FDA Receives NDA for Dordaviprone in Recurrent H3 K27M+ Glioma

Investigators are evaluating treatment with dordaviprone among patients with newly diagnosed diffuse glioma harboring H3 K27M mutations as part of the double-blind, parallel-group, international phase 3 ACTION study (NCT05580562),which is currently enrolling.

Developers Chimerix have submitted a new drug application (NDA) supporting the potential accelerated approval of dordaviprone (ONC201) as a treatment for patients with recurrent diffuse glioma harboring H3 K27M mutations, according to a press release from the developer.¹

The developers have requested priority review status as part of the NDA for dordaviprone. If the FDA accepts this request, the resulting review period would yield an expected Prescription Drug User Fee Act date in the third quarter of 2025. Additionally, the agent has received rare pediatric disease designation for this glioma population, and developers have applied for a rare pediatric disease priority review voucher for this indication.

“This NDA submission marks a pivotal moment for Chimerix in our mission to bring this potentially life-altering drug to patients diagnosed with recurrent H3 K27M-mutant diffuse glioma,” Mike Andriole, chief executive officer at Chimerix, said in the press release.¹ “With this submission, we now turn our attention to preparing for potential commercial launch in the US next year.”

Dordaviprone, an investigational first-in-class small molecule imipridone, was designed to selectively target the mitochondrial protease ClpP and dopamine receptor D2.

Investigators are evaluating treatment with dordaviprone among patients with newly diagnosed diffuse glioma harboring H3 K27M mutations as part of the double-blind, parallel-group, international phase 3 ACTION study (NCT05580562),which is currently enrolling. Details regarding the ACTION trial’s design were previously published in Neuro-Oncology.²

Patients enrolled on the ACTION study will be randomly assigned 1:1:1 to receive dordaviprone once weekly or twice weekly or matched placebo following radiotherapy at 54 to 60 Gy at 1.8 to 2.2 Gy per fraction and post-radiation MRI. Investigators will conduct on-treatment assessments on cycle 1, day 1; cycle 1, day 2; once every 4 weeks from cycles 2 to 12; and once every 8 weeks after cycle 13.

Patients with a weight of at least 52.5 kg will receive dordaviprone at 625 mg per dose. Those with a weight of less than 52.5 kg will receive a dose of the agent scaled by body weight rounded to the nearest 125 mg capsule. Patients are eligible to receive an extemporaneously dissolved formulation of the agent if they are unable to swallow capsules.

The trial’s primary end points are overall survival and progression-free survival (PFS) based on response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) per blinded independent central review. Secondary end points include the incidence of adverse effects, changes in clinical laboratory parameters, PFS for patients with a measurable contrast-enhancing disease, corticosteroid response, performance status response, performance status changes from baseline, changes in quality of life assessments from baseline, and changes from baseline neurologic assessment in neuro-oncology results.

Patients with a weight of 10 kg or higher and a diagnosis of H3 K27M-mutated diffuse glioma are eligible for enrollment on the trial. Mutations of H3 K27M must be confirmed via immunohistochemistry or gene sequencing of the tumor. Other requirements for study entry include having a Karnofsky or Lansky performance status of 70 or higher, stable or decreasing corticosteroid and anti-seizure medication doses for 7 days before beginning study treatment, and a sufficient washout period following prior treatment with agents such as DRD2 antagonists or strong CYP3A4/5 inhibitors and inducers.

Those with spinal tumors or a concurrent malignancy are ineligible for enrollment on the ACTION study. Additional exclusion criteria include having prior treatment with whole-brain radiotherapy, proton radiotherapy, bevacizumab (Avastin), or tumor-treating fields.

References

1. Chimerix submits dordaviprone new drug application for accelerated approval to U.S. FDA for patients with recurrent H3 K27M-mutant diffuse glioma. News release. Chimerix. December 30, 2024. Accessed January 2, 2025. https://tinyurl.com/4fhuw4fb
2. Arrillaga-Romany I, Lassman A, McGovern SL, et al. ACTION: a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Neuro Oncol. 2024;26(suppl 2):S173-S181. doi:10.1093/neuonc/noae031.