FDA Approves Modeyso as First-Ever Therapy for Pediatric Brain Tumor, H3 K27M+ Glioma

The FDA has granted accelerated approval to Modeyso™ (dordaviprone) as the first treatment for recurrent H3 K27M-mutant diffuse midline glioma—an aggressive pediatric brain tumor. In pooled Phase 2 data, the oral therapy achieved a 22% objective response rate, with a median response duration of 10.3 months. This marks a major breakthrough for a disease with historically no approved systemic options.

Jazz Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for Modeyso™ (dordaviprone) for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy. Continued approval awaits Phase 3 ACTION trial confirmation.

"This is a major turning point in neuro-oncology," said Dr. Patrick Wen, Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute. “For the first time, we have an FDA-approved therapy for patients with recurrent H3 K27M-mutant diffuse midline glioma. While outcomes remain challenging for many patients, the objective responses observed with dordaviprone, including durable benefit in some patients, represent a meaningful advancement.”

Histone H3 K27M mutations disrupt epigenetic regulation, contributing to the aggressive biology of these tumors. Until now, management relied on radiation therapy and experimental approaches with no approved systemic agents. Modeyso, an oral capsule taken once weekly, targets this molecular alteration directly.

Clinical Data Underpinning the Approval

The FDA’s decision was based on results from a multi-study integrated efficacy analysis involving 50 patients with progressive disease after prior therapy. (ONC006, ONC013, ONC014, ONC016, and ONC018).

ORR was 22%, with an additional responder identified by integrated RANO 2.0 criteria.
Median duration of response was 10.3 months.
73% of responders maintained benefit for ≥6 months.
27% sustained their response for at least one year.

The safety of Modeyso was evaluated in 376 adult and pediatric patients with glioma across four open-label clinical studies. Serious adverse reactions occurred in 33% of patients. Serious adverse reactions reported in more than 2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%) and muscular weakness (2.1%). The most common adverse reactions in patients who received Modeyso (≥20%) were fatigue, headache, vomiting, nausea and musculoskeletal pain.

Dr. Joshua Allen, Chief Scientific Officer at Chimerix, now part of Jazz Pharmaceuticals, emphasized the collaborative effort behind the drug's development. “This approval not only equips clinicians with the first targeted option for this disease but also signals a meaningful shift in what patients and families can expect after diagnosis.”

A Devastating Diagnosis with No Previous Options

Diffuse midline gliomas with H3 K27M mutation are particularly insidious. These tumors arise in critical midline structures of the brain and spinal cord, including the thalamus, brainstem, and spinal cord, and are most often diagnosed in pediatric populations. The prognosis is grim: median overall survival remains under a year in most cases, with rapid neurological decline and limited options for recurrence.

A Shift in the Treatment Paradigm

Modeyso’s approval is not only a therapeutic milestone but also a symbolic shift in expectations for a previously untreatable cancer. The development program was guided by tumor biology, offering the first targeted agent specifically designed for this genetic mutation.