The FDA has granted priority review to Chimerix's new drug application (NDA) for dordaviprone (ONC201) for the treatment of patients with recurrent H3 K27M-mutant diffuse glioma. This designation accelerates the review process for this novel agent, offering hope for a new treatment option for this aggressive brain cancer that primarily affects children and young adults.
The Prescription Drug User Fee Act (PDUFA) target action date has been set for August 18, 2025. Chimerix has also requested a Rare Pediatric Disease Priority Review Voucher, further expediting the potential approval pathway. Notably, the FDA does not currently plan to hold an advisory committee meeting to discuss the application.
Dordaviprone is a first-in-class, small molecule imipridone designed to selectively target the mitochondrial protease ClpP and dopamine receptor D2 (DRD2). This dual-targeting mechanism represents a novel approach to disrupting cancer cell growth and survival.
Clinical Efficacy and Safety
The NDA submission is supported by efficacy data from a pooled analysis of 50 patients treated across a phase 1 trial, three phase 2 trials, and a compassionate use program. The data, published in the Journal of Clinical Oncology, demonstrated an overall response rate (ORR) of 20% (95% CI, 10.0%-33.7%) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria. The disease control rate (DCR) was 40% (95% CI, 26.4%-54.8%), with a median duration of response (DOR) of 11.2 months (95% CI, 3.8-not reached).
Safety data indicated that the most common treatment-emergent adverse events (TEAEs) were fatigue (46%), nausea (36%), and headache (32%). Serious adverse events occurred in 46% of patients, including hydrocephalus and nausea (8% each).
Ongoing Phase 3 ACTION Study
Chimerix is also conducting the international phase 3 ACTION study (NCT05580562) to evaluate dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. This randomized, double-blind, placebo-controlled trial is enrolling patients who will receive dordaviprone once or twice weekly, or placebo, following radiotherapy.
The primary endpoints of the ACTION study are overall survival and progression-free survival (PFS) based on RANO-HGG criteria per blinded independent central review. Secondary endpoints include incidence of adverse events, changes in clinical laboratory parameters, and changes in quality-of-life assessments.
Management Commentary
"This significant milestone brings us one step closer to our goal of accelerating access to the first medicine specific to patients diagnosed with recurrent H3 K27M-mutant diffuse glioma," said Mike Andriole, Chief Executive Officer of Chimerix. "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 FDA to facilitate their review as we simultaneously prepare for a potential commercial launch in order to ensure rapid availability to patients in need."
