Dordaviprone Receives FDA Accelerated Approval: A Breakthrough for Rare and Aggressive Brain Tumors

Jazz Pharmaceuticals has announced a significant milestone in neuro-oncology with the FDA’s accelerated approval of Modeyso™ (dordaviprone), marking the first and only FDA-approved treatment for recurrent H3 K27M-mutant diffuse midline glioma. This ultra-rare brain tumor primarily affects children and young adults, with approximately 2,000 cases diagnosed annually in the United States.

Clinical Efficacy Data Shows Meaningful Patient Response

The FDA’s decision was grounded in a comprehensive efficacy analysis encompassing 50 patients with recurrent H3 K27M-mutant diffuse midline glioma across five clinical studies. Using blinded independent central review (BICR) with Response Assessment in Neuro-Oncology (RANO) 2.0 criteria, dordaviprone demonstrated an overall response rate (ORR) of 22%. Among patients who responded to treatment, the median duration of response reached 10.3 months, with 73% maintaining their response for at least six months and 27% sustaining benefits for at least 12 months.

Addressing an Urgent Unmet Medical Need

Prior to this approval, H3 K27M-mutant diffuse midline glioma had no effective systemic treatment options. The disease is characterized by rapid progression, with median survival approximately one year from diagnosis and less than six months after progression following initial therapy. Modeyso addresses this critical gap by offering patients a targeted oral treatment administered once weekly.

“This represents a transformative moment for patients and families who have endured years without viable options,” noted Joshua E. Allen, Ph.D., Chief Scientific Officer at Chimerix, a Jazz Pharmaceuticals Company. “Dordaviprone was specifically designed with the underlying biology of this tumor in mind, introducing a new pathway for intervention in a population with historically limited choices.”

Mechanism of Action and Drug Development

Dordaviprone functions as a protease activator of the mitochondrial caseinolytic protease P (ClpP) and also inhibits dopamine D2 receptor (DRD2). In laboratory studies, the compound activates the integrated stress response, induces apoptosis, and alters mitochondrial metabolism, ultimately leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma cells. This targeted mechanism distinguishes Modeyso from conventional approaches to treating this aggressive tumor type.

Safety Profile and Important Considerations

Safety data were evaluated across 376 adult and pediatric patients with glioma in four open-label clinical studies. Serious adverse reactions occurred in 33% of patients. Among these, the most frequently reported serious adverse events included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%), and muscular weakness (2.1%).

The most common adverse reactions overall were fatigue (34%), headache (32%), vomiting (24%), nausea (24%), and musculoskeletal pain (20%). Additionally, dordaviprone causes concentration-dependent QTc interval prolongation, requiring ECG monitoring and careful patient selection. The drug is contraindicated in pregnancy and requires effective contraception during and for one month after treatment.

Path to Commercialization and Future Trials

Modeyso is expected to be commercially available in the coming weeks. This accelerated approval is contingent upon verification and description of clinical benefit in the Phase 3 ACTION confirmatory trial, which is evaluating the safety and efficacy of dordaviprone in newly diagnosed patients with H3 K27M-mutant diffuse glioma following radiotherapy.

The drug was originally developed by Chimerix prior to its acquisition by Jazz Pharmaceuticals in April 2025. Notably, dordaviprone remains unapproved in any other region globally, making this U.S. approval a unique milestone for patients worldwide.

Clinical Perspective

Patrick Wen, M.D., Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and Professor of Neurology at Harvard Medical School, emphasized the significance: “For the first time, we have an FDA-approved therapy specifically designed for recurrent H3 K27M-mutant diffuse midline glioma. While outcomes remain challenging for many patients, the objective responses observed with dordaviprone, including durable benefits in some cases, represent a meaningful advancement that shifts what patients and families can realistically expect after diagnosis.”