FDA Accepts New Drug Application for Dordaviprone to Treat Recurrent H3 K27M-Mutant Diffuse Glioma

The FDA has accepted a new drug application seeking accelerated approval for dordaviprone (ONC201; Chimerix) as a treatment for patients with recurrent histone 3 (H3) K27M-mutant diffuse glioma. Currently, the treatment has a Prescription Drug User Fee Act target action date of August 18, 2025.¹

Image credit: Sebastian Kaulitzki | stock.adobe.com

Dordaviprone is a novel first-in-class small molecule imipridone that selectively targets the mitochondrial protease ClpP and dopamine receptor D2 (DRD2). It is administered orally, and in clinical trials, it has demonstrated to be well tolerated and active in patients with specific forms of advanced cancer.^1,2

H3 K27M is a specific mutation in one of the genes that encode for proteins and is almost exclusively found in glioma. Gliomas that contain the H3 K27M mutation undergo a specific change in H3 proteins that prevents methylation at a specific site, resulting in H3 K27M trimethyl loss that alters the expression of genes. The H3 K27M mutation is found in most diffuse midline gliomas (DMGs), which include tumors located in central regions of the central nervous system such as the brainstem and thalamus. Additionally, H3 K27M-mutant DMG is a grade 4 brain tumor, and radiation remains the sole standard of care intervention thought to provide transient benefit. Currently, no systemic therapy has proven efficacy for this disease, meaning relapse is unavoidable.²

The new drug application’s acceptance is supported by data from a program featuring a phase 1 trial (NCT03416530)³ and 3 different phase 2 trials (NCT03295396; NCT02525692; NCT03134131)^4-6 that show dordaviprone is well tolerated by patients.¹

Pooled data from 4 clinical trials published in the Journal of Clinical Oncology demonstrated efficacy of dordaviprone oral monotherapy when treating 50 patients (pediatric: n = 4; adult: n = 46) with recurrent H3 K27M-mutant DMG.⁷ The investigators found that dordaviprone resulted in an objective response rate (ORR) of approximately 20% (95% CI, 10.0 to 33.7) based on Response Assessment in Neuro-Oncology criteria. The ORR by combined RANO-HGG and RANO low-grade glioma criteria was about 30.0% (95% CI, 17.9 to 44.6). Median duration of response was about 11.2 months (95% CI, 3.8 to not reached).⁷

In addition, an at least 50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]), and performance score improvement was observed in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Further, grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in about 20.0% of patients, of which the most common was fatigue (n = 5; 10%). There were no grade 4 TR-TEAEs, deaths, or discontinuations that occurred.⁷

“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, CEO of Chimerix, in a news 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 FDA to facilitate their review as we simultaneously prepare for a potential commercial launch in order to ensure rapid availability to patients in need."¹

REFERENCES

1. Chimerix. Chimerix Announces FDA Acceptance and Priority Review of New Drug Application for Dordaviprone as Treatment for Recurrent H3 K27M-Mutant Diffuse Glioma. News release. February 18, 2024. Accessed https://ir.chimerix.com/news-releases/news-release-details/chimerix-announces-fda-acceptance-and-priority-review-new-drug

2. Chimerix. ONC201 dordaviprone. Accessed February 20, 2025. https://www.chimerix.com/our-pipeline/imipridones/onc201/

3. ONC201 in Pediatric H3 K27M Gliomas. ClinicalTrials.gov identifier: NCT03416530. Updated February 14, 2025. Accessed February 20, 2025. https://clinicaltrials.gov/study/NCT03416530

4. ONC201 in Adults With Recurrent H3 K27M-mutant Glioma. ClinicalTrials.gov identifier: NCT03295396. Updated August 15, 2023. Accessed February 20, 2025. https://clinicaltrials.gov/study/NCT03295396

5. Oral ONC201 in Adult Recurrent Glioblastoma. ClinicalTrials.gov identifier: NCT02525692. Updated December 24, 2024. Accessed February 20, 2025. https://clinicaltrials.gov/study/NCT02525692

6. Expanded Access to ONC201 for Patients With H3 K27M-mutant and/​or Midline High Grade Gliomas. ClinicalTrials.gov identifier: NCT03134131. Updated March 14, 2022. Accessed February 20, 2025. https://www.clinicaltrials.gov/study/NCT03134131

7. Arrillaga-Romany I, Gardner SL, Odia Y, et al. ONC201 (Dordaviprone) in Recurrent H3 K27M–Mutant Diffuse Midline Glioma. JCO. 2024;42(2):1542-1552. doi:10.1200/JCO.23.01134