October 2025

NEUROSCIENCES

QUICK READ: MODEYSO™ (DORDAVIPRONE) FOR H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA

Read time: 2 minutes
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Karan S. Dixit, MD, shares insights on the first FDA-approved treatment for recurrent H3 K27M-mutant diffuse midline glioma — a rare, aggressive brain tumor affecting midline CNS structures. Dr. Dixit co-authored the pivotal study that led to this approval.
Key Insights
  • Modeyso™ (dordaviprone) received accelerated FDA approval as the first and only treatment for recurrent H3 K27M-mutant diffuse midline glioma.
  • This offers a targeted therapy where none previously existed for patients with progressive disease.
  • The approval underscores the importance of comprehensive molecular profiling for all brain tumor patients.
  • Tissue samples can be sent to Northwestern Medicine Neuropathology for molecular testing to confirm eligibility.

Overview
  • H3 K27M-mutant diffuse midline glioma affects the midline structures of the central nervous system, including the brainstem and spinal cord, making it inoperable and historically difficult to treat.
  • Median survival for these patients is less than one year, and less than six months after progression.
  • Diagnosis typically involves biopsy or cerebrospinal fluid testing.
  • Traditional therapies include radiation and standard chemotherapy.
  • Modeyso is a new therapy for patients with progressive disease following prior treatment.
  • The mutation-specific nature of the drug means it only works for tumors with the H3 K27M mutation — not for other glioma types. Molecular profiling must be done to confirm eligibility.

Therapy highlights
  • Oral delivery: Once-weekly capsule, which can be taken at home. This is especially convenient for patients who have difficulty traveling. It is available in pill, liquid or openable capsule form.
    • The compound works by activating mitochondrial ClpP protease and inhibiting dopamine D2 receptors, disrupting cancer cell metabolism and restoring epigenetic regulation.
  • Tolerability: Minimal side effects; adverse reactions occurred in 33% of patients, with most common being: fatigue, headache, nausea and vomiting.
  • Efficacy: Meaningful improvement for patients with progressive disease based on retrospective analysis.
    • Objective response rate: 22%
    • Median duration of response: 10.3 months
    • Durable benefit: 73% of responders maintained benefit for more than 6 months; 27% for more than 12 months
    • Some patients showed neurological function preservation and corticosteroid dose reduction. 

Eligibility and approval criteria
  • Approved for patients age 1 year and older with a confirmatory H3 K27M-mutant diffuse midline glioma diagnosis
  • Indicated for progressive disease only, following prior radiation and chemotherapy

​Next steps
  • Jazz is conducting a global phase 3 trial to evaluate Modeyso as a first-line therapy for H3 K27M-mutant diffuse midline glioma diagnosis.
  • Future directions include combination trials with standard therapies and potential expansion to other cancers.
​​Karan Dixit, MD, Assistant Professor of  Neurology (Neuro-oncology) and Neurology (Hospital Neurology)

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