FDA Reviews NDA for Dordaviprone in Recurrent H3 K27M-Mutant Diffuse Glioma

The U.S. Food and Drug Administration (FDA) received a new drug application (NDA) from Chimerix, which seeks accelerated approval for dordaviprone as a treatment for patients with recurrent H3 K27M-mutant diffuse glioma in the United States, according to a news release from the drug’s manufacturer.

According to the release, dordaviprone (ONC201), a novel small molecule imipridone, is the first of its kind to selectively target the mitochondrial protease and the dopamine receptor D2 (DRD2).

Imipridones are a new class of selective cancer therapies that target specific G protein-coupled receptors and mitochondrial caseinolytic protease, which results in cancer cell death, according to Chimerix.

“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,” said Mike Andriole, Chief Executive Officer of Chimerix, in a statement included in a news release issued by the company. “With this submission, we now turn our attention to preparing for potential commercial launch in the U.S. next year.”

H3 K27M-mutant diffuse glioma, a rare and aggressive brain cancer primarily affecting children and young adults, has a poor prognosis with limited treatment options. However, dordaviprone has shown efficacy in treating recurrent disease, offering hope for the development of a new treatment for this cancer, according to information on the trial published in Neuro-Oncology.

Chimerix is seeking a priority review for the NDA which gives the FDA a six-month period to review and possibly approve the drug for use. 

The Ongoing ACTION Clinical Trial

An international, randomized, double-blind, placebo-controlled, parallel-group, phase 3 ACTION study is currently evaluating the drug’s ability to extend overall survival and progression-free survival in patients with newly diagnosed H3 K27-mutant diffuse glioma following radiotherapy with an estimated enrollment size of 450 patients, according to the trial’s listing on clinicaltrials.gov.

In this trial patients are randomized to receive either once-weekly dordaviprone, twice-weekly dordaviprone on two consecutive days or a placebo regimen.

In the twice-weekly group, participants weighing 52.5 kilograms or more will receive 625 milligrams (mg) of dordaviprone (five 125 mg capsules) on dosing days. Those weighing less than 52.5 kilograms will receive a weight-scaled dose, rounded to the nearest 125-mg increment.

In the once-weekly group, participants will follow the same dosing regimen but will also receive matching placebo capsules on dosing days.

To be eligible, patients must have histologically confirmed H3 K27M-mutant diffuse glioma, Karnofsky/Lansky performance status of 70 or more and completed first-line radiotherapy. Age is unrestricted, but patients must weigh 10 kg or more at randomization. Exclusion criteria included primary spinal tumors, diffuse intrinsic pontine glioma, leptomeningeal disease or cerebrospinal fluid dissemination.

The primary end goals of the trial include overall survival and progression-free survival after approximately 44 months. Secondary end goals include safety, additional efficacy endpoints, clinical benefit and quality of life.

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