FDA Grants First Accelerated Approval for H3 K27M-Mutated Diffuse Midline Glioma with Dordaviprone
核心洞察
The FDA has granted accelerated approval to dordaviprone (Modeyso (搜索)) for adult and pediatric patients aged 1 year and older with H3 K27M-mutated diffuse midline glioma (搜索) following disease progression after prior therapy.
This represents the first FDA approval of a systemic therapy specifically for H3 K27M-mutant diffuse midline glioma (搜索), addressing a significant unmet medical need.
Clinical trials demonstrated a 22% overall response rate with a median duration of response of 10.3 months among 50 patients with recurrent disease.
The U.S. Food and Drug Administration has granted accelerated approval to dordaviprone (Modeyso (搜索)), marking the first systemic therapy approved specifically for patients with H3 K27M-mutated diffuse midline glioma (搜索). The approval covers adult and pediatric patients aged 1 year and older whose disease has progressed following previous therapy.
Clinical Trial Results Drive Approval
The efficacy and safety of dordaviprone, a protease activator, was evaluated across five clinical trials (ONC006, ONC013, ONC014, ONC016, and ONC018) involving 50 adult and pediatric patients with recurrent H3 K27M-mutated diffuse midline glioma (搜索) who received dordaviprone monotherapy.
The overall response rate (ORR), assessed by blinded independent central review according to RANO 2.0 criteria, reached 22% (95% CI, 12%-36%). The median duration of response was 10.3 months (95% CI, 7.3-15.2 months). Among the 11 patients who achieved objective response, 73% maintained their response for at least 6 months, while 27% sustained responses for 12 months or longer.
Patient Selection and Trial Design
The integrated efficacy population comprised patients with progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria. All participants were at least 90 days post-radiation therapy and had completed an adequate washout period from prior anticancer therapies. Eligible patients maintained a Karnofsky Performance Status/Lansky Performance Status (KPS/LPS) score of at least 60 and demonstrated stable or decreasing corticosteroid use.
The trials excluded patients with diffuse intrinsic pontine glioma (搜索), primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination.
Dosing and Safety Profile
For adult patients, the recommended dordaviprone dosage is 625 mg taken orally once weekly. Pediatric dosing is weight-based. The drug's prescribing information includes warnings for hypersensitivity, QTc interval prolongation, and embryo-fetal toxicity.
Regulatory Pathway and Future Development
Dordaviprone received multiple FDA designations including Priority Review, Orphan Drug, Rare Pediatric Disease, and Fast Track status. The FDA utilized an Assessment Aid, a voluntary submission from the applicant, to facilitate the review process.
The phase 3 ACTION trial (NCT05580562) is currently recruiting patients to further examine whether dordaviprone can prolong overall survival and progression-free survival in patients with newly diagnosed H3 K27M-mutant diffuse glioma.
Mechanism of Action
Dordaviprone, previously known as ONC201, is a first-in-class small molecule imipridone that binds selectively to the G-protein coupled dopamine receptor D2 (搜索), according to Chimerix, a subset of Jazz Pharmaceuticals Company responsible for developing the drug.