Modeyso (dordaviprone) represents the first FDA-approved treatment option for H3 K27M-mutant diffuse midline glioma, providing hope for patients with this ultra-rare and aggressive brain tumor. The drug’s rapid inclusion in NCCN Guidelines as a category 2A recommendation underscores its clinical significance for both pediatric and adult patients with recurrent or progressive disease.
Drug Profile & Mechanism
- Novel mechanism: Protease activator of mitochondrial caseinolytic protease P (ClpP) and dopamine D2 receptor (DRD2) inhibitor
- Target population: Adult and pediatric patients ≥1 year with H3 K27M-mutant diffuse midline glioma and progressive disease following prior therapy
- Administration: Orally administered small molecule given once weekly
- Molecular effects: Activates integrated stress response, induces apoptosis, alters mitochondrial metabolism, and restores histone H3 K27 trimethylation
Regulatory Milestone Details
- FDA accelerated approval: Granted August 6, 2025, based on integrated efficacy analysis of 50 patients across five open-label studies
- NCCN Guidelines inclusion: Added to both Pediatric CNS Cancers and CNS Cancers guidelines as category 2A single-agent treatment
- Efficacy data: 22% overall response rate (95% CI: 12-36) with median duration of response of 10.3 months
- Safety profile: Evaluated in 376 patients; most common adverse reactions (≥20%) included fatigue, headache, vomiting, nausea, and musculoskeletal pain
Practice Implications
- First-line option: Establishes initial treatment pathway for recurrent H3 K27M-mutant diffuse midline glioma patients
- Broad applicability: Covers both pediatric and adult populations with this rare tumor type
- Treatment sequencing: Provides option following progression on prior therapy in a disease with historically limited therapeutic choices
- Commercial availability: Currently available in the United States
Development Status & Next Steps
- Confirmatory trial: Phase 3 ACTION trial (NCT05580562) ongoing to verify clinical benefit in newly diagnosed patients
- Continued approval contingency: May depend on ACTION trial results demonstrating clinical benefit
- Geographic availability: Currently approved only in the United States
- Development history: Originally developed by Chimerix, acquired by Jazz Pharmaceuticals in April 2025
