On August 6, 2025, the U.S. Food and Drug Administration (FDA) granted accelerated approval to dordaviprone (Modeyso, Jazz Pharmaceuticals), a protease activator, for adult and pediatric patients (≥1 year) with progressive H3 K27M-mutant diffuse midline glioma (DMG) following prior therapy. This marks the first FDA approval of a systemic therapy for this aggressive tumor type.
Significance of the Approval
DMG is a highly lethal central nervous system tumor with very limited treatment options, particularly for patients harboring the H3 K27M mutation. The approval of dordaviprone represents a major milestone, offering a systemic therapeutic option for the first time.
Clinical Trial Overview
- Population: 50 adult and pediatric patients with recurrent H3 K27M-mutant DMG
- Design: Five open-label, non-randomized U.S. trials (NCT02525692, NCT03295396, NCT03416530, NCT05392374, NCT03134131)
- Primary Endpoint: Overall response rate (ORR) per blinded independent central review (RANO 2.0)
- Results: ORR 22% (95% CI: 12–36), median duration of response (DOR) 10.3 months
- Among responders: 73% maintained response ≥6 months, 27% ≥12 months
Safety and Dosage
The prescribing information includes warnings for hypersensitivity, QTc prolongation, and embryo-fetal toxicity. The recommended adult dose is 625 mg orally once weekly, with pediatric dosing based on body weight.
Regulatory Designations
Dordaviprone received orphan drug designation, rare pediatric disease designation, and fast track designation, and was reviewed under priority review status.
Outlook
This approval may stimulate further research in DMG therapeutics. Ongoing studies will be crucial to confirm long-term benefits and safety.
Source: FDA, AACR FDA Approval Alert (August 6, 2025)
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