Dordaviprone Receives Accelerated FDA Approval for Diffuse Midline Glioma

The US FDA has granted accelerated approval to dordaviprone (Modeyso), a novel systemic therapy for the treatment of diffuse midline glioma (DMG) with an H3 K27M mutation.¹

DMG is a rare and highly aggressive form of pediatric high-grade glioma, primarily affecting children and young adults. The H3 K27M mutation is a defining molecular feature of this disease, associated with a particularly poor prognosis. Historically, treatment options have been limited to radiation therapy, with no FDA-approved systemic therapies available. The accelerated approval of dordaviprone addresses a critical unmet need for patients with this devastating diagnosis.

This approval marks a significant milestone in the oncology landscape, offering the first targeted systemic therapeutic option for both adult and pediatric patients aged 1 year and older with recurrent disease following prior therapy. The approval of dordaviprone, a brain-penetrant, small-molecule imipridone, was supported by data from 5 nonrandomized clinical trials involving 50 patients with recurrent H3 K27M-mutant DMG.

Data Supporting the Approval of Dordaviprone

Efficacy was primarily evaluated by the overall response rate (ORR), a key end point for accelerated approvals. The trials demonstrated an ORR of 22%, with the median duration of response (DOR) reported as 10.3 months. A substantial portion of responding patients maintained their response for an extended period, with 73% achieving a DOR of 6 months or more and 27% having a DOR of 12 months or longer. These results provide clinical evidence of dordaviprone's therapeutic activity in a disease setting where responses to therapy are rare.

Regarding safety reports from the pooled analysis, which was published in the Journal of Clinical Oncology, 49 of 50 patients experienced at least 1 treatment-emergent adverse event (AE), with the most frequently reported being fatigue (46%), nausea (36%), and headache (32%).² Treatment-related AEs of any grade were observed in 60% of patients, including fatigue (34%), nausea (18%), and decreased lymphocyte levels (14%). Grade 3 treatment-related AEs were seen in 20% of patients, with fatigue (10%) being the only one occurring in more than 2 individuals. No grade 4 treatment-related AEs or deaths were reported.

Clinicians should be aware of the associated warnings and precautions with dordaviprone. These include the potential for hypersensitivity reactions, QTc interval prolongation, and embryo-fetal toxicity. Regular monitoring of patients for these AEs is essential.

The recommended adult dosage is 625 mg orally once weekly, with pediatric dosing based on body weight.

About Dordaviprone

In February 2025, the FDA granted the new drug application of dordaviprone priority review.³ This accelerated approval comes earlier than the anticipated August 18, 2025, target action date.

The dordaviprone development program also received other designations from the FDA, including orphan drug, rare pediatric disease, and fast track.¹ These designations underscore the high-priority nature of this disease and the urgent need for new therapies. The accelerated approval pathway allows for earlier access to a drug for a serious condition based on a surrogate end point that is reasonably likely to predict clinical benefit. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The mechanism of action for dordaviprone involves its dual function as a mitochondrial caseinolytic protease P (ClpP) agonist and a dopamine receptor D2 (DRD2) antagonist. By targeting these pathways, dordaviprone is thought to induce selective apoptosis in H3 K27M-mutant glioma cells, representing a novel approach to therapy for this specific malignancy. This targeted mechanism offers a new paradigm for treating DMG beyond conventional chemotherapy.

REFERENCES:

1. FDA grants accelerated approval to dordaviprone for diffuse midline glioma. News release. US FDA. August 6, 2025. Accessed August 6, 2025. https://tinyurl.com/kkjddc32

2. 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 August 6, 2025. https://tinyurl.com/57y3rxm9

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