FDA Grants Priority Review to Dordaviprone in Recurrent H3K27M+ Diffuse Glioma

The FDA has accepted and granted priority review to a new drug application (NDA) seeking accelerated approval of the novel, small molecule imipridone dordaviprone (ONC201) for the treatment of patients with recurrent H3K27M-mutant diffuse glioma.1

The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of August 18, 2025, to the application. The FDA also granted rare pediatric disease designation to dordaviprone for H3K27M-mutant glioma, and Chimerix, the developer of the agent, has applied for rare pediatric disease priority review voucher (PRV) in the NDA submission.

“This significant milestone brings us one step closer to our goal of accelerating access to the first medicine specific to patients diagnosed with recurrent H3K27M-mutant diffuse glioma," Mike Andriole, chief executive officer of Chimerix, stated in a press release. "Patients with this form of high-grade glioma face a very difficult prognosis with few treatment options beyond palliative care. Our team is working expeditiously with [the] FDA to facilitate their review as we simultaneously prepare for a potential commercial launch in order to ensure rapid availability to patients in need."

Dordaviprone is a novel, first-in-class, small molecule imipridone designed to selectively target the mitochondrial protease ClpP and DRD2.

The NDA is supported by results from a compassionate use program, a phase 1 trial (NCT03416530), and 3 phase 2 trials (NCT03295396; NCT02525692; NCT03134131).2,3

Pooled efficacy data, which were published in the Journal of Clinical Oncology, demonstrated an objective response rate (ORR) of 20% (95% CI, 10.0%-33.7%) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria among patients with H3K27M-mutant diffuse glioma (n = 50) at the data cutoff date of May 31, 2021. This comprised 1 complete response and 9 partial responses. The disease control rate (DCR) was 40% (95% CI, 26.4%-54.8%), the median duration of response (DOR) was 11.2 months (95% CI, 3.8-not reached), and the median time to response (TTR) was 8.3 months (range, 1.9-15.9).

The pooled analysis included patients with recurrent and/or progressive H3K27M-mutant diffuse glioma that was measurable per RANO-HGG criteria. Patients were required to be 2 years of age or older; have a Karnofsky/Lansky performance status of at least 60; and have previously received radiation therapy with a washout period of at least 90 days before the first dose of dordaviprone.

The primary end point of the analysis was ORR per RANO-HGG criteria according to the blinded independent central review (BICR); secondary end points included ORR by RANO low-grade glioma criteria, DOR, TTR, DCR, best overall response, progression-free survival, overall survival, corticosteroid response rate, and performance status response rate.

Regarding safety, the majority of patients in the analysis (n = 49/50) experienced at least 1 treatment-emergent adverse effect (TEAE), the most common of which were fatigue (46.0%), nausea (36.0%), and headache (32.0%). Any-grade treatment-related AEs (TRAEs) were reported in 60.0% of patients; these included fatigue (34.0%), nausea (18.0%), and decreased levels of lymphocytes (14.0%). Grade 3 TRAEs occurred in 20% of patients; the only grade 3 TRAE occurring in more than 2 patients was fatigue (10.0%). No grade 4 TRAEs or treatment-related deaths were reported.

Notably, serious AEs occurred in 46.0% of patients, the most common of which were hydrocephalus (8.0%) and nausea (8.0%). TEAEs leading to treatment discontinuation, dose reduction, or dose interruption of dordaviprone occurred in 4 patients, although there were no reported treatment discontinuations due to TRAEs. One patient underwent dose reduction/interruption after experiencing treatment-related pulmonary embolism.

References

1. 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 February 18, 2025. https://ir.chimerix.com/news-releases/news-release-details/chimerix-announces-fda-acceptance-and-priority-review-new-drug
2. Chimerix to submit dordaviprone for accelerated approval to U.S. FDA for patients with recurrent H3 K27M-mutant diffuse glioma before year-end. News release. Chimerix. December 9, 2024. Accessed February 18, 2025. https://ir.chimerix.com/news-releases/news-release-details/chimerix-submit-dordaviprone-accelerated-approval-us-fda
3. Arrillaga-Romany I, Gardner SL, Odia Y, et al. ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma. J Clin Oncol. 2024;42(13):1542-1552. doi:10.1200/JCO.23.01134