—or do they mainly add adverse effects? We integrate regulatory developments, observational and translational data, and the current clinical trial landscape to provide a balanced, evidence-based appraisal.