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A NDA has been submitted to the FDA seeking the approval of dordaviprone for recurrent H3K27M-mutant diffuse glioma.
The FDA has received a new drug application (NDA) seeking the accelerated approval of dordaviprone (ONC201) for the treatment for patients with recurrent H3K27M-mutant diffuse glioma.1
Chimerix, the developer of dordaviprone, has requested priority review of the NDA by the regulatory agency, which would lead to a potential Prescription Drug User Fee Act target action date in the third quarter of 2025. Previously, the FDA granted rare pediatric disease designation to dordaviprone for H3K27M-mutant glioma.
The NDA includes efficacy data from 50 patients treated across a phase 1 trial (NCT03416530), 3 phase 2 trials (NCT02525692; NCT03295396; NCT03134131), and a compassionate use program.2,3
Pooled efficacy data published in the Journal of Clinical Oncology showed that patients experienced an overall response rate (ORR) of 20.0% (95% CI, 10.0%-33.7%) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria, and the disease control rate (DCR) was 40.0% (95% CI, 26.4%-54.8%).3 The median time to response was 8.3 months (range, 1.9-15.9), and the median duration of response was 11.2 months (95% CI, 3.8-not reached).
Per RANO-HGG/low-grade glioma (LGG) criteria, the ORR was 30.0% (95% CI, 17.9%-44.6%), and the DCR was 44.0% (95% CI, 30.0%-58.7%).
“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, CEO of Chimerix, stated in a news release.1 “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.”
Dordaviprone is a novel, first-in-class, small molecule imipridone designed to selectively target the mitochondrial protease ClpP and DRD2.
The pooled analysis included patients with at least 2 years of age with recurrent and/or progressive H3K27M-mutant glioma with measurable disease per RANO-HGG criteria.3 A Karnofsky/Lansky performance status of at least 60 was required. A washout period of at least 90 days was required after the last treatment with radiation therapy.
During the studies, patients at least 18 years of age received dordaviprone 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.
ORR per RANO-HGG criteria as assessed by blinded independent central review served as the primary end point of the analysis.
Safety data showed that 49 of 50 patients experienced at least 1 treatment-emergent adverse effect (TEAE). The most common any-grade TEAEs included fatigue (46.0%), nausea (36%), and headache (32.0%).
Any-grade treatment-related AEs (TRAEs) were reported in 60.0% of patients, including 20% who had grade 3 TRAEs. The most common any-grade TRAEs consisted of fatigue (34.0%), nausea (18.0%), decreased lymphocyte count (14.0%), headache (10.0%), vomiting (10.0%), anemia (6.0%), decreased appetite (6.0%), dizziness (6.0%), fall (6.0%), hemiparesis (6.0%), and maculopapular rash (6.0%).
Serious AEs were reported in 46.0% of patients; hydrocephalus and nausea were the most common at 8.0% each.
TEAEs led to treatment discontinuation, dose reduction, or dose interruption in 8.0% of patients. TRAEs did not lead to any treatment discontinuations, and 1 patient (2.0%) required dose reduction/interruption due to a TRAE (pulmonary embolism).
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