FDA Grants Accelerated Approval to Dordaviprone in Diffuse Midline Glioma

The FDA has approved the first systemic therapy for patients with H3 K27M-mutant midline glioma.

The FDA has granted accelerated approval to the protease activator dordaviprone (Modeyso) as a treatment for pediatric and adult patients who are 1 year or older with H3 K27M-mutated diffuse midline glioma that has progressed after prior therapy, according to a news release from the FDA.1

This decision represents the first approval of a systemic therapy for those with diffuse midline glioma harboring H3 K27M mutations.

Supporting data for the approval came from 5 open-label trials conducted across the US, which all evaluated dordaviprone monotherapy for patients with diffuse midline glioma harboring an H3 K27M mutation and progressive, evaluable disease based on Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria. These studies included the ONC006 trial (NCT02525692), ONC013 trial (NCT03295396), ONC014 trial (NCT03416530), ONC016 trial (NCT05392374), and ONC018 trial (NCT03134131).

In an integrated efficacy population consisting of 50 evaluable adult and pediatric patients, dordaviprone demonstrated an overall response rate (ORR) of 22% (95% CI, 12%-36%). Additionally, the median duration of response (DOR) was 10.3 months (95% CI, 7.3-15.2); of those who responded, 73% and 27% experienced a response lasting at least 6 months and 12 months, respectively.

The prescribing information for dordaviprone includes warning and precautions for hypersensitivity, QTc interval prolongation, and embryo-fetal toxicity.

The FDA approved dordaviprone at a recommended dose of 625 mg orally once a week for adult patients. Pediatric patients are recommended to receive the agent based on individual body weight.

The aforementioned trials included patients who were at least 90 days removed from prior radiotherapy. Eligible patients also had an adequate washout period following previous anticancer treatment, a Karnofsky performance status or Lanksky performance status of at least 60, and stable or decreasing use of corticosteroids. Those with diffuse intrinsic pontine glioma, primary spinal disease, atypical histologies, or cerebrospinal fluid dissemination were ineligible for study entry.

The major efficacy end point across these trials was ORR per blinded independent central review using RANO 2.0 criteria. DOR was a secondary end point.

The FDA previously granted priority review to dordaviprone as a treatment for this patient population in February 2025.2

References

1. FDA grants accelerated approval to dordaviprone for diffuse midline glioma. News release. FDA. August 6, 2025. Accessed August 6, 2025. https://tinyurl.com/5hdypp4h
2. Chimerix announces FDA acceptance and priority review of new drug application for dordaviprone as treatment for recurrent H3 K28M-mutant diffuse glioma. News release. Chimerix. February 18, 2025. Accessed August 6, 2025. https://tinyurl.com/4rkkwkcb