Dordaviprone Granted Accelerated Approval for H3 K27M–Mutant Diffuse Midline Glioma
Expert Perspectives · Lyn Brook · 2025-08-12
The FDA has granted accelerated approval to dordaviprone (Modeyso™, Jazz Pharmaceuticals, Inc.), a protease activator, for adult and pediatric patients one year of age and older with diffuse midline glioma harboring an H3 K27M mutation and progressive disease following prior therapy. This is the first FDA approval of a systemic therapy for H3 K27M–mutant diffuse midline glioma.
Why This Approval Matters
Patients with H3 K27M–mutant diffuse midline glioma face an aggressive disease with limited therapeutic options after standard treatments. The accelerated approval of dordaviprone provides a first-in-class systemic option for this population and is supported by clinically meaningful antitumor activity, addressing a critical unmet need in both adult and pediatric patients.
Breaking Down the ONC Trials
Efficacy and safety were evaluated across five open-label, non-randomized US studies: ONC006 (NCT02525692), ONC013 (NCT03295396), ONC014 (NCT03416530), ONC016 (NCT05392374), and ONC018 (NCT03134131). An integrated efficacy population of 50 adults and children with recurrent H3 K27M–mutant diffuse midline glioma treated with single-agent dordaviprone was assessed.
Eligible patients had received single-agent dordaviprone for diffuse midline glioma harboring an H3 K27M mutation; had progressive, measurable disease per Response Assessment in Neuro-Oncology–High Grade Glioma (RANO-HGG) criteria; were at least 90 days post–radiation therapy; and had adequate washout from prior anticancer therapies, a Karnofsky or Lansky Performance Status score of at least 60, and stable or decreasing corticosteroid use. Patients with diffuse intrinsic pontine glioma, primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination were excluded.
The primary efficacy end point was overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) per RANO 2.0, and the key secondary end point was duration of response (DOR).
Dordaviprone produced an ORR was 22% (95% CI: 12, 36). Median DOR was 10.3 months (95% CI: 7.3, 15.2). Among the 11 patients with objective responses, 73% had responses lasting at least 6 months, and 27% had responses lasting at least 12 months.
Managing Adverse Events
The dordaviprone prescribing information includes warnings and precautions for hypersensitivity reactions, QTc interval prolongation, and embryo-fetal toxicity. Clinicians should monitor patients for these risks and manage according to established guidance, including appropriate cardiac monitoring and pregnancy prevention measures as indicated.
Clinical Implications and Future Outlook
This accelerated approval introduces a systemic therapy option for a historically refractory disease, with observed responses in both adult and pediatric patients after prior therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Dosing and Administration
The recommended dosage of dordaviprone for adults is 625 mg orally, once weekly. The recommended dosage for pediatric patients is based on body weight. See the full prescribing information for pediatric dosing details and additional administration considerations. Treatment should continue until disease progression or unacceptable toxicity.
References
Clinicaltrials.gov (2024). Oral ONC201 in adult recurrent glioblastoma. NLM identifier: NCT02525692.
Clinicaltrials.gov (2025). ONC201 in pediatric H3 K27M gliomas. NLM identifier: NCT03416530.