FDA Reviews NDA for Dordaviprone in H3K27M-Mutant Diffuse Glioma
A new drug application seeking the accelerated approval of dordaviprone forrecurrent for H3K27M-mutant diffuse glioma treatment was submitted to the FDA.
- The FDA is reviewing a new drug application (NDA) for dordaviprone (ONC201), a potential treatment for patients with recurrent H3K27M-mutant diffuse glioma.
- Clinical data show a 20% overall response rate (ORR) and a median response duration (DOR) of 11.2 months, with manageable safety profiles observed across multiple trials and a compassionate use program.
- With this, there is potential for a target action date in the third quarter of 2025 under the Prescription Drug User Fee Act (PDUFA).
An NDA seeking the accelerated approval of dordaviprone has been submitted to the FDA for the treatment for patients with recurrent H3K27M-mutant diffuse glioma.1
“This NDA submission marks a pivotal moment for Chimerix in our mission to bring this potentially life-altering drug to patients diagnosed with recurrent H3K27M-mutant diffuse glioma,” Mike Andriole, chief executive officer of Chimerix, the developer of dordaviprone, stated in a news release.
Chimerix has requested priority review, which could lead to a target action date in the third quarter of 2025 under the PDUFA. Dordaviprone previously received a rare pediatric disease designation for this indication.
Tumor in brain : © peterschreiber.media - stock.adobe.com
Dordaviprone has been evaluated in multiple clinical trials, including a phase 1 study (NCT03416530), 3 phase 2 trials (NCT02525692; NCT03295396; NCT03134131), and a compassionate use program. In a pooled analysis published in the Journal of Clinical Oncology, the ORR among patients treated was 20% (95% CI, 10%-33.7%) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria, with a disease control rate (DCR) of 40% (95% CI, 26.4%-54.8%). The median DOR was 11.2 months (95% CI, 3.8-not reached).2
“With this submission, we now turn our attention to preparing for potential commercial launch in the US next year. To maximize availability and access of dordaviprone at launch, we have enhanced our commercial capabilities across multiple functions including market access, distribution, reimbursement, patient services, marketing and commercial operations, all supported by a robust manufacturing and quality management system,” added Andriole in the press release.1
Dordaviprone is a first-in-class imipridone designed to target mitochondrial protease ClpP and DRD2. It is being developed for patients with measurable, recurrent H3K27M-mutant gliomas who have a Karnofsky/Lansky performance status of at least 60 and have undergone prior radiation therapy with a sufficient washout period.
During the studies of dordaviprone, patients at least 18 years of age received the agent at 625 mg, and pediatric patients were administered the agent at a dose based on body weight. Patients were treated once per week or once every 3 weeks in treatment cycles of 3 to 4 weeks, depending on the specific study design. Treatment continued until disease progression and the primary end point of the analysis was ORR per RANO-HGG criteria as assessed by blinded independent central review.
Safety data indicated that nearly all patients experienced at least 1 treatment-emergent adverse event (TEAE), with the most common being fatigue (46%), nausea (36%), and headache (32%). Serious AEs occurred in 46% of patients, including hydrocephalus and nausea (8% each).
Chimerix is also conducting the international phase 3 ACTION study (NCT05580562) to evaluate dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma.3
The study is currently enrolling patients who will then be randomized 1:1:1 to receive dordaviprone once 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. On-treatment assessments will be conducted 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.
The primary end points of the study include overall survival and progression-free survival (PFS) based on RANO-HGG per blinded independent central review. Incidence of adverse events, 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 serve as the secondary end points of the study.
REFERENCES
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 3, 2025. https://tinyurl.com/pn7jmchmhttps://ir.chimerix.com/news-releases/news-release-details/chimerix-submits-dordaviprone-new-drug-application-accelerated
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
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
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