Dordaviprone Approved for H3 K27M-mutated Diffuse Midline Glioma
The FDA has approved the first-in-class therapeutic dordaviprone for certain adult and pediatric patients with H3 K27M-mutated diffuse midline glioma.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to dordaviprone (Modeyso) for the treatment of patients 1 year and older with diffuse midline glioma (DMG) that has progressed after prior therapy and has the H3 K27M mutation.
Dordaviprone is a first-in-class targeted therapy that functions through two distinct mechanisms. First, dordaviprone overactivates the mitochondrial enzyme ClpP, which cleaves proteins and can cause cell death. Second, dordaviprone inhibits the D2/3 dopamine receptor that can promote cancer cell growth. This is the first FDA approval for dordaviprone, and the first FDA approval of any targeted therapeutic for patients with DMG with the H3 K27M mutation, which broadly alters gene expression and is linked with aggressive disease, poor response to chemoradiation, and poor prognosis.
The approval is based on results from five open-label, non-randomized clinical trials—ONC006, ONC013, ONC014, ONC016, and ONC018—that collectively evaluated the efficacy of dordaviprone treatment in 50 adult and pediatric patients with recurrent H3 K27M-mutated DMG. Patients with diffuse intrinsic pontine glioma or primary spinal tumors were excluded.
Twenty-two percent (11/50) of patients experienced responses, with 73% of those responses persisting at least six months, 50% at least 10.3 months, and 27% at least one year.
The recommended dose for dordaviprone is 625 mg orally once per week for adults and pediatric patients who weigh at least 52.5 kg. For pediatric patients who weigh less than 52.5 kg, the recommended dose is 500 mg orally once per week for patients who weigh between 42.5 kg and 52.5 kg, 375 mg for patients who weigh between 27.5 kg and 42.5 kg, 250 mg for patients who weigh between 12.5 kg and 27.5 kg, and 125 mg for pediatric patients who weigh between 10 kg and 12.5 kg.
Diffuse midline glioma is a type of cancer that begins in the brain or spinal cord. The H3 K27M mutation commonly occurs in diffuse midline glioma in both adult and pediatric patients. According to federal statistics, it was estimated that 24,820 individuals would be diagnosed with brain and nervous system cancers and approximately 18,330 patients would die of the disease in the United States in 2025. Brain and nervous system cancers were estimated to represent 15.1% of all childhood cancer cases diagnosed between 2018 and 2022, with 2.9 new cases per 100,000 children each year within this time frame and 0.6 deaths per 100,000 children per year between 2019 and 2023.
The FDA rendered its decision on August 6, 2025. Accelerated approval means that continued approval may be contingent upon a confirmatory trial. Please check this FDA web page for information about any accelerated approvals in oncology that may have been subsequently withdrawn and are no longer FDA-approved. Check this resource for updated information on all therapeutics regulated by the FDA.