FDA Approves Drug for Aggressive Glioma

The FDA has granted accelerated approval to dordaviprone (Modeyso, Jazz Pharmaceuticals) for H3 K27M-mutant diffuse glioma, marking the first time a systemic therapy has been approved for the aggressive glioma subtype.

H3 K27M-mutant diffuse glioma is a grade 4 midline tumor that primarily affects children and young adults. Median survival is about a year. Historically, treatment has been limited to radiation, with few options available after recurrence besides palliative care.

Dordaviprone is a first-in-class oral imipridone that disrupts tumor cell metabolism and increases tumor susceptibility to immune-mediated attack.

Jazz Pharmaceuticals bought Chimerix in early 2025 for almost $1 billion based on dordaviprone’s commercial prospects.

“Dordaviprone has the potential to rapidly become a standard of care for a rare oncology disease and also contribute durable revenue beginning in the near-term,” Jazz CEO Bruce Cozadd, said in a press release at the time.

Approval was based on a pooled analysis of five single-arm studies enrolling 46 adults and four children with recurrent tumors previously treated with radiation, according to a statement from the FDA. Adults received 625 mg once weekly while pediatric patients received lower, weight-adjusted weekly doses. Mutation status was confirmed by immunohistochemistry or sequencing of archival tumor tissue.

The overall response rate was 22%. The median time to response was 8.3 months, and the median duration of response (DOR) was 10.3 months. 

Among 11 patients with objective responses, 73% had a DOR of at least 6 months, and 27% had a DOR of at least 12 months.

Seven of 15 evaluable patients (46.7%) were able to have corticosteroid dose reductions of at least 50%, and performance status improved in six of 34 (20.6%) patients.

Sixty percent of subjects experienced treatment-related, treatment-emergent adverse events (TR-TEAEs), including fatigue (34%), nausea (18%), decreased lymphocyte levels (14%). The most common serious adverse events were hydrocephalus (8%) and nausea (8%). Grade 3 TR-TEAEs occurred in 20%, most commonly fatigue (10%).

One case each of seizure and pulmonary embolism were seen. There were no treatment-related deaths.

The drug’s prescribing information includes warnings and precautions for hypersensitivity, QTc interval prolongation, and embryo-fetal toxicity, according to the FDA statement.

A phase 3 trial is underway to confirm the benefit of dordaviprone for recurrent H3 K27M-mutant diffuse glioma. 

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com