FDA Grants Accelerated Approval to Dordaviprone for H3 K27M-Mutated Diffuse Glioma

The FDA's approval of dordaviprone is based on findings from 5 clinical trials evaluating this patient population.

The FDA has granted accelerated approval to dordaviprone (Modeyso) for use in adult and pediatric patients aged at least 1 year who have diffuse midline glioma with an H3 K27M mutation whose disease has progressed following previous therapy.

The efficacy and safety of dordaviprone, a protease activator, was evaluated across 5 clinical trials (ONC006 [NCT02525692], ONC013 [NCT03295396], ONC014 [NCT03416530], ONC016 [NCT05392374], and ONC018 [NCT03134131]) that observed 50 adult and pediatric patients with recurrent H3 K27M-mutated diffuse midline glioma who received dordaviprone monotherapy.

The overall response rate (ORR) as assessed by blinded independent central review (BICR), which was a primary end point of the trials, was 22% (95% CI, 12%-36%). Likewise, median duration of response (DOR), the secondary end point of the trials, was 10.3 months (95% CI, 7.3-15.2).

In total, 11 patients achieved objective response, 73% of whom had a DOR of 6 months or more, and 27% of whom had a DOR of at least 12 months.

Label Warnings and Dosage

Dordaviprone’s label includes warnings for hypersensitivity, QTc interval prolongation, and embryo-fetal toxicity, according to the FDA’s announcement. The recommended dosage for adult patients is 625 mg taken orally once weekly; for children, dordaviprone’s dosage is based on body weight.

Trial Inclusion Criteria

Patients enrolled in the trials had received radiation at least 90 days prior and had a washout period from previous oncologic treatment. They also had a Karnofsky Performance Status/Lansky Performance Status (KPS/LPS) score of at least 60, along with either stable or decreasing use of corticosteroids. Those with disffuse intrinsic pontine glioma, primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination were not included in the trials.

About Dordaviprone

Dordaviprone, previously known as ONC201 is a first-in-class small molecule imipridone that binds selectively to the G-protein coupled dopamine receptor D2, according to Chimerix, a subset of Jazz Pharmaceuticals Company that is responsible for developing dordavidprine.²

The phase 3 ACTION trial (NCT05580562) is recruiting patients to further examine whether the use of dordaviprone will prolong overall survival and progression-free survival in patients with newly diagnosed H3 K27M-mutant diffuse glioma.³

Reference

1. FDA grants accelerated approval to dordaviprone for diffuse midline glioma. FDA. August 6, 2025. Accessed August 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dordaviprone-diffuse-midline-glioma
2. ONC201 dordaviprone. Jazz Pharmaceuticals Company. Accessed August 6, 2025. https://www.chimerix.com/our-pipeline/imipridones/onc201/
3. ONC201 in H3 K27M-mutant diffuse glioma following radiotherapy (the ACTION Study) (ACTION). ClinicalTrials.Gov. October 14, 2022. Updated July 8, 2025. Accessed August 6, 2025. https://clinicaltrials.gov/study/NCT05580562#study-record-dates